Oligodeoxynucleosides with Olefin Bridges - Macromolecules (ACS

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Oligodeoxynucleosides with Olefin Bridges Li Wang, Meng Wang, Ling-Xiang Guo, Ying Sun, Xue-Qin Zhang, Bao-Ping Lin, and Hong Yang* School of Chemistry and Chemical Engineering, Jiangsu Province Hi-Tech Key Laboratory for Bio-medical Research, Jiangsu Key Laboratory for Science and Application of Molecular Ferroelectrics, Southeast University, Nanjing, Jiangsu Province 211189, China

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S Supporting Information *

ABSTRACT: The synthesis and self-assembly studies of DNA/RNA-mimic artificial polymers have drawn extensive scientific attention since synthetic chemists can manipulate the functions of these modified nucleic acid molecules by varying their macromolecular backbone and nucleoside unit structures. In this paper, we report two types of modified nucleic acids with olefin bridges prepared by acyclic diene metathesis polymerization (ADMET). The 3′-OH and 5′-OH groups of deoxythymidine and deoxyadenosine analogue monomers are functionalized with either two terminal allyl units or allyl and acryloyl units, respectively. The consequent ADMET approaches provide either regio-uncontrolled oligodeoxynucleosides with poor E/Z selectivity or well-defined oligodeoxynucleosides built in a highly ordered head-to-tail addition manner. These two different macromolecular structures markedly influence the self-assembly morphologies of the corresponding oligodeoxynucleosides, which show spherical and filamentous helix nanostructures, respectively.

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bridges),44−51 while preserving the nucleobase units for hydrogen bonding purposes. Inspired by the above pioneering works, we report in this article two types of modified nucleic acids with olefin bridges. As schematically illustrated in Figure 1b−d, we applied the classical acyclic diene metathesis polymerization (ADMET) method55−68 to synthesize two series of oligodeoxynucleosides with olefin linkers. At first, we designed two monomers (1 and 2) by functionalizing the hydroxyl groups of deoxythymidine and deoxyadenosine with two terminal allyl units (Figure 1b). However, since these α,ω-diene nucleic acid monomers had asymmetric molecular structures, performing ADMET polycondensation reaction would provide regio-uncontrolled polymer chains with poor E/Z selectivity.55−59 Each olefin metathesis point would have three connection choices (3′-allyl and 5′-allyl, 3′-allyl and 3′-allyl, or 5′-allyl and 5′-allyl) as shown in Figure 1c, while the DNA molecule on the contrary had a well-defined macromolecular backbone with the phosphoryl groups always linking on the 3′ carbon of one ribose and the 5′ carbon of another adjacent ribose as shown in Figure 1a. To solve this complexity, we designed two other monomers (3 and 4) by functionalizing the 3′-OH and 5′-OH groups of the deoxynucleosides with allyl and acryloyl units, respectively (Figure 1b), and applied an alternative terminal acrylate−olefin cross-metathesis polymerization method.60−64 This strategy was built on the fact that the homodimerization rates of acrylates were much slower than those of terminal olefins; thus, this terminal acrylate−olefin cross-metathesis

INTRODUCTION Studying the self-assembly of biological macromolecules has been an intriguing research subject for decades. A typical example is deoxyribonucleic acid (DNA), which can selfassemble into a thread-like double helix,1−3 carrying the genetic information contributed to the reproduction, growth, and function of living organisms. Such a fascinating selfassembly phenomenon of DNA derives from its unique molecular structure which is composed of alternating phosphate and deoxynucleoside units (Figure 1a). Each deoxynucleoside contains a deoxyribose ring attached with one of four nucleobases (adenine (A), thymine (T), guanine (G), and cytosine (C)); the nitrogenous bases of two separate DNA chains are paired together via hydrogen bonds (A−T and G−C) to form the double-helix morphology. In recent years, the synthesis and self-assembly studies of DNA/RNA-mimic artificial polymers, such as peptide nucleic acid (PNA),4,5 threofuranosyl nucleic acid (TNA),6,7 glycol nucleic acid (GNA),8−17 nucleobase-functionalized polymers,18−43 and oligonucleotide analogues with monophosphate-alternative bridges,44−51 have drawn extensive attention from the scientific community since synthetic chemists could manipulate the self-assembly behaviors and functions of these modified nucleic acid molecules by varying their macromolecular backbone and nucleoside unit structures and even hybridize them with DNA/RNA counter-strands for pursuing alternative genetic carriers. Most of the known modification strategies either replaced the phosphate−deoxyribose backbone completely with other polymer chains (such as peptide, glycol, etc.)4−43 or replaced the phosphodiester linker with other groups (such as dimethylene sulfone/sulfide/sulfoxide, carbonic ester, pyrophosphate, and ethyl phosphate © XXXX American Chemical Society

Received: October 1, 2018 Revised: December 21, 2018

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DOI: 10.1021/acs.macromol.8b02115 Macromolecules XXXX, XXX, XXX−XXX

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Figure 1. Molecular structures of (a) the classic DNA model, (b) the designed monomers, and the designed polydeoxynucleosides synthesized via (c) regio-uncontrolled ADMET and (d) regio-controlled, terminal acrylate−olefin cross-metathesis polymerization.

polymerization would fabricate more defined polydeoxynucleoside structures in a highly ordered head-to-tail addition manner (Figure 1d)60−64 and meanwhile provide almost quantitatively E-selective products.62 These two different ADMET approaches markedly influenced the self-assembly morphologies of the corresponding polydeoxynucleosides, which showed spherical and filamentous nanostructures, respectively.

deoxyadenosine (9) were chosen as the starting materials. We first synthesized compound 6 through the reaction of the primary hydroxyl of 2′-deoxythymidine (5) with tributylsilyl chloride (TBS-Cl) in dry pyridine;69 the measured optical −1 rotation [α]20 D of compound 6 (+2°, c = 1.0 g L , 98% CHCl3) 1 and its H NMR spectrum (Figure S1) were fully consistent with the literature data.69 Then we applied Zerrouki’s selective 3′-O-allylation method to synthesize compound 7 under ultrasound conditions.70 Its measured optical rotation [α]20 D (+20°, c = 1.0 g L−1, 98% CHCl3) and 1H NMR spectrum (Figure S6) were also consistent with the literature data.69 Interestingly, we could directly obtain the diallyl-functionalized

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RESULTS AND DISCUSSION The synthetic routes of terminal alkene-functionalized deoxynucleoside monomers 1−4 are presented in Scheme 1. The commercial available 2′-deoxythymidine (5) and 2′B


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Macromolecules Scheme 1. Synthetic Routes of Terminal Alkene-Functionalized Deoxynucleoside Monomers 1−4

Figure 2. 1H NMR spectra of (a) monomer 1, monomer 2, and monomers 1 and 2 with equal molar amount and (b) monomer 3, monomer 4, and monomers 3 and 4 with equal molar amount.

with a triphenylmethyl (trityl) group; the crude product was directly treated with TBAF to provide compound 11 ([α]20 D = −12°, c = 1.0 g L−1, 98% CHCl3). Following the protocol as described above, intermediates 12 and 13 were successfully prepared. Removing the trityl protection of compound 13 was performed in 80% acetic acid at 80 °C for 30 min to provide −1 monomer 2 ([α]20 D = −13°, c = 1.0 g L , 98% CHCl3). Compound 12 could be converted to compound 14 ([α]20 D = −11°, c = 1.0 g L−1, 98% CHCl3) in a high yield of 99.1% when the ultrasound activation time for allylation reaction was limited to 1 h. After a series of consecutive reactions including TBS deprotection, acryloylation, and trityl deprotection, the designed deoxyadenosine monomer 4 ([α]20 D = −6°, c = 1.0 g L−1, 98% CHCl3) was eventually prepared. It is well-known that hydrogen bonds are present between adenine and thymine, and these formed hydrogen bonds are much stronger than their self-complementary hydrogen

monomer 1 if the ultrasound activation time was extended to 12 h, which provided a facile one-pot approach to synthesize monomer 1 from compound 6; the possible reaction mechanism is presented in Figure S54. The measured optical −1 rotation [α]20 D of monomer 1 (c = 1.0 g L , 98% CHCl3) was +20°. To prepare monomer 3, compound 7 was first treated with tetrabutylammonium fluoride (TBAF) to give compound −1 8 ([α]20 D = +30°, c = 1.0 g L , 98% CHCl3), which was further reacted with acryloyl chloride to give the desired product 3 −1 ([α]20 D = +6°, c = 1.0 g L , 98% CHCl3). Compared with monomers 1 and 3, the synthetic procedures of alkene-functionalized deoxyadenosine monomers 2 and 4 were much more complicated. To avoid the interference of amino group for functionalizing hydroxyl groups, the two hydroxyls of compound 9 were first protected with TBS groups to obtain compound 10 ([α]20 D = −6°, c = 1.0 g L−1, 98% CHCl3),71 whose amino unit was then decorated C


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Figure 3. Variable-temperature UV spectra and the maximum optical absorbance values of (a, b) OONA-1, (c, d) OONA-2, (e, f) OONA-3, (g, h) the mixture of OONA-1 and OONA-2 with equal monomeric molar amount, (i, j) OANA-1, (k, l) OANA-2, (m, n) OANA-3, and (o, p) the mixture of OANA-1 and OANA-2 with equal monomeric molar amount, measured in 1,4-dioxane (50 mg/L) heated from 10 to 90 °C.

10.51 M−1 through NMR titration experiment (Figures S58 and S59). Both the above association constants Ka of complexes -1 and -2 and complexes -3 and -4 were consistent with the normal association constant values (10−100 M−1, CDCl3) of adenine−thymine complex reported in the literature.75,76 With all the monomers in hand, we started to apply the ADMET method to synthesize regio-uncontrolled poly(3′-Oallyl-5′-O-allyl nucleic acid)s OONA and regio-defined poly(3′-O-allyl-5′-O-acrolyl nucleic acid)s OANA. The detailed synthetic procedures are described in the Supporting Information and Table S1. All the feeding molar ratios of monomers and Grubbs second-generation catalyst were set as 20/1, and all the polymerization reactions were performed in anhydrous 1,2-dichloroethane at 50 °C. Overall, we prepared six oligodeoxynucleosides with olefin bridges, OONA-1, OONA-2, OONA-3, OANA-1, OANA-2, and OANA-3 (Figure 1c,d), starting with monomer 1, monomer 2, complexes -1 and -2, monomer 3, monomer 4, and complexes -3 and -4, respectively. All the products were short oligomers and their degree of polymerization (DP) values were in a range of 5−11, which were determined by the liquid chromatography quadrupole time-of-flight mass (LC-QTOF-MS) technique. The relatively low DP values possibly derived from the fact

bonds.1−3 We have measured 1H NMR spectra of monomer 1, monomer 2, and a mixture composed of monomers 1 and 2 with equal molar amount (complexes -1 and -2) in CDCl3, respectively (Figure 2a). As shown in Figure 2a, the chemical shifts of −NH− in monomer 1 and −NH2 in monomer 2 appear at 8.822 and 6.136 ppm, respectively. When monomers 1 and 2 in equal molar amount were mixed in CDCl3, we found that the chemical shifts of −NH− and −NH2 shifted downfield to 11.607 and 6.194 ppm, respectively, which implied that more stable hydrogen bonds might have been formed between monomers 1 and 2. The association constant Ka between monomers 1 and 2 was measured as 15.82 M−1 through the NMR titration experiment based on the Benesi− Hildebrand model (Figures S56 and S57).72−74 Similarly, we have also measured the 1H NMR spectra of monomer 3, monomer 4, and a mixture composed of monomers 3 and 4 with equal molar amount (complexes -3 and -4) in CDCl3, respectively. As can be seen from Figure 2b, the chemical shifts of the −NH− group in monomer 3 and the −NH2 group in monomer 4 shifted respectively to 11.807 and 6.244 ppm from 9.084 and 6.193 ppm after equal molar amounts of monomers 3 and 4 were mixed, which verified the formation of hydrogen bonds between monomers 3 and 4 in CDCl3. The association constant Ka between monomers 3 and 4 was determined to be D


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Figure 4. CD spectra of (a) monomer 1, monomer 2, and monomers 1 and 2 with equal molar amount and (b) monomer 3, monomer 4, and monomers 3 and 4 with equal molar amount measured in acetonitrile at 25 °C. Variable-temperature CD spectra of (c) OONA-1, (d) OONA-2, (e) OONA-3, (f) OANA-1, (g) OANA-2, and (h) OANA-3 measured in acetonitrile from 10 to 70 °C.

VT-UV spectra of the saturated aqueous solution of OONA-1 from 10 to 90 °C and the VT-UV spectra of the saturated aqueous solutions of OONA-2, OONA-3, OANA-1, OANA-2, and OANA-3 at 25 and 80 °C (Figure S68). The obtained optical absorbance values at different temperatures did not have an obvious variation, possibly because the oligodeoxynucleosides with olefin bridges were not DNA-like amphiphiles, the solubilities of these oligodeoxynucleosides in water were very low (ca. 0.01 g/L), and their internal hydrogen bonds were very strong which could not be departed by even boiling water. Alternatively, we adopted acetonitrile (boiling point: 81.6 °C) as the solvent to measure the VT-UV spectra of oligodeoxynucleosides (Figure S69) from 10 to 75 °C (heating rate: 0.5 °C/min), the optical absorbances at around 265 nm showed a decreasing trend with increasing temperature, but the resulting mutative intervals of optical absorbances in acetonitrile were obviously small and were not conducive to our study. Finally, we measured the VT-UV spectra (Figure 3) of oligodeoxynucleosides in 1,4-dioxane (boiling point: 101 °C) from 10 to 90 °C (heating rate: 0.5 °C/min).77 As illustrated in Figure 3, the optical absorbances of all oligodeoxynucleosides gradually decreased along with the rising temperature (Figure 3a,c,e,g,i,k,m,o). Their maximum absorbance values at ca. 270 nm were plotted against temperature, as presented in Figure 3b,d,f,h,j,l,n,p. The maximum absorbances of OONA-1 (Figure 3b), OONA-2 (Figure 3d), OONA-3 (Figure 3f), and the mixture of OONA1 and OONA-2 with equal monomeric molar amount (Figure 3h) all exhibited a slow decreasing trend from 10 to 60 °C and a sharp decreasing trend when the temperature exceeded 60 °C. Similarly, the recorded maximum absorbances of OANA-1 (Figure 3j), OANA-2 (Figure 3l), OANA-3 (Figure 3n), and the mixture of OANA-1 and OANA-2 with equal molar amount (Figure 3p) also showed a slow decreasing trend below 50 °C and a sharp decreasing trend beyond 50 °C. These oligodeoxynucleosides with olefin bridges behaved like previously reported thermosensitive polymers.78−84 The oligodeoxynucleosides could form hydrogen bonds with 1,4dioxane, which also improved the solubility of oligodeoxynucleosides in 1,4-dioxane; these hydrogen bonds were gradually destroyed along with the increasing temperature,

that the amino and imino groups of nucleic acid analogues might deactivate the ruthenium catalyst to some extent. We have also tried to change the reaction conditions, such as changing the reaction solvent with dry dichloromethane (DCM), chloroform, tetrahydrofuran (THF), and 1,2-dichlorobenzene (o-DCB), adding new phosphine ligands, and increasing the reaction temperature, to improve the polymerization results; however, no significant improvements on DP values were achieved. The ultraviolet−visible (UV) absorption spectra (Figures S63−S66) of all the monomers and polymers were measured in acetonitrile at 25 °C. As shown in Figure S63, the absorption peaks of monomers 1 and 2 appeared at 265 and 259 nm, respectively. When monomers 1 and 2 were mixed in a 1:1 molar ratio, the absorption peak appeared at 261 nm with a blue shift compared with that of monomer 1 and a red shift with respect to monomer 2. The same phenomenon also occurred in 3′-O-allyl-5′-O-acrolyl nucleic acid monomers. After mixing an equal molar amount of monomers 3 and 4, the UV absorption peak (Figure S65) of the mixture appeared at 260 nm, which had a blue shift compared with that of monomer 3 (266 nm) and a red shift with respect to monomer 4 (258 nm). We also measured UV data of polymers (Figures S64 and S66) of OONA-1, OONA-2, OONA-3, OANA-1, OANA-2, and OANA-3 whose maximum absorption peaks displayed at 264, 260, 261, 265, 259, and 260 nm, respectively, in acetonitrile at 25 °C. Similarly, the maximum absorption peaks of OONA-3 and OANA-3 appeared in the middle regions of those of OONA-1 and OANA-1 and OONA-2 and OANA-2. To measure the variable-temperature UV (VT-UV) spectra of oligodeoxynucleosides, the first problem to be solved was to select an appropriate solvent. We examined the VT-UV spectra of pure dimethylformamide (DMF), dimethyl sulfoxide (DMSO), 1,4-dioxane, water, acetonitrile, and ethanol at 25 and 80 °C (Figure S67). Among them, DMF, DMSO, and ethanol have strong hyperchromic effects in the wavelength range of 200−350 nm which would interfere with the optical absorptions of the obtained oligodeoxynucleosides; thus, we had to choose water, acetonitrile, and 1,4-dioxane as the solvents for the VT-UV experiments. First, we examined the E


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Figure 5. TEM images of (a, b) OONA-1, (c, d) OONA-2, and (e, f) OONA-3.

and the oligodeoxynucleosides would precipitated from 1,4dioxane, which caused a gradual decrease of optical absorbances.82−84 The thermoresponsive behaviors of oligodeoxynucleosides were similar to those of thermosensitive polymers reported in the literature,78−80 indicating that the prepared oligodeoxynucleosides with olefin bridges might be used in the development of new thermosensitive polymers;78,80 these application prospects need further in-depth research. The circular dichroism (CD) spectra of monomers were examined in acetonitrile (50 mg/L) at 25 °C. As presented in Figure 4a, monomer 1 had a negative peak at 256 nm and a positive peak at 285 nm with a zero-crossing point at 275 nm, while monomer 2 possessed only a negative peak (259 nm) with a zero-crossing point at 288 nm. After monomers 1 and 2 were mixed in equal molar amount, the CD data (negative peak at 259 nm, positive peak at 285 nm, and zero crossing at 279 nm) of the mixture showed a slight red-shift compared with that of monomer 1. In 3′-O-allyl-5′-O-acrolyl nucleic acid monomers 3 and 4, a similar CD variation phenomenon was also observed (Figure 4b). As demonstrated in Figure 4a,b, the different nucleobases (adenine and thymine) of these monomers would have disparate absorptions of left circularly polarized (LCP) and right circularly polarized (RCP) light, so that monomers 1 and 3 had a positive peak and a negative peak

while monomers 2 and 4 possessed only one negative peak.85−87 We have also measured the variable-temperature CD (VTCD) spectra of OONA-1, OONA-2, OONA-3, OANA-1, OANA-2, and OANA-3 in acetonitrile in a temperature range from 10 to 70 °C. As shown in Figure 4c, OONA-1 had a positive peak (ca. 277 nm) and a negative peak (ca. 248 nm) with zero crossing at ca. 261 nm; its analogue thyminefunctionalized OANA-1 polymer presented similar CD information (Figure 4f), which was close to the characteristics of the reported single-stranded DNA poly(deoxythymidylic acid) (poly(dT)) in the literature.88,89 As for adeninefunctionalized polymers, both OONA-2 (Figure 4d) and OANA-2 (Figure 4g) presented only a negative peak at around 262−265 nm and a zero-crossing point at 287−289 nm, which were also consistent with the CD data of single-stranded DNA poly(deoxyadenylic acid) (poly(dA)) reported in the literature.88,89 The CD spectra of A−T paired copolymers OONA3 (Figure 4e) and OANA-3 (Figure 4h) were similar to those of thymine-functionalized polymers, which indicated a possibly existing right-handed helical stacking.90,91 The temperature factor obviously affected the interactions of nucleobases, which could be reflected in their VT-CD signals. As shown in Figure 4c−h, the delta absorbance which was defined as the absorbance difference between LCP light and RCP light F


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Figure 6. TEM images of (a−d) OANA-1, (e−h) OANA-2, (i−l) OANA-3, and (m−p) the mixture of OANA-1 and OANA-2 with equal monomeric molar amount.

gradually decreased along with the increasing of temperature, which suggested that the interactions between nucleobases would become more intensive at lower temperatures and declined at higher temperatures.90,92,93 Transmission electron microscopy (TEM) was applied to study the self-assembly behaviors of these oligodeoxynucleosides with olefin bridges. Basically, the alkene-functionalized deoxynucleoside monomers and their corresponding polymers were dissolved in chloroform (60 mg/L); three drops of each prepared solution were cast on a copper mesh, which was ready for TEM observation after evaporation of solvents. The TEM images of monomers are presented in Figure S60; they all formed nanospheres. The regio-uncontrolled oligodeoxynucleosides OONA-1, OONA-2, and OONA-3 also exhibited spherical nanostructures as shown in Figure 5. The measured diameters of nanospheres of monomer 1 ranged from 211 to 483 nm (Figure S60a), which were much smaller than its corresponding OONA-1 polymer (ranging from 1075 to 1375 nm, Figure 5a,b). The same phenomena were also presented in monomer 2 as well as and complexes -1 and -2 (Figure S60b,c), which showed smaller average diameters than their corresponding OONA-2 and OONA-3 polymers (Figure 5c− f). We further used TEM (Figure 6 and Figure S61) and field emission scanning electron microscope (FESEM, Figure S76) techniques to study the self-assembly morphologies of three regio-defined oligodeoxynucleosides: OANA-1, OANA-2, and OANA-3. The obtained TEM images of OANA-1 (Figure 6a−

d), OANA-2 (Figure 6e−h), and OANA-3 (Figure 6i−l) all exhibited filamentous nanostructures. Some of the thread-like nanofibers exhibited helical structures which could be seen in the enlarged areas of Figure 6. In particular, as shown in Figure 6a−d, the possibly existing helical nanostructures could be observed on various locations, and the diameters of these helical nanofibers were in the range 6−34 nm. Furthermore, we also tried to mix two chloroform solutions containing OANA-1 and OANA-2 with equal monomeric molar amount and investigated the self-assembly morphologies of the resulting mixture which also showed thread-like nanowires as illustrated in Figure 6m−p. We have further studied the selfassembly behavior of these new oligonucleosides “in water”. In a typical experimental procedure, OANA-3 (20 mg) was dissolved in THF (0.5 mL), and then water (2 mL) was slowly added into this solution. THF was removed via dialysis to give an aqueous solution of OANA-3. The self-assembled images of OANA-3 were observed via TEM. The experimental results showed that it still self-assembled into filamentous nanostructures as presented in Figure S61. In addition, some 20 nm diameter OANA-2 filaments presented a fascinating double-helical structure which is shown in Figure 6e. Furthermore, OANA-3 (Figure 6j,l) and the mixture of OANA-1 and OANA-2 with equal monomeric molar amount (Figure 6m,n) also exhibited double-helical structures. Apparently, these double-helical structures were not induced by two single A−T paired polymer chains whose helix diameter should be no more than 3.0 nm, but formed by G


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several entangled filaments, which were barely observed in DNA molecules. Different from DNA, there were no electric repulsions in the polymeric backbones of these oligodeoxynucleoside analogues, which however provided the possibility of intertwining many oligodeoxynucleoside chains through hydrogen bonds. Interestingly, most of the thread-like nanofibers showed a helical multistrand entanglement. For example, two 34 nm diameter OANA-1 helical filaments were convolved into a 43 nm diameter double-helix filament (Figure 6a). As shown in Figure 6g,h, two 13 nm diameter OANA-2 filaments could be intertwined into a 20 nm diameter helical filament; one of these 13 nm diameter filaments was further unwound by two 7 nm diameter filaments (Figure 6h). OANA-3 could also show the entangled helical structure (Figure 6k) presented a 24 nm diameter double-helical filament which was actually twined by two 15 nm diameter filaments. Similar to those of OANA-1, OANA-2, and OANA-3, the filamentous nanostructures of the mixture of OANA-1 and OANA-2 with equal monomeric molar amount also showed entangled helixes. For example, Figure 6o illustrated a 9 nm diameter filament and a 15 nm diameter filament intertwined together to form a double-helical nanowire with a diameter of about 24 nm. These filamentous nanostructures of OANA-1, OANA-2, OANA-3, and the mixture of OANA-1 and OANA-2 with equal molar amount were significantly different from the spherical nanostructures of their corresponding monomers (Figure S60d−f) and were also distinct from the self-assembled nanospheres of OONA-1, OONA-2, and OONA-3 (Figure 5). Apparently, all the above monomers and polymers possessed hydrogen bonds; the only difference was the polymeric backbones. The molecular structures of regio-uncontrolled ADMET products OONA-1, OONA-2, and OONA-3 became tangled (Figure 1c), which induced disorganized arrangements of nucleobases and hydrogen bondings, so that the adjacent oligodeoxynucleoside chains were packed disorderly and wrapped up into spherical nanostructures. On the contrary, the regio-defined ADMET products OANA-1, OANA-2, and OANA-3 were synthesized in a highly ordered head-to-tail addition manner with high E-olefin selectivity, so that the adjacent oligodeoxynucleoside chains were perfectly matched and paired, resulting in DNA-like filamentous threads. In addition, the presence of hydrogen bonds inside filamentous OANA-1, OANA-2, and OANA-3 might cause these filaments to become entangled with each other to form double-helix structures with various diameters (Figure 6).

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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.macromol.8b02115. Instrumentation descriptions, starting materials, the detailed synthetic procedures and NMR spectra of monomers 1−4 and oligodeoxynuclesoides OONA-1, OONA-2, OONA-3, OANA-1, OANA-2, and OANA-3; UV spectra, FESEM and TEM images of monomers and polymers, and LC-QTOF-MS spectra of polymers (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Ying Sun: 0000-0002-1217-0547 Hong Yang: 0000-0003-4647-1388 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This research was supported by Jiangsu Provincial Natural Science Foundation of China (BK20170024), the Fundamental Research Funds for the Central Universities (2242017K3DN12), and the Priority Academic Program Development of Jiangsu Higher Education Institutions.

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REFERENCES

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CONCLUSIONS In conclusion, we applied the ADMET method to synthesize two series of oligodeoxynucleosides with olefin linkers. The 3′OH and 5′-OH groups of deoxythymidine and deoxyadenosine analogue monomers were functionalized with either two terminal allyl units or allyl and acryloyl units, respectively. The consequent ADMET approaches provided either regiouncontrolled oligodeoxynucleosides with poor E/Z selectivity or well-defined oligodeoxynucleosides built in a highly ordered head-to-tail addition manner with high E-selectivity. These two different macromolecular structures markedly influenced the self-assembly morphologies of the corresponding oligodeoxynucleosides, which exhibited spherical and filamentous helix nanostructures. We hope these findings will provide a new perspective for developing nucleobase-functionalized polymers and multifunctional nanomaterials. H


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