Letter Cite This: Org. Lett. 2018, 20, 7811−7815
pubs.acs.org/OrgLett
Synthesis of Pyridodiindoles with Anticancer Activity by a ThreeComponent Cascade Condensation Zhong-Zhu Chen,†,§ Shi-Qiang Li,†,§ Ya-Jun Zhang,† Dian-Yong Tang,† Jiang-Ping Meng,† Jie Lei,† Hong-Yu Li,*,‡ and Zhi-Gang Xu*,† †
Org. Lett. 2018.20:7811-7815. Downloaded from pubs.acs.org by STOCKHOLM UNIV on 12/21/18. For personal use only.
Chongqing Engineering Laboratory of Targeted and Innovative Therapeutics, Chongqing Key Laboratory of Kinase Modulators as Innovative Medicine, IATTI, Chongqing University of Arts and Sciences. 319 Honghe Avenue, Yongchuan, Chongqing 402160, China ‡ Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, United States S Supporting Information *
ABSTRACT: A novel three-component cascade reaction was discovered and developed to synthesize pyridodiindoles with the assistance of microwave irradiation. A collection of pyridodiindoles was prepared by means of the mild reaction and simple operation procedure, which could be applicable to a broad scope of functional aldehydes. Screening demonstrated that compound 5g exhibited a good potency in HCT116 cell lines, and this work validated the feasibility of this novel reaction for generating promising bioactive compounds.
T
he concept of high atom economy was widely used in traditional two-component reactions, but in most cases, these reactions involved either nonavailable starting materials or harsh synthetic methods.1 In contrast, the Groebke−Blackburn−Bienaymé reaction (GBBR) as a key three-component and atom-economic reaction (MCR) continues to attract considerable interest from researchers.2 It is a versatile and highly efficient synthetic method for the preparation of heterocyclic compounds.3−5 3-Aminoindoles and their substituted compounds are important chemical intermediates or pharmaceutical cores in drug discovery research.6,7 The 3-amino-2-substituted indoles were usually accessible by a metal catalyst reaction. Metal catalysts such Ru, Au, Ag, Pd, and Cu have been used to activate the C2 position to form a new C−C bond.6 Notably, Tambar’s group reported the Brønsted acid catalyzed enantioselective indole aza-Claisen rearrangement for the synthesis of chiral 3amino-2-substituted indoles.7 The cost-effective and environmentally friendly conditions, short reaction steps, and simple work up are desirable. Because of its tautomeric properties, 3aminoindole would be a good replacement for 2-amidine in GBBR, as shown in Figure 1. Thus, the substituted pyrroloindoles could be synthesized through a similar GBBR mechanism.8 In continuation of our ongoing research toward the development of new strategies for the synthesis of novel © 2018 American Chemical Society
Figure 1. Groebke−Blackburn−Bienaymé multicomponent reaction.
heterocycles, we here report novel three-component involved Boc-protected 3-aminoindoles (1a), benzyl isocyanide (2a), and Received: October 11, 2018 Published: December 4, 2018 7811
DOI: 10.1021/acs.orglett.8b03245 Org. Lett. 2018, 20, 7811−7815
Letter
Organic Letters
including TFA, HCl, AcOH, CH3SO3H, H5IO6, TsOH and HClO4 were tested;2a the use of HClO4 under microwave irradiation conditions at different temperatures gave compound 5a in 35−76% yields (Table 1, entries 9−15). However, high microwave temperature (110 °C) afforded a lower yield (entry 13). Varying the loading of HClO4 or conducting the reaction under nitrogen atmosphere did not impact the yield (entries 12, 14, and 15). The best result was obtained with 10% HClO4/ MeOH in 76% yield under microwave irradiation at 100 °C for 10 min (entry 11). It is worth mentioning that although the reaction worked with all acid catalysts, base catalysts failed to afford any detectable product (entries 15−21). With the optimized conditions in hand, we proceeded to investigate the scope of the reaction using various starting materials to prepare a small library of pyridodiindole 5 (Scheme 2). The one-pot protocol directly afforded pyridodiindole 5a−m in 62−85% yields. Importantly, aldehyde substrates were unrestricted to aromatic compounds. When alkyl aldehydes (3b, 3d, and 3m) were used in the reaction, all of the substrates were well tolerated and were converted to the corresponding products in moderate to good yields. The high reaction yield and broad scope further confirm the utility of this new reaction. In addition, there were many natural and synthetic pyridodiindoles reported to bear important biological activities, highlighting the potential application of this methodology for the preparation of biologically relevant compounds. Fascaplysin as a natural product with a pyridodiindole core has antitumor activity against ovarian cancer cell lines,10 and synthetic pyridodiindole analogues demonstrated bioactivities in assays involving benzodiazepine receptor,11 GABA receptor,12 CDK4 kinase,13 P-gp,14 and cervical cancer HeLa cells.15 However, these pyridodiindole analogues were usually synthesized in multiple steps with noncommercial starting materials.16 A plausible mechanism is shown in Scheme 3. The deprotected Schiff base 6 could be formed first and would be attached with the isonitrile to give the intermediate 7.
Scheme 1. One-Pot Synthesis of Pyridodiindole 5a
benzaldehyde (3a) for the synthesis of pyridodiindoles (Scheme 1). Boc-protected 3-aminoindoles demonstrated unique properties in the post-Ugi cascade reaction. Using the same principle reported,9 we planned to synthesize pyrroloindoles by reacting the Schiff base formed between Boc-protected 3-aminoindole (1a) and benzaldehyde (3a) with benzyl isocyanide (2a) (Scheme 1). However, the subsequent cyclization under thermal conditions in the presence of acid did not proceed to afford the anticipated product 4a but instead gave an unexpected ringexpanded pyridodiindole analogue 5a. The structure of pyridodiindole 5d was confirmed through X-ray crystallography (in the Supporting Information). We also synthesized compound 5g to further confirm the observation. Since pyridodiindole 5g demonstrated decent anticancer activity in a primary screening (Figure 2), we then optimized the reaction conditions, together with an evaluation of its scope, for a library synthesis of substituted pyridodiindoles. The three-component reaction was carried out in methanol at room temperature overnight and did not initially furnish the products in optimal yield; further optimization with variation of temperature, time and solvent was conducted. Different acids Table 1. Optimization for Synthesis of Compounds 5a entry 1 2 3 4 5 6 7 8 9 10 11 12b 13 14 15 16 17 18 19 20 21
solvent 10% TFA/MeOH 10% HCl/MeOH 10% AcOH/MeOH 10% L-Proline/MeOH 10% HCOOH/MeOH 10% CH3SO3H/MeOH 10% H5IO6/MeOH 10% TsOH/MeOH 10% HClO4/MeOH 10% HClO4/MeOH 10% HClO4/MeOH 10% HClO4/MeOH 10% HClO4/MeOH 5% HClO4/MeOH 15% HClO4/MeOH DMF DMF DMF DMF DMF DMF
cat.
K2CO3 Cs2CO3 NaOH DBU DIPEA DIPA
equiv
2.0 2.0 2.0 2.0 2.0 2.0
temp (°C) (MW) 100 100 100 100 100 100 100 100 80 90 100 100 110 100 100 130 130 130 130 130 130
time (min) 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10
yielda (%) of 5a 10 16 21 NR 23 NR 13 NR 35 61 76 74 52 45 57 NR NR NR NR NR NR
a
Yield of isolated product. MW = microwave. bThe reaction was conducted under nitrogen atmosphere. 7812
DOI: 10.1021/acs.orglett.8b03245 Org. Lett. 2018, 20, 7811−7815
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Organic Letters Scheme 2. One-Pot Microwave-Assisted Synthesis of Pyridodiindoles 5a−m
Scheme 3. Proposed Synthetic Route Leading to Compound 5
Scheme 4. Further Modification of Pyridodiindole Compounds
functionality of an indole moiety of compound 5i, compound 11 with a 7-fused ring system was obtained through a coppercatalyzed Buchwald ring-closing reaction. Compound 14 was synthesized by using methyl 2-formylbenzoate 12 as a starting material through an intermolecular amide formation of the plausible intermediate 13. To evaluate the potential for developing a drug lead from synthesized compounds, the MTT assay was used to measure cancer cell viability upon the drug treatment. The cancer cell line HCT116 was selected in Table 2. Compound 14 exhibited anticancer activities in the human colon cancer cell line
Subsequently, an oxidative dehydrogenation reaction would occur to form a stabilized azirine 8 through the aromatic conjugation. The reaction would then proceed through the intermediate azirine 8 followed by a pseudo-Neber rearrangement.17 We expected that the rate-limiting step would be cleavage of the C−N single bond of the azirine core to form intermediate 9 for the π participation from the aromatic benzene ring. The intermediate 10 would be sequentially attached by the C2 of the indole moiety by leaving a proton of the benzene ring to form another new indole to give the final compound 5. No Boc-protected 3-aminoindole was tested in this novel threecomponent cascade reaction. Pyridodiindole 5a could be still obtained, but with a lower yield (43%, Supporting Information). Encouraged by the scope of this new reaction and the potential to generate more complex pyridodiindole analogues, we investigated the feasibility of using this methodology to build increasingly elaborate molecular scaffolds (in Scheme 4). By attaching a leaving group such as bromine adjacent to the NH
Table 2. Anticancer Activities of Compounds 5a−m, 11, and 14a compd
HCT116 IC50 (μM)
compd
HCT116 IC50 (μM)
5a 5b 5c 5d 5e 5f 5g 5h
>40 23.1 ± 4.0 >40 11.5 ± 3.0 23.4 ± 5.0 14.9 ± 2.0 1.2 ± 0.6 12.3 ± 3.0
5i 5j 5k 5l 5m 11 14 paclitaxel
>40 17.3 ± 5.0 23.2 ± 4.0 12.5 ± 2.0 33.5 ± 6.0 26.6 ± 8.0 4.4 ± 0.7 0.14 ± 0.05
a
Each IC50 value was calculated from three independent experiments conducted in sextuplicate.
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DOI: 10.1021/acs.orglett.8b03245 Org. Lett. 2018, 20, 7811−7815
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Organic Letters HCT116 with an IC50 of 4.4 μM. Remarkably, compound 5g inhibited the HCT116 cell viability with an IC50 of 1.2 μM, which is only 10 times less active than legendary anticancer drug paclitaxel. As shown in Figure 2A, the compound 5g efficiently
generation anticancer therapeutics. Further research is underway for in-depth studies of the mechanism of action of lead 5g and the optimization of its potency and drug properties in the drug discovery value chain.
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b03245. General experimental procedures; compound characterization data; 1H and 13C spectra of all compounds (PDF) Accession Codes
CCDC 1872670 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
[email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: + 44 1223 336033.
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AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected]. *E-mail:
[email protected]. ORCID
Dian-Yong Tang: 0000-0001-9389-870X Hong-Yu Li: 0000-0001-9212-2010 Zhi-Gang Xu: 0000-0003-0190-1313 Author Contributions §
Figure 2. Anticancer activities of compound 5g against HCT116. (A) HCT116 cell was treated with the different concentrations of compound 5g for 24, 48, and 72 h. Cell viability was measured with the MTT assay. Data are the mean ± SD of three independent experiments, and each experiment was conducted in sextuplicate. All data were demonstrated as the mean ± SD of three independent experiments. *P < 0.05; **P < 0.01; ***P < 0.001 versus vehicle. (B) Pictures of HCT116 cell was determined by BrdU staining assay with the treatment of compound 5g for 48 h. Scale bar, 100 μm. (C) The soft agar assay was employed to detect colony formation in vitro after treating with the indicated concentrations of compound 5g for 14 days.
Z.-Z.C. and S.Q.L. contributed equally to this work.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We thank the Science and Technology Research Program of Chongqing Municipal Education Commission (KJZH17129, KJQN201801321, KJZD-M201801301), the Natural Science Foundation Project of CQ CSTSC (CSTC2015ZDCYZTZX120003, cstc2018jszx-cyzd0110, and cstc2018jszxcyzdX0023), and the Scientific Research Foundation of the Chongqing University of Arts and Sciences (Z2016BX02). H.L. was supported by the grants NIH 1R01CA194094-010 and 1R01CA197178-01A1 and UAMS start-up funding. We also thank Ms. H. Z. Liu and J. Xu for obtaining the LC/MS, HRMS, and NMR data.
inhibited HCT116 cell viability in a time- and dose-dependent manner. Moreover, BrdU staining assay analysis in HCT116 cell showed that compound 5g reduced a prominent decrease in the percent of BrdU-positive cells (Figure 2B). In addition, a soft agar assay in vitro was performed to evaluate the effect of compound 5g in colony formation, and the results demonstrate that smaller and lesser colonies were formed in treated groups (1, 2, and 4 μmol/L) compared with the control groups in HCT116 (Figure 2C). These results support the fact that compound 5g dramatically inhibited cell viability and proliferation in human colon cell HCT116. In conclusion, we have developed a novel three-component cascade reaction for the construction of highly functionalized pyridodiindoles. A small collection of pyridodiindoles has been synthesized under microwave irradiation with a mild reaction, good yields, and a simple operation procedure. The screening results are promising, particularly with low micromolar inhibition (5g) in the HCT116 cell lines. Because compound 5g is only 10 times less active than the most popular anticancer drug paclitaxel, it is a promising starting point to develop next-
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