Development of Isoselenocyanate Compounds' Syntheses and

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Development of Isoselenocyanate Compounds’ Syntheses and Biological Applications Emily Frieben, Shantu Amin, and Arun K. Sharma J. Med. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jmedchem.8b01698 • Publication Date (Web): 11 Jan 2019 Downloaded from http://pubs.acs.org on January 13, 2019

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Journal of Medicinal Chemistry

Development of Isoselenocyanate Compounds’ Syntheses and Biological Applications Emily E. Frieben, Shantu Amin, Arun K. Sharma* Department of Pharmacology, Penn State Cancer Institute, CH72, Penn State College of Medicine, 500 University Drive, Hershey, Pennsylvania, 17033, United States

KEYWORDS

isoselenocyanates;

isothiocyanates;

selenium;

cancer;

therapeutics;

chemoprevention

ACS Paragon Plus Environment

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ABSTRACT

Since the number of cases and cancer-related deaths are projected to rise in upcoming years, it is urgent to find ways to prevent or treat cancer. As such, food-derived products have gained attention as potential chemopreventive agents due to their availability, safety, and low cost. Isothiocyanates, the breakdown products of sulfur-containing glucosinolates in cruciferous vegetables, have shown substantial anticarcinogenic and chemopreventive activities for different human cancers. Furthermore, organoselenium compounds are known to exhibit chemopreventive and chemotherapeutic activity; moreover, these compounds are more effective anticancer agents than their sulfur isosteres. Hence, isothiocyanates have been modified to yield isoselenocyanates, which are more cytotoxic towards cancer cells when compared to their corresponding sulfur analogs. Herein, the synthesis and development of isoselenocyanates as novel treatments for cancer and other diseases will be reviewed, highlighting the diverse chemistry and computational studies of this class of compounds, as well as their pertinent biological applications.


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INTRODUCTION The chemistry and biology of isoselenocyanates (ISCs) has recently evolved due to the discovery of new methods for their synthesis as well as the identification of their therapeutic promise for various diseases, particularly cancer. Cancer is one of the leading causes of death worldwide, responsible for 14.1 million new cases and 8.2 million deaths in 2012.1 With growth and aging of the population, as well as sustaining lifestyle behaviors that are known to increase the risk of cancer, such as a poor diet, physical inactivity, and smoking, these numbers are expected to rise. By the year 2030, the number of new cases and deaths are projected to rise to 21.7 million and 13 million, respectively.2 Accordingly, cancer is a major health problem and significant burden on society; with the projected rise in numbers, there is a pressing need to develop novel, effective therapeutics. Selenium (Se) is an essential trace element that has been shown to exhibit chemopreventive and chemotherapeutic activity. In fact, a number of epidemiological studies have indicated an inverse association between Se intake and cancer risk (reviewed in 3). In two-thirds of in vivo chemical and viral carcinogenesis studies, a reduced incidence of tumors was observed following Se supplementation.3 Furthermore, organoselenium compounds have been shown to inhibit the initiation and post-initiation phases of chemical carcinogenesis.4 In cancer cells, Se compounds have also demonstrated anti-tumorigenic, anti-angiogenic, and pro-oxidant activities.3, 5-7 While the underlying anticancer mechanisms of action are complex and not fully understood, they are believed to be related to the Se compounds’ abilities to induce DNA damage, regulate the cell cycle, inhibit cellular growth, induce apoptosis, and generate reactive oxygen species (ROS).3, 5-7

Nonetheless, the biological effects of Se compounds are known to be speciation- and

concentration-dependent.6 For example, speciation-dependence has been evidenced by the


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conflicting results of the Nutritional Prevention of Cancer (NPC) and Se and Vitamin E Cancer Prevention Trial (SELECT) clinical trials. Although the same daily dose of Se was given (200 µg/day), it was found that supplementation with Se-enriched yeast reduced cancer incidence in the NPC trial, while supplementation with selenomethionine (SeMet), a major component of Se yeast, resulted in no reduction in the incidence of prostate cancer in the SELECT trial.8 Regarding concentration-dependence, dietary levels (55 µg/day) of Se compounds are known to prevent the development of various cancers, whereas high Se concentrations (>350 µg/day) can be carcinogenic, genotoxic, and cytotoxic.5, 8 The chemopreventive effects of low doses of Se are often attributed to the compounds’ ability to serve as an antioxidant and control the redox status of the cell, protecting against oxidative stress.6 In contrast, high doses enable the compounds to become redox-active, pro-oxidative, and cytotoxic to tumor cells, which, due to the Warburg effect, contain increased levels of ROS and reducing equivalents.5-6, 9 Furthermore, patients with melanoma, breast cancer, ovarian cancer, colon cancer, head and neck cancer, and pancreatic cancer have exhibited decreased Se levels in whole blood or serum compared to healthy controls.10 Therefore, based on their dual chemopreventive and chemotherapeutic effects, in addition to the observed Se deficiency in cancer patients, organoselenium compounds show vast potential for cancer, which has led to the synthesis and development of novel Se compounds. Particularly, one current and most prominent example is the development of ISCs, the selenium isosteres of naturally occurring isothiocyanates (ITCs).10 In recent years, food-derived products have especially gained attention as potential chemopreventive agents, due to their availability, safety, and low cost.11 In fact, a number of epidemiological studies have shown an inverse association between fruit and vegetable intake and the risk of developing cancer at major sites.12-14 Particularly, a strong inverse correlation has been


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observed for the consumption of cruciferous vegetables and cancer risk.15-17 Cruciferous vegetables, such as brussels sprouts, broccoli, cauliflower, cabbage, and watercress, are rich sources of sulfur-containing compounds known as glucosinolates.16 The bioactive breakdown products of glucosinolates, namely ITCs and indoles, are generated by the activity of the vacuolar, hydrolytic enzyme, myrosinase.16-19 These bioactive compounds have previously shown substantial anticarcinogenic and chemopreventive activities for different human cancers, in a number of in vitro and in vivo studies.11,

17, 20

In addition, ITCs have been shown to act

synergistically with standard chemotherapies to enhance tumor regression.21 The anticarcinogenic effects of ITCs have largely been attributed to their capacity to alter detoxification pathways. ITCs have been shown to inhibit phase I cytochrome P-450 (CYP) enzymes involved in procarcinogen activation.22-23 In addition, they have induced phase II enzymes, which detoxify residual electrophilic metabolites produced by phase I enzymes.22-25 Furthermore, ITCs protect against oxidative stress through transcriptional stimulation of antioxidant enzymes and proteins, as well as by enhancing free-radical scavenging properties.16, 26-28

ITCs have also demonstrated antitumor, antiangiogenesis, and antimetastasis activity.

Namely, they have been shown to inhibit cell cycle progression,29-30 conjugate with thiols,31 generate ROS,29-30, 32-34 and induce apoptosis in human cancer cells.29-30, 32, 34-35 In addition, they have been shown to alter estrogen metabolism and downregulate the estrogen receptor,16,

36-37

modulate mitogen-activated protein kinase (MAPK) signaling and protein kinase C (PKC),30, 38 inhibit histone deacetylase (HDAC),39 regulate the activation of nuclear factor kappa B (NF-𝛋B), NF-E2 p45-related factor 2 (Nrf2),40 and signal transducer and activator of transcription 3 (STAT3),11 and selectively deplete mutant p53.41 However, the anticancer activity of ITCs has


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been studied in cells with a different p53 status (wild-type, mutant, knock-down), indicating that it is not clear whether their anticancer effects are p53-dependent or p53-independent.42-46 Prior studies have demonstrated that the activity of ITCs varies with its chemical composition. For instance, high lipophilicity or increased alkyl chain length of ITCs have been shown to increase the potency of inhibition of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumorigenesis in A/J mice.47-49 Increased potency with increasing ITC alkyl chain length has also been observed in head and neck squamous cell carcinoma.50 In contrast, other structure-activity relationship (SAR) studies have reported that alkyl chain length influences but does not directly correspond with inhibitory potency,41, 51 and that the optimal chain length varies with the type of cancer.51 Regardless of these findings, ITCs have been shown to be preferentially cytotoxic towards cancer cells.52-53 Particularly, phenylethyl isothiocyanate (PEITC) not only displayed greater selectivity towards the transformed ovarian cell line (T72Ras) over the nonmalignant ovarian epithelial line (T72), with a selectivity index (SI) of 3.9, but its selectivity was also greater than cisplatin (SI = 1.0) in the same cell lines.54 Therefore, the established chemopreventive effects rendered ITCs as lead compounds for structural optimization.55 Based on the observation that selenium compounds are more active in cancer prevention than their sulfur analogs,56 as well as the vast body of evidence supporting organoselenium compounds for the treatment and prevention of cancer, SARs were conducted on ITCs, replacing sulfur with its isostere selenium to yield novel ISCs.10 These novel ISCs have been shown to be more cytotoxic towards cancer cells as compared to their corresponding ITCs. In light of these SARs, the aim of the present perspective is to discuss the utility of ISCs as potential chemotherapeutic and chemopreventive agents. In particular, we have summarized recent advances in the synthesis and development of ISCs for melanoma, lung cancer, colon cancer, liver


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cancer, prostate cancer, and breast cancer, as well as other diseases, and applications of ISCs in additional areas of chemistry.

THE CHEMISTRY OF ISOSELENOCYANATES Chemically, what is the significance of ISCs? First and foremost, ISCs serve as precursors and essential intermediates for a variety of organoselenium compounds (such as heterocycles, selenocarbamates, and selenoureas), which are all biologically active. Aside from serving as precursors of biologically active compounds, ISCs have been studied and used for a variety of applications in many chemical disciplines (i.e., organic, computational, theoretical, inorganic, organometallic, and polymer chemistry), which will be highlighted and discussed in the following sub-sections.

Methods of Preparation of ISCs and Associated Challenges Classically, organic ISCs have been synthesized by the direct addition of elemental selenium to isocyanides,57 in either chloroform or tetrahydrofuran (THF) (Figure 1). Although this method provides moderate to high yields of ISCs, and despite the fact that elemental Se is less expensive than other Se reagents, a disadvantage to this method is the toxicity and extremely pungent odor associated with isocyanide use.58-59 In addition, synthesis of the desired isocyanide starting material may require harsh, drastic conditions which may alter the other sensitive functionalities in the molecule.59 ISCs have also been synthesized by using a primary amine, CSe2, and HgCl2 in the presence of triethylamine (Et3N) (Figure 1).59 However, the downside to this method is that the resultant ISC and amine-mercuric chloride adduct leads to the formation of side products such


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as selenourea, carbodiimide, or isocyanide,59 which may complicate isolation and purification of the desired product.

Figure 1. Various synthetic approaches used to attain isoselenocyanates from different types of starting materials. While other methods can be used to attain ISCs, they have limited applications. Such alternate methods include reaction of isocyanates with phosphorus(V)selenide (Figure 1),60 reaction of sodium selenide with N-arylcarbimidic dichlorides (Figure 2),61 and photochemical rearrangement of selenocyanates (Figure 1).62 ISCs have also been synthesized in situ by a one-pot cycloaddition, by reacting nitrile oxides with primary selenoamides (Figure 2).63 Additionally, acylisoselenocyanates have been prepared directly from an acyl chloride and KSeCN (Figure 2).58, 64-66 In fact, triphenylmethyl ISC was originally described as a selenocyanate but later found to be an ISC.64, 66 Imidoyl ISCs have also been prepared in the same manner, instead with an imidoyl chloride as a starting reactant (Figure 2).67


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Figure 2. Synthetic methods for isoselenocyanates from chloride-containing starting materials. Barton et al. developed a convenient, one-pot procedure for the preparation of ISCs with high yields. In this procedure, ISCs are prepared from their corresponding formamides in toluene; the formamides undergo dehydration with phosgene, which is done in the presence of elemental Se and a base such as Et3N (Figure 3).58 Since then, the procedure has been modified by other researchers, in order to prevent polymerization of intermediate compounds as well as to increase yields.10,

68

Such modifications include the use of triphosgene in the place of highly toxic

phosgene,68 which is a less hazardous reagent, as well as using dichloromethane in the place of toluene (Figure 3), as the lower refluxing temperature for the reaction is believed to lead to less polymerization. These modifications have been shown to successfully lead to the formation of novel phenylalkyl ISCs, aryl ISCs, and sugar-derived ISCs in decent yields.10, 69 An additional variation of the method involves the reaction of formamides with bis(trichloromethyl)carbonate and Se (Figure 3).70


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In recent years, Zakrzewski et al. proposed a new method for ISC synthesis, involving a biphasic aqueous/organic system that operates under strong alkaline conditions. Particularly, ISCs can be formed under phase transfer conditions (50% aqueous NaOH, CH2Cl2, ammonium salt Aliquat 336), when Se is added to various isocyanides or to corresponding amines (Figure 1).71 An overview of the above-described ISC synthetic methods are summarized in Figures 1-3.

Figure 3. Different approaches used to prepare isoselenocyanates from formamides. As evidenced by these studies, simpler and safer methods to synthesize ISCs are still being developed, since ISCs are useful starting materials or intermediates of a variety of organoselenium compounds. Aside from the previously mentioned caveats of ISC synthetic methods, other problems with ISC stability can arise. For example, HNCSe is unstable in aqueous solution,72 in the gaseous phase, and under broad-band UV irradiation in a low-temperature inert matrix,73 rapidly decomposing to hydrogen cyanide and Se.73-74 Other ISCs are sensitive to sunlight and could undergo decomposition to release elemental Se.69 Moreover, while ISC moieties have


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successfully been incorporated into transition metal complexes,75-76 the ISC group has also been shown to rapidly decompose following its incorporation into the metal complex, through the loss of Se.77 Thus, these stability challenges further strengthen the need for newer, simpler, and safer ISC synthetic methods.

Applications of ISCs in Other Areas of Chemistry ISCs are known to be precursors of organoselenium compounds that contain the -NHC(Se)- unit, which upon deprotonation, can then function as monoanionic Se- ligands of metals.64 Hence, ISC compounds have been studied in the discipline of coordination chemistry and investigated as precursor compounds that can be used in the preparation of ligands for various metal complexes. For example, Ben Dahman Andaloussi et al. were able to prepare trityl ISC using a safer method, from trityl chloride and potassium selenocyanate.64 The reactivity and ability of trityl ISC to prepare functionalized organoselenium compounds was also examined; trityl ISC was found to react with primary amines to yield selenourea derivatives and with hydrazine to yield trityl selenosemicarbazide.

Trityl selenosemicarbazide was then able to undergo a subsequent

condensation reaction with salicylaldehyde to yield an imine in a reasonable yield.64 Aside from serving as precursors of ligands of metal complexes, ISCs themselves have been used as a component of terminal or bridging ligands in various metal coordination complexes, as the ISC anion has a strong coordination ability. While ISC moieties have successfully been incorporated into a number of transition metal complexes,75-76 the ISC group has also been shown to rapidly decompose following its incorporation into the metal complex, through the loss of Se.77 Interestingly, this instability was found only for coordinated ISCs, as the free form did not decompose to cyanide.77


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Zheng et al. conducted a comparison of thermal spin crossover (SCO) behavior, transition temperature, and cooperativity of SCO for various iron(II) complexes containing bis(ITC) or bis(ISC) ligands.78 Several of the ISC analogs were found to have similar packing and molecular geometry to their corresponding ITC analog. In addition, thermal SCO behavior was displayed, and the ISC iron(II) complexes had a higher SCO transition temperature than their corresponding ITC iron(II) complex. With some of the ISC ligands, the presence and extent of intermolecular NH⋅⋅⋅Se hydrogen bonding networks within the crystal structure of the iron(II) complex were found to be important for increasing SCO cooperativity.78 Other work has demonstrated the incorporation of ISC or ITC anions into the framework of nickel(II) coordination polymers that contain one-dimensional micropores.79 Because the hydroxy group of micropore guest molecules (such as water, methanol, ethanol) can interact with S or Se as hydrogen bond acceptors, the porous properties of these coordination polymers were compared, since they have similar electronegativities yet differing van der Waals radii. Raman and infrared (IR) spectral analyses, X-ray diffraction, and thermogravimetric analyses indicated that while hydrogen bonding networks were formed between Se and guest molecules, the size, shape, volume and desorption behavior of the micropores were less affected by replacing S with Se in the framework of the nickel (II) coordination polymer.79 Synthetic methodologies with ISCs as intermediates have also been utilized to develop novel multicomponent polymerization reactions (MCPs) for the synthesis of advanced sequenceregulated polymers. The generation of Se-macromolecules from these methodologies may have applications in the development of new biomaterials or materials for advanced imaging purposes.80 Recent work has demonstrated the introduction of elemental Se into polymer chains. Particularly, a library of new polyselenourea polymers were generated using elemental Se as a monomer.80 In


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the MCP reaction, elemental Se reacted with alkyl isocyanides to form ISCs in situ, which then reacted with amine monomers to form selenourea linking motifs. This method was demonstrated to occur rapidly at room temperature and under atmospheric conditions, with 100% atom economy.80

Theoretical and Computational Research on ISCs ISCs have been used in a number of theoretical studies, either as the central focus or as a means to better understand various other physical phenomena. For example, electron delocalization was studied in isocyanates, ureas, and formamides containing various chalcogens (oxygen (O), sulfur (S), or Se), to explain trends in C-N rotational barriers and N-inversion barriers.81 In the isocyanates, ab initio molecular orbital (MO) and density functional theory (DFT) calculations indicated that C-N partial double bond character and electron delocalization increased in the order of O < S < Se. The ISCs had the greatest partial double bond character and electron delocalization. Natural bond orbital (NBO) analyses indicated that the observed trends in electron delocalization did not correlate with the electronegativity of the chalcogens. Rather, orbital interactions formed the basis of the observed trends: the lesser the energy difference between the interacting orbitals involved in the delocalization led to a greater resonance.81 Aside from electron delocalization, the ability of cyclopentadienyl ISCs, ITCs, isocyanates, and isotellurocyanates to undergo rearrangement has been studied using dynamic nuclear magnetic resonance (NMR) spectroscopy and DFT. While pentaphenylcyclopentadienyl isocyanate and pentaphenylcyclopentadienyl ITC remained structurally rigid over the thermal scale, pentaphenylcyclopentadienyl ISC underwent a reversible hetero-Cope rearrangement, yielding an isomeric selenocyanate in which the SeCN group undergoes low energy 1,5-sigmatropic shifts


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along the perimeter of the cyclopentadiene ring.82 The lack of rearrangement for the isocyanate and ITC forms was attributed to a greater thermodynamic stability than their corresponding isomeric cyanate and thiocyanate forms. Conversely, the isomeric ISC and selenocyanate forms were close in energy because of secondary orbital interactions between 𝜋-electrons of the cyclopentadiene ring and the pz-orbital of Se, which allowed for the rearrangement to occur. In accordance with this finding, the activation barrier for the 3,3-shift of the ISC group of pentaphenylcyclopentadienyl ISC was 7.6 kcal mol-1 lower than its unsubstituted form, due to better localization of electron density in the phenyl-substituted form.82 Using DFT approaches, Trujillo et al. studied the effects of halogen (F, Cl, Br) and methyl substituents on bonding and stability of selenocyanates and ISCs.83 Halogenated selenocyanates were more stable than halogenated ISCs, whereas methylated ISCs were more stable than methylated selenocyanates. These observations were attributed to bonding behavior. Namely, the selenium-halogen bond (F, Cl, Br) had strong ionic character and a greater bond dissociation energy than when Se was bound to the methyl group, a bond which instead had covalent character and a weaker bond dissociation energy. Also, the nitrogen-methyl bond was much stronger and had a greater dissociation energy than the nitrogen-halogen (F, Cl, Br) bond. Moreover, with the ISC derivatives, the CN bond of the methylated form retained triple bond character, whereas the halogen derivative CN bond weakened and displayed double bond behavior. Further, with halogenation of the ISC, the electron density decreased at the bond critical point (BCP), which implicated that a greater destabilization of the system occurred when changing from the selenocyanate isomer to the ISC; this result was in contrast to the methylation of ISC, where a larger electron density was apparent at the CN BCP.83


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Spectroscopic and computational methods have also been used to study vibration and rotation, and to elucidate the rotameric conformations of the isoselenocyanate group within different ISCs. For example, the physical and chemical properties of isoselenocyanic acid HNCSe must be determined with indirect methods, due to its instability in aqueous solution, which rapidly decomposes into hydrogen cyanide and selenium.72 Comparisons among the vibration and rotation spectra of gaseous HNCSe have indicated that isoselenocyanic acid cannot be classified as a rigid, bent molecule, but rather as a quasilinear compound.72, 74 In the case of methyl ISC, its characterization has differed among studies. Infrared studies done by Franklin et al. suggested that the methyl group of methyl ISC had essentially free internal rotation.84 In another study, the microwave (MW) spectrum of methyl ISC was found to fit the rigid-rotor approximation, converse to that for methyl isocyanate and methyl ITC, which did not fit the semirigid-rotor approximation.85 Assuming linearity for the linkage of NCSe atoms, the angle of the CNC bond was calculated to be 157°. This finding was consistent with other studies that measured the bond angle of HNC-X, CNC-X, or C2H5-X, where the bond angle increased with X = O < X = S < X = Se.85-86 In contrast, reinvestigation of the MW spectrum of methyl ISC revealed that methyl ISC was consistent with that of a nonrigid, quasi-symmetric top molecule.87 The calculated potential function for CNC bending vibration was very anharmonic, and the CNC bond angle was found to be 161.3°. Elucidation of the energy of the ground vibrational state and the barrier to linearity revealed that the ground vibrational state energy was higher than that for the barrier to linearity. In addition, the energy of the first vibrational excited state of the CNC bending mode was found to be higher than the ground vibrational state.87


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Since there are relatively few reports of the properties of gaseous ISCs in the literature, Møllendal et al. synthesized vinyl ISC and investigated its MW spectrum, which was done in conjunction with quantum mechanical calculations. Previous microwave studies have shown that vinyl isocyanate can exist as a synperiplanar or antiperiplanar conformer, while vinyl ITC exists only as an antiperiplanar rotamer.74 While vinyl ISC has been predicted to exist in either the synperiplanar or antiperiplanar form,88 four different quantum calculation methods used by Møllendal et al. all predicted that the CNC bond of vinyl ISC exists in the antiperiplanar form. Calculation of potential functions of the CNC bending vibrations revealed extremely low and anharmonic lowest in-plane bending vibrations as well as extremely varied centrifugal distortion constants. Based on these prior observations, in addition to calculated CNC bond angles ranging from 151-170° (depending on the quantum chemical method of calculation), these characteristic findings indicated that vinyl ISC should be classified as having a quasilinear CNCSe atom linkage instead of a rigid, bent antiperiplanar form.74 Most recently, the physicochemical properties of various unsaturated or pseudounsaturated ISCs (vinyl-, 2-propenyl-, and cyclopropyl-ISC) were studied using UV photoelectron spectroscopy and quantum chemical calculations, in order to identify interactions between NCSe and the unsaturated moiety.89 Comparisons were also made to the corresponding unsaturated isocyanate and ITC. Analysis and comparison of the first ionization energies (IE) revealed that the type of chalcogen atom influences the IE and highest occupied molecular orbital (HOMO) energy. Namely, when compared to vinyl isocyanate, the IE values decreased and HOMO energy increased for vinyl ITC and vinyl ISC, suggesting that p-orbital contribution was important and played a role in weakening the strength of interactions between the vinyl substituent with the -NCX (X = S, Se, O) moiety, as well as in lowering the first IE of vinyl ITC and vinyl ISC. For the cyclopropyl analogs, a similar


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effect was observed. Particularly, for cyclopropyl isocyanate, a significant stabilizing and withdrawing effect was observed due to the oxygen atom, which resulted in higher IE values compared to the corresponding S or Se analog. Therefore, these findings suggested that the ITCs and ISCs contained weaker interactions between the unsaturated constituent and the -NCX moiety, when compared to isocyanate. Moreover, with allyl unsaturated moieties, replacement of the oxygen atom in -NCX by S or Se leads to a destabilization of the HOMO. Only in the case of allyl isocyanate, an interaction between the isocyanate group and allyl group was observed, leading the authors to conclude that consideration of the two non-interacting functional groups is requisite.89

APPLICATIONS OF ISCs IN CANCER AND OTHER DISEASES In addition to having a number of useful chemical applications, several ISCs have also been shown to possess potent biological activity. The ISC compounds have been shown to be effective against several disease types; their application as anticancer agents being particularly wellestablished. The biological activity of these compounds will be highlighted in the following sections according to the disease(s) in which they are effective.

Cancer. In the past decade, research has shown the potent cancer preventive and therapeutic effects of various ISCs. Both in vitro and in vivo models have demonstrated a greater cytotoxicity of ISCs towards cancer cells when compared to their corresponding ITCs.10,

90-91

Moreover, this

tremendous therapeutic potential has been demonstrated in a variety of different cancers, such as melanoma, lung cancer, liver cancer, etc. Melanoma.


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Several different ISCs have been shown to be effective in models of melanoma. Sharma et al. compared the biological activity of phenylalkyl ISCs, which contained differing alkyl chain lengths between the phenyl ring and the ISC moiety.10 Such compounds included benzylisoselenocyanate

(ISC-1),

phenylethylisoselenocyanate

(ISC-2),

phenylbutylisoselenocyanate (ISC-4), and phenylhexylisoselenocyanate (ISC-6). The anti-cancer efficacy, both in vitro and in vivo, and compound stability was found to increase with increasing alkyl chain length. ISC-4 and ISC-6 with 4- and 6-carbon alkyl chain lengths, respectively, were identified as the most effective compounds. As such, Sharma et al. later demonstrated that ISC-4 and ISC-6 (Table 1) were both more potent and effective at reducing the viability of UACC 903, 1205 Lu, WM115 melanoma cells than their corresponding ITCs, phenylbutyl isothiocyanate (PBITC) and phenylhexyl isothiocyanate (PHITC).90 They were also found to be more effective at reducing cell viability than phenylhexyl selenocyanate (PHSC) or API-2, an Akt inhibitor. Moreover, melanoma cells were more sensitive to the effects of ISC-4 than normal human fibroblast cells, suggesting that these compounds may be selective towards cancerous cells. Further analyses also indicated that ISC-4 and ISC-6 inhibited Akt3 signaling in vitro and in vivo, a signaling pathway activated in ~70% of melanomas and involved in decreasing melanoma cell apoptosis.90 This was evidenced by decreased phospho-Akt and decreased phospho-proline-rich Akt substrate of 40 kDa (phospho-PRAS40). Furthermore, ISC-4 and ISC-6 not only inhibited Akt signaling but also induced apoptosis at doses lower than their corresponding ITCs, both in vitro and in xenograft tumor models.10, 90 ISC-4 was subsequently chosen over ISC-6 for further study because it was considered more drug-like, exhibiting a favorable LogP value (cLogP 4.4) and molecular weight (MW = 238),10 which satisfied Lipinski’s “Rule-of-Five” for druglikeness. In contrast, ISC-6 was more lipophilic and had an unfavorable LogP value (cLogP 5.5).10


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Hence, based on these findings, our group sought to elucidate the effects of ISC-4 on early melanocytic lesions and normal skin cells. We demonstrated that ISC-4 was 2- to 5-fold more effective at inducing cytotoxicity in both melanocytic lesion cells derived from the radial growth phase and advanced stage melanoma cells, when compared to normal melanocytes.92 ISC-4 was found to decrease Akt3 activity and induce apoptosis in both melanocytic lesion cells and advanced stage melanoma cells. Moreover, a 77% reduction in tumor size was observed with topical application of ISC-4 on nude mice, without evidence of systemic toxicity. Likewise, systemic administration of ISC-4 caused negligible organ-related toxicity, thus indicating that ISC-4 may be a viable treatment for melanoma without significant off-target effects.92 Phenylalkyl isoselenocyanates were further optimized by replacing phenyl ring by the naphthalimide moiety to generate naphthalimide isoselenocyanates (NISC) as dual topoisomerase II and Akt pathway inhibitors.93 Based on the knowledge that mitonafide, a naphthalimide analog and potent topoisomerase-IIα (Topo-IIα) inhibitor, failed clinical trials due to issues related to systemic toxicity, our research group conducted a SAR by initially modifying and introducing ITC functionalities to yield NITC analogs with varying alkyl chain lengths. Because the ITC moiety was shown to reduce the systemic toxicity issues that were associated with mitonafide,94 the ITC groups were further replaced with the ISC moieties as in the above-mentioned studies,10, 90, 92 and it was hypothesized that a safer, dual Akt/Topo-IIα inhibitor would be attained. Out of the analogs, NISC-6, having –N=C=Se functionality connected to naphthalimide moiety through a 6-carbon alkyl chain (Table 1), was identified as the lead-compound.93 It was equally effective in both wild-type (WT) and BRAFV600E mutant melanoma cell lines, and it exhibited the greatest cytotoxic potency at 48 h and 72 h time points, compared to the other analogs. In addition, while NISC-6 was less potent than mitonafide with respect to cytotoxicity, it


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was selective towards cancer cells over normal human dermal fibroblasts (nHDF), unlike mitonafide. Further, in silico molecular docking, in conjunction with in vitro studies, not only showed that NISC-6 fit into the active site of both Akt and Topo-IIα, but also indicated that TopoIIα activity was inhibited as well as phosphorylation of Akt. Moreover, the cell death caused by NISC-6 was found to be due to induction of apoptosis. Tumor growth in xenograft mouse models of melanoma was inhibited by ~69% compared to vehicle-treated mice, and no apparent signs of systemic toxicity were observed. Thus, tumor inhibition data, in conjunction with in vitro studies, indicate that NISC-6 is a tolerable, dual acting therapeutic agent with potential for the treatment of melanoma.93 Lung Cancer. Currently, there are two published reports on ISCs in lung cancer. An in vivo study in A/J mice, which was based on the known chemopreventive properties of ITCs in lung cancer, assessed the chemopreventive potential of ISC-4.95 Administration of a single dose of ISC-4 resulted in a time-dependent increase of serum, liver, and lung selenium levels, revealing that ISC-4 was orally bioavailable in the mice. ISC-4 modulated the relative mRNA expression and activity levels of phase I (CYP450) and phase II metabolic enzymes in liver and lung tissue, through inhibition of phase I enzymes and induction of phase II enzymes. Additionally, in mice fed a diet containing ISC-4, a decrease and inhibition in the formation of liver methyl DNA adducts was observed following treatment with the tobacco-specific procarcinogen NNK.95 These studies therefore suggest that ISC-4 may be a suitable lung cancer chemopreventive agent due to its anti-initiation effects of inhibiting carcinogen metabolism and increasing detoxification. A subsequent in vitro SAR compared the actions of various phenylalkyl ISCs of increasing alkyl chain lengths (ISC-1, ISC-2, ISC-4, ISC-6; Figure 5) to their corresponding phenylalkyl ITCs


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in A549 lung adenocarcinoma cells.31 Comparable to studies in other types of cancer, the ISCs were more potent than their corresponding ITCs in inducing cancer cell death. Crampsie et al. found that while both ITCs and ISCs depleted reduced glutathione (GSH), the ISCs accomplished the depletion more rapidly than the ITCs. In contrast, the ITCs depleted reduced GSH to a greater extent than the ISCs. Furthermore, the ISCs displayed a greater ability to redox cycle and to induce ROS at higher levels than the ITC analogs. Interestingly, only the ITCs were shown to induce cell cycle arrest, implying that the intracellular targets differ between the S- and Se-substituted analogs.31 Colon Cancer. In several different colon cancer cell lines, ISC-4 potently inhibited cell growth in a dosedependent manner.91 In HT-29 colon cancer cells, ISC-4 was found to be more potent than its corresponding sulfur analog (PBITC) as well as the commercially available Akt inhibitor API-2. In a xenograft model of colon cancer, ISC-4 reduced tumor growth and slowed the growth rate of the tumors, with no apparent systemic toxicity. Analysis of tumor tissues showed a downregulation of Akt1, Prostate apoptosis response protein-4 (Par-4), and phospho-Akt levels in the ISC-4 cohort of mice. Addition of the standard of care treatment 5-fluorouracil (5-FU) was found to enhance the growth inhibition caused by ISC-4. Moreover, tumor growth was slowed further with the addition of tumor suppressor protein Par-4.91 In another study, the synergistic capabilities of ISC-4 were assessed.96 To see if the efficacy of ISC-4 could be improved in colon cancer, the activity of ISC-4 was compared alone or in combination with 19 Food and Drug Administration (FDA)-approved anti-cancer therapies in RKO and SW480 cells. Out of the combinations, the combination of ISC-4 with cetuximab was found to display synergy. Particularly, this synergy was observed only in the RKO cell line, which


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contains wild-type KRAS: this finding was consistent with the requisite of wild-type KRAS for the efficacy of cetuximab.97-98 Accordingly, ISC-4 and cetuximab acted synergistically to inhibit cell proliferation in cell lines with wild-type KRAS, in a manner dependent on the dose of ISC-4 but independent for cetuximab. Likewise, this effect correlated with a reduction in phospho-Akt levels and an increase in apoptosis.96 Furthermore, in a model of 5-FU-resistant colon cancer, the synergistic capacity of ISC-4 and cetuximab was found to be retained, both in vitro and in vivo. Additionally, the in vivo studies revealed that the combination of drugs was tolerable and did not cause any significant toxicity.96 Overall, these reports indicate that ISC-4 has the potential to act as a colon cancer therapeutic, both as a single agent and in combination with chemotherapy. Liver Cancer. The ITC, sulforaphane (SFN), is among the most potent inducers of the Nrf2/antioxidant response element (ARE) signaling pathway.99 In fully-developed cancer, however, Nrf2 activation is a double-edged sword, as Nrf2 activation modulates pathways involved in the detoxification of anticancer drugs, which may lead to chemoresistance in cancer cells.100-102 SFN-mediated induction of this pathway leads to the upregulation of GSH biosynthetic enzymes such as the ratelimiting glutamate cysteine ligase (GCLc) and Phase II detoxification enzymes. Because enhancement of GSH and its induction plays an important role in chemoprevention by SFN, and due to the known chemopreventive effects of Se compounds, Emmert et al. hypothesized that substitution of the sulfur atom of the ITC moiety with Se may render a sulforaphane isoselenocyanate (SFN-isoSe) (Table 1) with a greater enhanced capability to induce ARE signaling and Nrf2.99 The hypothesis was first tested in HepG2 ARE-luciferase reporter cells for a 6 h drug treatment period. While viability was not affected by either compound at doses at or below 10 µM, over a 50% reduction in cell viability was observed only with SNF-isoSe at 20 µM. It was


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concluded that the ISCs were more effective than ITCs in reducing cell viability over a 6 h drug exposure. Namely, the viability of HepG2 cells was reduced to 0%, 14%, and 0% of controls, corresponding

to

SFN-isoSe,

phenylethylisoselenocyanate

(PEISC,

or

ISC-2),

and

benzylisoselenocyanate (BISC, or ISC-1) treatments, respectively.99 Similar to the viability studies, the effects of ARE induction were identical between SFN and SFN-isoSe at 0, 5 and 10 µM doses. At 20 µM doses, the level of luciferase activity induced by SFN-isoSe was more than double that for SFN. Unlike control compounds PEISC and BISC, the increase in ARE induction and decrease in cell viability was dose-dependent for SFN-isoSe.99 Nuclear Nrf2 levels were also shown to be induced to a greater level by SFN-isoSe than SFN in non-cancerous mouse embryonic fibroblast (MEF) cells, irrespective of the concentration. Further experiments in MEFs showed that a two-fold induction of GSH by SFN-isoSe was dependent on Nrf2, which was in contrast to SFN, which showed depletion of GSH. Taken together, these findings revealed that elevation of nuclear Nrf2 by SFN-isoSe lead to AREmediated upregulation of GSH enzymes, such as GCLc, which ultimately results in higher GSH levels.99 GSH induction by SFN-isoSe and GSH depletion by SFN also suggest that SFN-isoSe was less toxic to MEFs than SFN. Therefore, these results, in conjunction with the greater cytotoxicity imparted on cancer cells by SFN-isoSe over SFN, indicate that SFN-isoSe may be a potential candidate for a chemopreventive agent. Prostate Cancer. Having previously shown efficacy in other types of cancer, Wu et al. investigated the effects of ISC-4 in the context of prostate cancer.103 ISC-4 was found to be four times more potent than the corresponding S analog PBITC in reducing LNCaP cell viability and inducing apoptosis. In contrast to earlier reported work in colon cancer and melanoma, ISC-4 did not inhibit


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phosphorylation of Akt, indicating that Akt inhibition was not responsible for ISC-4’s mechanism of cytotoxicity in LNCaP prostate cancer cells. Instead, ISC-4 was shown to decrease androgen receptor (AR) and prostate specific antigen (PSA) levels post-transcriptionally, independent of apoptosis.103 Other experiments showed that ISC-4 induced ROS, which not only suppressed AR/PSA but also promoted apoptosis through activation of p53 signaling. Particularly, it was found that the p53-p53 upregulated modulator of apoptosis (PUMA)-Bax (BCL-2-associated X protein) intrinsic apoptotic cascade was activated. Loss of p53 led to attenuation of apoptosis – an effect found to be independent of ISC-4’s effects on AR/PSA, and knockdown of the downstream targets of p53 also attenuated ISC-4-mediated apoptosis.103 Breast Cancer. Cierpiał et al. synthesized a series of organofluorine ISC sulforaphane analogs with varying chemical compositions, and compared their anti-cancer activities relative to ITC sulforaphane.104 Because SFN is known to induce cell cycle arrest and cell death in breast cancer, the analogs were screened in various breast cancer cell lines. Across several tests, the new analogs were found to exhibit more potent and selective inhibition of cancer cell growth, over normal cell growth, relative to SFN. Out of the various analogs, 4-isoselenocyanato-1-butyl 4’-fluorobenzyl sulfoxide (compound 8i) (Table 1) was identified as a potential lead compound. While it was potent in both breast cancer cell lines tested (MDA-MB-231 and MCF7), it was most selective towards hormoneindependent, triple-negative MDA-MB-231 cells, which served as a model of aggressive breast cancer that is resistant to traditional, targeted, or hormone-based therapeutics. Moreover,


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compound 8i was selective towards the cancer cells in general: it was less toxic than SFN in normal cell lines, and in cancer cells, compound 8i induced cytotoxicity more potently than SFN.104

Infectious Diseases. Malaria. Nieves et al. synthesized several compounds that were based on the structure of (-)-8,15diisocyano-11(20)-amphilectene,

a

metabolite

with

known

potent

antimalarial

and

antimycobacterial effects that is isolated from the marine sponge Svenzea flava.105 Prior SAR studies revealed that the isocyanide functionally is requisite for biological activity, and that its location is also important for activity.106 With this in mind, and based on observations that spongederived isocyanide-, ITC-, and formamide- diterpenoids are also biologically active, their novel amphilectane diterpenes incorporated ISCs and ITCs in various positions to test as potential pharmacophores.105 Screening of the analogs in two different P. falciparum malarial parasite lines (chloroquine-sensitive 3D7 and drug-resistant Dd2) revealed that all the ISC analogs displayed sub-micromolar antiplasmodial activities. Of these hybrid compounds, compound 5 (Table 1), which contained two ISC moieties, was more potent than standard drug chloroquine in Dd2 (IC50 of 0.0066 µM compared to 0.0519 µM). Furthermore, it displayed greater selectivity towards the drug-resistant line, with a higher selectivity index value (SI = 7356) compared to that of chloroquine (SI = 4518).105

Tuberculosis. In the same study described in the previous section, Nieves et al. also screened their ITCand ISC-amphilectane diterpenes against Mtb H37Rv to elucidate the minimum inhibitory


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concentration (MIC).105 The ISC-functionalized hybrid compounds were found to have the lowest MIC values – particularly, hybrid compounds 5 and 6, with MICs of 3.9 and 2.1 µM. In contrast, the ITC-functionalized amphilectane diterpenes had poor MICs ranging from 26.8-99.1 µM. Moreover, of the hybrid compounds 5 and 6, compound 6 was identified as the most potent, selective, and least toxic of two (Table 1). This finding, in conjunction with the data on the ITChybrid analogs, again suggests that the selenium is playing a role in the selectivity and potent cytotoxicity of these compounds.105

Leishmaniasis. Because selenocompounds and anti-tumor agents have both demonstrated leishmanicidal activity,107 the antiproliferative activity of ISC derivatives was studied in promastigote and intracellular amastigote forms of Leishmania major and Leishmania amazonensis.108 Out of the tested analogs, NISC-6 was found to inhibit Leishmania promastigotes proliferation with nanomolar range IC50 values, which was up to three-fold higher than that of reference drug amphotericin B (Ampho B). Moreover, in L. major, NISC-6 displayed the highest selectivity index value (SI = 416.7), which was nearly ten-fold higher than the reference drug. While the American strain L. amazonensis was less sensitive to both Ampho B and NISC-6, the SI of NISC-6 (SI = 41.7) was still two-fold greater than that for Ampho B (SI = 20.5). NISC-6 was also shown to induce cell cycle arrest, as evidenced by a decrease in mRNA levels of replication-associated genes such as proliferating cell nuclear antigen (PCNA), topoisomerase-2 (TOP2), and minichromosome maintenance complex 4 (MCM4). Additionally, relative to untreated cells, NISC-6 treatment resulted in increased numbers of parasitic cells in the G1 phase and reduced numbers in the S phase (Table 1). 108


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Table 1. Structures of ISCs and their corresponding effects in different types of cancers or infectious diseases.

CONCLUSIONS AND PERSPECTIVES From the previous sections, it is apparent that ISCs show much potential for use in a number of chemical disciplines, such as theoretical, computational, organometallic, polymer, and inorganic chemistry (Figure 4).


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O

IE1 (eV)

N C Se

N NCSe

Low

O

R1 N C Se

CH3

R2 N C Se R3 N C Se

N C Se

H

H 2C H

Medicinal

H

SeCN

CH3

R3 N C S R2 N C S

C Cl

KSeCN

C N C Se

+

?

Functionalized Organoselenium Compounds as Potential Ligands

R1 N C S High

Isoselenocyanates (-R-N=C=Se) in Diverse Areas of Chemistry

Theoretical/ Computational ,

R1

N

Se C

Se R1

N

C

H 2N Se

R2

R1

N H

N H

Polymer

R2

Inorganic

n

Organometallic

[Fe(R2bapbpy)(NCSe)2] [Fe2O(µ-XDK)(bpy)2(NCSe)2] {[Ni2(NCSe)4(azpy)4] MeOH}n(2 MeOH) {[Ni2(NCSe)4(azpy)4] H2O}n(2 H2O) [Mo2Ni(dpa)4(NCSe)2]

Figure 4. Applications of ISCs in various areas of chemistry. ISCs have been used in a number of studies within these disciplines. See text for in-depth explanations.

However, of these uses, the application as anticancer agents is especially of interest, due to the lack of effective, long-term treatments as well as the expected rise in cancer cases and deaths. Furthermore, the described studies have shown that ISCs are efficacious and potent anticancer and chemopreventive agents, in most cases more potent than the corresponding ITCs. With phenylalkyl ISCs (ISC-1, ISC-2, ISC-4, ISC-6), increasing the alkyl chain length bridging the phenyl ring and ISC moiety increased the growth inhibitory potency both in vitro and in vivo (Figure 5).10, 90 This finding was similar to previous in vitro reports of various phenylalkyl ITCs, where increased potency was observed with increasing alkyl chain length up to eight carbons,47-50 yet different from the in vivo studies of ITCs, where increased alkyl chain length did not


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correspond to greater tumor inhibition in vivo.109 Importantly, in ISC studies, a lack of efficacy observed with control selenocyanate PHSC indicated that Se alone was not responsible for the enhanced growth inhibitory effects caused by ISCs, but rather as a combination of the structure of the ISC along with Se.90 It was also reasoned that the longer alkyl chain length may facilitate access and binding of the ISC or ITC group to critical residues needed for enzymatic activity.31 In the case of the NISC analogs, however, increased alkyl chain length did not consistently correspond to more potent biological activity, despite identifying NISC-6 as the most effective compound with a 6-carbon alkyl chain, the longest alkyl chain tested.93 This was in contrast to corresponding sulfur analogs, where increased alkyl chain length increased potency.94 Moreover, unlike the sulfur analog NNITC-2, where nitro substitution of the naphthalimide ring system enhanced the potency compared to its unsubstituted form (NITC-2), NNISC-2 was less cytotoxic than NNITC-2 and NISC-2, indicating that nitro substitution was unfavorable in the case of the Se analog (Figure 5).93 For the organofluorine ISC analogs of SFN, oxidation of the sulfur atom, when in conjunction with a methylene group between the 4-fluorophenyl ring and the sulfoxide group, was found to increase the anticancer potency.104 In addition, increasing the alkyl chain length (from 4 carbons to 5 carbons) between the sulfur-based functionality and the ISC moiety resulted in increased cytotoxicity to the normal cell line and therefore a decrease in the compound’s cancer cell selectivity (Figure 5).104


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Figure 5. Comparison of the effects of SARs on the anti-cancer effects of ISCs vs. ITCs, detailed in Refs. 10, 47-50, 90, 92, 104, 109.

Based on the observations from these SARs, it can be concluded that the oxidation state, ring substitutions, and alkyl chain length contribute to the efficacy and potency of the ISCs. Likewise, these factors all contribute to the druglikeness of these compounds, which is an imperative property to consider for the optimization and advancement of these compounds as potential anti-cancer therapeutics and chemopreventive agents. As such, the druglikeness has been considered in some of the above-mentioned SAR studies. For example, computational analysis indicated that NISC-6 was in compliance with the principles of Lipinski’s Rule of Five, and its computed topological polar surface area was predicted to have high oral bioavailability.93 Additionally, with the phenylalkyl ISCs, Sharma et al. noted that increasing the alkyl chain length between the phenyl


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ring and ISC functionality increased the lipophilicity and CLogP values for both ITCs and ISCs, but to a greater extent for the ISCs.10 With increasing alkyl chain length, the compound should be able to diffuse into cells more readily and efficiently. While ISC-4 and ISC-6 were equally effective, the CLogP of only ISC-4 was in accordance with Lipinski’s Rule of Five.10 Hence, this knowledge, as well as the known induction of esophageal carcinogenesis in rats due to the higher lipophilicity of PHITC,109 rendered ISC-6 as a less suitable anti-cancer and/or chemopreventive agent.10 So, these points get back to another important issue: why selenium? What is different between sulfur and selenium, two members of the same family on the periodic table, with the same oxidation states, that leads to greater anti-cancer efficacy and potency? The SARs have shown that the ISCs are more potent than ITCs in vitro and in vivo, and have greater lipophilicity. Perhaps these differences in biological activity can be rationalized on the basis of their atomic and electronic properties as opposed to solely their molecular properties. While it is known that S and Se have similar electronegativity values, they differ in their atomic, ionic, and van der Waals radii as well as their hydrogen-bonding capacities. Se has larger atomic, ionic, and van der Waals radii than S, with a more diffuse charge on the Se atom, which can weaken intermolecular interactions. Se also has a greater 𝜋-bonding ability than S. In addition, while S is sometimes considered a hydrogen bond acceptor, hydrogen bonding with Se is known to be negligible. Perhaps, the combination of the subtle differences between these two elements add together when in the context of a whole molecule interacting with its corresponding target protein(s), accounting for the observed differences in anti-cancer efficacy and potency. As described earlier, Crampsie et al. attempted to elucidate the differences between S and Se in phenylalkyl ITCs vs ISCs, in terms of biological mechanisms.31 “Pseudo first order” kinetic


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experiments indicated that the rate of reaction with GSH decreased with increasing alkyl chain length for both ITCs and ISCs. While the ISCs reacted more quickly than ITCs, no significant differences in equilibrium concentrations of GSH conjugates were observed between the S and Se analogs. In lung cancer cells, GSH was depleted more rapidly with ISCs, but total depletion was greater for ITCs. Perhaps the greater reactivity of the ISCs can be attributed to the fact that Se’s valence electrons are more labile than sulfur, as it was reasoned that the C=Se bond was less stable than C=S, making it more reactive towards thiol nucleophiles. The reactivity of ISC compounds with nucleophiles, similar to as reported for ITCs, does suggest their poor overall stability in the in vivo system and thus compromises their drug-like properties. Owing to the electrophilic nature of ITC functionality, the half-life of naturally occurring ITC SFN has been reported to be only 1.77±0.13 h in humans.110 However, since thiol conjugate metabolites of both ISC and ITC compounds, formed on reaction with protein thiols (such as glutathione, cysteine, and N-acetylcysteine) or formed during the mercapturic acid pathway,111 have also been shown to be effective anticancer agents,10, 112 these compounds can together last relatively longer as active metabolites, thus contributing to the efficacy of ITCs and ISCs. However, the poor stability limitations can be overcome by creating more stable and water-soluble pro-drugs similar to as reported recently by Jiang et al. for SFN113 to create clinically relevant ISC based drug candidates in future. Furthermore, the ISCs redox cycled and generated ROS more efficiently and to greater extents than their corresponding ITCs, which was in accordance with the fact that -SeH is known for redox cycling and greater reactivity than -SH.31 Therefore, the data suggested that the cytotoxic effects of ISCs and ITCs are associated with thiol interactions. Particularly, for the ISCs, the enhanced cytotoxic effects are believed to be due to overall GSH depletion and redox cycling, but not related


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to the rate of GSH reaction – as the data refuted the original hypothesis that replacement of S with Se would decrease the electrophilicity of the carbon atom and thereby reduce thiol reactivity.31 Regardless, the ISCs have shown much promise as potential cancer therapeutics or chemopreventive agents. Future cancer-related ISC research should look into additional potential combination therapies aside from just ISC-4 and cetuximab. For example, could dual Akt and Topo-IIα inhibitor NISC-6 act synergistically with BRAFV600E inhibitor PLX4032 to help delay the onset of its resistance in melanoma? Could the aggressiveness of triple negative breast cancer be slowed down when an organofluorine ISC sulforaphane analog is used in conjunction with a standard chemotherapy? In addition, the described ISCs could be modified in a manner analogous to NISC-6, where the ISC moiety and requisite groups are conjugated to the bioactive functionalities of known inhibitors and chemotherapeutic agents, and the bioactivity of the hybrids can be compared to their respective parent compounds. Also, the reactivity of these ISCs could be investigated upon incorporation of several ISC and/or ITC moieties. Furthermore, one type of aggressive cancer for which there are no potent ISC analogs is glioblastoma. Future research could also focus on the synthesis of potent, targeted ISC analogs that are capable of crossing the blood-brain-barrier. As suggested by the biological studies, the attainment of a very potent, cancer-cell selective, and bioavailable ISC requires a fine balance of optimizing the lipophilicity (i.e., alkyl chain length), oxidation state and/or aromatic ring substitutions, without losing the known biological activity. To attain these optimized ISCs, it is also imperative to have reliable, simple, and safe synthetic methods. While some of the described synthetic approaches have their caveats, future research can strive to achieve greener methods that generate the desired ISCs in good yields. Development of such synthetic methodologies should expedite the structural optimization of these compounds.


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Aside from the anti-cancer ISCs, it is also important to highlight the utility of ISCs in the context of other diseases. As shown by Nieves et al., novel ISCs are being developed as anti-malarial and anti-tuberculosis agents.105 By extension of these findings, future research could concentrate on developing ISCs for other infectious diseases, such as cholera or meningitis. ISC moieties could be added to existing anti-bacterial drugs, the bioactive portions of anti-bacterial drugs could be fused to existing ISC compounds, and the synergistic effects of ISCs could be assessed when used with various anti-infectives. As a closing thought, ISCs have the capacity to shape a number of areas of chemistry in the years to come, such as theoretical, organometallic, polymer, and inorganic chemistry - which has been evidenced by the research already conducted with them. They are especially promising in the realm of medicinal chemistry and in the context of cancer and human diseases, as they have been shown to be more effective than their isosteric sulfur analogs. With more research and structural optimization, it is with great hope that new ISC compounds, as well as some of the ISC compounds described in this review, can advance to clinical trials and eventually to the clinic as novel cancer drugs and chemopreventive agents.


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AUTHOR INFORMATION Corresponding Author *Department of Pharmacology, Penn State College of Medicine, Penn State Cancer Institute, CH72, Penn State Milton S. Hershey Medical Center, 500 University Drive, Hershey, PA, 17033. Phone: 717-531-4563. Fax: 717-531-0244. Email: [email protected] Author Contributions The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

ACKNOWLEDGMENTS We thank the Department of Pharmacology, Penn State College of Medicine, and Penn State Cancer Institute for the financial support.

ABBREVIATIONS Ampho B, amphotericin B; ARE, antioxidant response element; AR, androgen receptor; Bax, BCL-2-associated X protein; BCP, bond critical point; BISC, benzylisoselenocyanate; BITC, benzylisothiocyanate; CYP, cytochrome P-450; DFT, density functional theory; Et3N, triethylamine; 5-FU, 5-fluorouracil; GCLc, glutamate cysteine ligase; GSH, glutathione; HDAC, histone deacetylase; HOMO, highest occupied molecular orbital; IE, ionization energy; IR, infrared; ISC, isoselenocyanate; ISC-4, phenylbutyl isoselenocyanate; ISC-6, phenylhexyl isoselenocyanate; ITC, isothiocyanate; MAPK, mitogen-activated protein kinase; MCM4, mini-


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chromosome maintenance complex 4; MCP, multicomponent polymerization reaction; MEF, mouse embryonic fibroblast; MIC, minimum inhibitory concentration; MO, molecular orbital; MW, microwave; NBO, natural bond orbital; NF-𝛋B, nuclear factor kappa B; nHDF, normal human dermal fibroblast; NISC, naphthalimide isoselenocyanate; NISC-6, naphthalimide isoselenocyanate-6; NMR, nuclear magnetic resonance; NNK, 4-(methylnitrosamino)-1-(3pyridyl)-1-butanone; NPC, Nutritional Prevention of Cancer; Nrf2, NF-E2 p45-related factor 2; O, oxygen; Par-4, Prostate apoptosis response protein-4; PBITC, phenylbutyl isothiocyanate; PCNA, proliferating cell nuclear antigen; PEISC, phenylethylisoselenocyanate; PEITC, phenylethyl

isothiocyanate;

PHITC,

phenylhexyl

isothiocyanate;

PHSC,

phenylhexyl

selenocyanate; PKC, protein kinase C; PRAS40, proline-rich Akt substrate of 40 kDa; PSA, prostate specific antigen; PUMA, p53 upregulated modulator of apoptosis; ROS, reactive oxygen species; S, sulfur; SAR, structure-activity relationship; Se, selenium; SELECT, Se and Vitamin E Cancer Prevention Trial; SeMet, selenomethionine; SCO, spin crossover; SFN, sulforaphane; SFN-isoSe, sulforaphane isoselenocyanate; SI, selectivity index; STAT3, signal transducer and activator of transcription 3; THF, tetrahydrofuran; TOP2, topoisomerase-2; Topo-IIα, topoisomerase-IIα; WT, wild-type.

AUTHOR BIOGRAPHIES Emily E. Frieben received her BS in Chemistry with a concentration in Biochemistry in 2016 from Shippensburg University, Shippensburg, PA. While at Shippensburg University, she studied orphan G protein-coupled receptors under the mentorship of Dr. Thomas Frielle. She is currently a pharmacology graduate student at the Penn State College of Medicine, Hershey, PA, and is


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working in the laboratory of Dr. Arun K. Sharma, where she is synthesizing and developing novel organoselenium compounds for cancer prevention and therapy. Shantu Amin received his Ph.D. in Organic Chemistry in 1975 from Stevens Institute of Technology, NJ. He is currently a Professor of Pharmacology at Penn State College of Medicine, PA, and the Director of the Penn State Cancer Institute’s Organic Synthesis Shared Resource. His laboratory has been recognized nationally for developing synthetic methodologies for chemical carcinogens, chemopreventive agents, and anticancer agents. His laboratory uses the knowledge gained from carcinogenic structure-activity relationship studies to develop novel chemopreventive agents. Aside from synthesis and elucidation of efficacy of novel anticancer agents, Dr. Amin’s laboratory also studies drug metabolism. Arun K. Sharma received his Ph.D. in Heterocyclic Chemistry in 1997 from North-Eastern Hill University, India. He is currently an Associate Professor of Pharmacology at the Penn State College of Medicine, PA, as well as a Co-Director of the Penn State Cancer Institute’s Organic Synthesis Shared Resource. The major focuses of his research include the development of novel small drug-like molecules for cancer therapy and chemoprevention, in addition to elucidating their efficacy and mechanism of action in in vitro and in vivo models of cancer. He has extensive expertise in the synthesis, properties, metabolism, pharmacokinetics, and efficacy determination of organoselenium compounds.


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Table of Contents (TOC) Graphic

Oxygen 8

O 15.999 Sulfur 16

S 32.06

-R-N=C=S

ANTITUMOR ACTIVITY

Selenium 32

Se 78.963

–R-N=C=Se

Tellurium 52

Te

CYTOTOXICITY

127.60 Polonium 84

Po 208.98

REACTIVITY

Livermorium 116

Lv 293


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Development of Isoselenocyanate Compounds' Syntheses and

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