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1.
Inspection of Maruzen models and force‐field calculations suggest that oligonucleotide analogues integrating backbone and bases (ONIBs) with an aminomethylene linker form similar cyclic duplexes as the analogous oxymethylene linked dinucleosides. The self‐complementary adenosine‐ and uridine‐derived aminomethylene‐linked A*[n ]U dinucleosides 15 – 17 were prepared by an aza‐Wittig reaction of the aldehyde 10 with an iminophosphorane derived from azide 6 . The sequence‐isomeric U*[n ]A dinucleosides 18 – 20 were similarly prepared from aldehyde 3 and azide 12 . The N‐ethylamine 5 , the acetamides 7 and 14 , and the amine 13 were prepared as references for the conformational analysis of the dinucleosides. In contradistinction to the results of calculations, the N‐ethylamine 5 exists as intramolecularly H‐bonded hydroxyimino tautomer. The association in CDCl3 of these dinucleosides was studied by 1H‐NMR and CD spectroscopy. The A*[n ]U dinucleosides 16 and 17 associate more strongly than the sequence isomers 19 and 20 ; the cyclic duplexes of 16 form preferentially Watson–Crick‐type base pairs, while 17, 19 , and 20 show both Watson–Crick‐ and Hoogsteen‐type base pairing. The cyclic duplexes of the aminomethylene‐linked dinucleosides prefer a gg‐orientation of the linker. No evidence was found for an intramolecular H‐bond of the aminomethylene group. The CD spectra of 16 and 17 show a strong, those of 19 a weak, and those of 20 almost no temperature dependence. 相似文献
2.
The self‐complementary aminomethylene‐linked A*[n] U* dinucleosides 23 – 26 were prepared by reductive coupling of aldehyde 10 and azide 8 . The U*[n] A* sequence isomers 19 – 21 were similarly prepared from aldehyde 14 and azide 3 . The substituents at C(6/I) of 23 – 26 and at C(8/I) of 19 – 21 strongly favour the syn‐conformation. The A*[n] U* dinucleoside 23 associates more strongly than the sequence‐isomeric U*[n] A* dinucleoside 19 . The A*[n] U* dinucleosides 23 and 24 associate more strongly than the analogues devoid of the substituent at C(6/I), while the U*[n] A* dinucleoside 19 associates less strongly than the analogue devoid of the substituent at C(8/I). While 23 and 24 form cyclic duplexes mostly by Watson–Crick‐type base pairing, 25 only forms linear associates. The U*[n] A* dinucleoside 19 forms mostly linear duplexes and higher associates, and 21 forms cyclic duplexes showing both Watson–Crick‐ and Hoogsteen‐type base pairing. The cyclic duplexes of the aminomethylene‐linked dinucleosides show both the gg‐ and gt‐orientation of the linker, with the gg‐orientation being preferred. 相似文献
3.
The ability of A*[s ]U dinucleosides to gel organic solvents and water is modulated by changing the nature of the substituents at O C(2′) and O C(3′), as evidenced by comparing the gelation of the dinucleosides 7 – 9 and the properties of the gels. A mere extension of the hydrophobic moiety, by replacing the isopropylidene groups of 2 by cyclohexylidene groups, as in 7 , has a small effect, while changing the conformation of the ribose ring and reducing the size of the hydrophobic moiety, as in 8 , has a strong effect on the scope of gelation, the minimum gelation concentration, as low as 0.07% for pentanol and decanol, and the properties of the gel. The fully deprotected dinucleoside 9 gels water at a minimal gelation concentration of 0.6%. A TEM of the corresponding xerogel shows the formation of fibers with a diameter of ca. 30 to 90 nm. 相似文献
4.
5.
The self‐complementary tetrameric propargyl triols 8, 14, 18 , and 21 were synthesized to investigate the duplex formation of self‐complementary, ethynylene‐linked UUAA, AAUU, UAUA, and AUAU analogues with integrated bases and backbone (ONIBs). The linear synthesis is based on repetitive Sonogashira couplings and C‐desilylations (34–72% yield), starting from the monomeric propargyl alcohols 9 and 15 and the iodinated nucleosides 3, 7, 11 , and 13 . Strongly persistent intramolecular H‐bonds from the propargylic OH groups to N(3) of the adenosine units prevent the gg‐type orientation of the ethynyl groups at C(5′). As such, an orientation is required for the formation of cyclic duplexes, this H‐bond prevents the formation of duplexes connected by all four base pairs. However, the central units of the UAUA and AAUU analogues 18 and 14 associate in CDCl3/(D6)DMSO 10 : 1 to form a cyclic duplex characterized by reverse Hoogsteen base pairing. The UUAA tetramer 8 forms a cyclic UU homoduplex, while the AUAU tetramer 21 forms only linear associates. Duplex formation of the O‐silylated UUAA and AAUU tetramers is no longer prevented. The self‐complementary UUAA tetramer 22 forms Watson–Crick‐ and Hoogsteen‐type base‐paired cyclic duplexes more readily than the sequence‐isomeric AAUU tetramer 23 , further illustrating the sequence selectivity of duplex formation. 相似文献
6.
The self‐complementary, ethylene‐linked U*[ca]A(*) dinucleotide analogues 8, 10, 12, 14, 16 , and 18 , and the sequence‐isomeric A*[ca]U(*) analogues 20, 22, 24, 26, 28 , and 30 were obtained by Pd/C‐catalyzed hydrogenation of the corresponding, known ethynylene‐linked dimers. The association of the ethylene‐linked dimers was investigated by NMR and CD spectroscopy. The U*[ca]A(*) dimers form linear duplexes and higher associates (K between 29 and 114M ?1). The A*[ca]U(*) dimers, while associating more strongly (K between 88 and 345M ?1), lead mostly to linear duplexes and higher associates; they form only minor amounts of cyclic duplexes. The enthalpy–entropy compensation characterizing the association of the U*[cx]A(*) and A*[cx]U(*) dimers (x=y, e, and a) is discussed. 相似文献
7.
Nicolas Bogliotti Anne Ritter Séverine Hebbe Andrea Vasella 《Helvetica chimica acta》2008,91(11):2181-2202
The A*[s]U(*) dinucleosides 1 and 2 form thermoreversible gels in organic solvents. The basis of the gelation is the formation of linear aggregates by base pairing following desolvation of the nucleobases. This is evidenced by the absence of gel formation by the C(6)‐deaminated analogue 3 of 1 , the correlation of gelation with the anti‐conformation, as preferred for 1 , and the temperature‐, concentration‐, and time‐dependent CD spectra. The gels were also characterized by the minimum gelation concentration, the gel–sol transition (melting) temperature, and rheological properties. 相似文献
8.
The formation of cyclic duplexes (pairing) of known oxymethylene‐linked self‐complementary U*[o]A(*) dinucleosides contrasts with the absence of pairing of the ethylene‐linked U*[ca]A(*) analogues. The origin of this difference, and the expected association of U*[x]A(*) and A*[x]U(*) dinucleosides with x=CH2, O, or S was analysed. According to this analysis, pairing occurs via constitutionally isomeric Watson–Crick, reverse Watson–Crick, Hoogsteen, or reverse Hoogsteen H‐bonded linear duplexes. Each one of them may give rise to three diastereoisomeric cyclic duplexes, and each one of them can adopt three main conformations. The relative stability of all conformers with x=CH2, O, or S were analysed. U*[x]A(*) dinucleosides with x=CH2 do not form stable cyclic duplexes, dinucleosides with x=O may form cyclic duplexes with a gg‐conformation about the C(4′)? C(5′) bond, and dinucleosides with x=S may form cyclic duplexes with a gt‐conformation about this bond. The temperature dependence of the chemical shift of H? N(3) of the self‐complementary, oxymethylene‐linked U*[o]A(*) dinucleosides 1 – 6 in CDCl3 in the concentration range of 0.4–50 mM evidences equilibria between the monoplex, mainly linear duplexes, and higher associates for 3 , between the monoplex and cyclic duplexes for 6 , and between the monoplex, linear, and cyclic duplexes as well as higher associates for 1, 2, 4 , and 5 . The self‐complementary, thiomethylene‐linked U*[s]A(*) dinucleosides 27 – 32 and the sequence isomeric A*[s]U(*) analogues 33 – 38 were prepared by S‐alkylation of the 6‐(mesyloxymethyl)uridine 12 and the 8‐(bromomethyl)adenosine 22 . The required thiolates were prepared in situ from the C(5′)‐acetylthio derivatives 9, 15, 19 , and 25 . The association in CHCl3 of the thiomethylene‐linked dinucleoside analogues was studied by 1H‐NMR and CD spectroscopy, and by vapour‐pressure osmometric determination of the apparent molecular mass. The U*[s]A(*) alcohols 28, 30 , and 31 form cyclic duplexes connected by Watson–Crick H‐bonds, while the fully protected dimers 27 and 29 form mainly linear duplexes and higher associates. The diol 32 forms mainly cyclic duplexes in solution and corrugated ribbons in the solid state. The nucleobases of crystalline 32 form reverse Hoogsteen H‐bonds, and the resulting ribbons are cross‐linked by H‐bonds between HOCH2? C(8/I) and N(3/I). Among the A*[s]U(*) dimers, only the C(8/I)‐hydroxymethylated 37 forms (mainly) a cyclic duplex, characterized by reverse Hoogsteen base pairing. The dimers 34 – 36 form mainly linear duplexes and higher associates. Dimers 34 and particularly 38 gelate CHCl3. Temperature‐dependent CD spectra of 28, 30, 31 , and 37 evidence π‐stacking in the cyclic duplexes. Base stacking in the particularly strongly associating diol 32 in CHCl3 solution is evidenced by a melting temperature of ca. 2°. 相似文献
9.
The self‐complementary UA and AU dinucleotide analogues 41 – 45, 47, 48 , and 51 – 60 were prepared by Sonogashira coupling of 6‐iodouridines with C(5′)‐ethynylated adenosines and of 8‐iodoadenosines with C(5′)‐ethynylated uridines. The dinucleotide analogues associate in CDCl3 solution. The C(6/I)‐unsubstituted AU dimers 51 and 54 prefer an anti‐oriented uracilyl group and form stretched linear duplexes. The UA propargyl alcohols 41 and 43 – 45 possess a persistent intramolecular O(5′/I)? H???N(3/I) H‐bond and, thus, a syn‐oriented adeninyl and a gt‐ or tg‐oriented ethynyl moiety; they form corrugated linear duplexes. All other dimers form cyclic duplexes characterized by syn‐oriented nucleobases. The preferred orientation of the ethynyl moiety (the C(4′),C(5′) torsion angle) defines a conformation between gg and one where the ethynyl group eclipses O(4′/I). The UA dimers 42, 47 , and 48 form Watson–Crick H‐bonds, the AU dimers 56 and 58 – 60 H‐bonds of the Watson–Crick‐type, the AU dimers 53 and 55 reverse‐Hoogsteen, and 57 Hoogsteen H‐bonds. The pairing mode depends on the substituent of C(5′/I) (H, OSiiPr3; OH) and on the H‐bonds of HO? C(5′/I) in the AU dimers. Association constants were derived from the concentration‐dependent chemical shift for HN(3) of the uracilyl moiety; they vary from 45–104 M ?1 for linear duplexes to 197–2307 M ?1 for cyclic duplexes. The thermodynamic parameters were determined by van't Hoff analysis of the temperature‐dependence of the (concentration‐dependent) chemical shift for HN(3) of the uracilyl moiety. Neglecting stacking energies, one finds an average energy of 3.5–4.0 kcal/mol per intermolecular H‐bond. Base stacking is evidenced by the temperature‐dependent CD spectra. The crystal structure of 54 shows two antiparallel chains of dimers connected by Watson‐Crick H‐bonds. The chains are bridged by a strong H‐bond between the propargylic OH and O?C(4) and by weak reverse A ? A Hoogsteen H‐bonds. 相似文献
10.
The protected G*[s ]C*[s ]U*[s ]A*[s ]U*[s ]A*[s ]G*[s ]C* octanucleoside 24 was prepared by S‐alkylation of the thiolate derived from tetranucleoside 23 with the methanesulfonate 22 , and transformed to the silylated and isopropylidenated 25 , and further into the fully deprotected octanucleoside 26 . Compound 22 was derived from the methoxytrityl‐protected tetranucleoside 21 , and 21 was obtained by S‐alkylation of the thiolate derived from the dinucleoside 19 with methanesulfonate 17 derived from 16 by detritylation and mesylation. Similarly, tetranucleoside 23 resulted from S‐alkylation of the thiolate derived from 18 with the methanesulfonate 20 derived from 19 . Dinucleosides 16 and 18 resulted from S‐alkylation of the thiolate derived from the known cytidine‐derived thioacetate 15 with the C(8)‐substituted guanosine‐derived methanesulfonates 12 and 14 , respectively, that were synthesized from the protected precursors 4 and 7 by formylation, reduction, protection, and mesylation. The structures of the duplexes of 25 and 26 were calculated using AMBER* modelling and based on the known structure of the core tetranucleoside U*[s ]A*[s ]U*[s ]A*. The former shows a helix with a bent helix axis and strong buckle and propeller twists, whereas the latter is a regular, right‐handed, and apparently strain‐free helix. In agreement with modelling, the silylated and isopropylidenated octanucleoside 25 in (CDCl2)2 solution led to a mixture of associated species possessing at most four Watson? Crick base pairs, while the fully deprotected octanucleoside 26 in aqueous medium forms a duplex, as evidenced by a decreasing CD absorption upon increasing the temperature and by a UV‐melting curve with a melting temperature of ca. 10° below the one of the corresponding RNA octamer, indicating cooperativity between base pairing and base‐pair stacking. 相似文献
11.
The protected hydrazide‐linked uracil‐ and adenine‐derived tetranucleoside analogues 17, 19 , and 21 were synthesized in solution by coupling the dimeric hydrazines 6 and 10 with the carboxylic acids 7, 11 , and 16 . These hydrazines and acids were obtained by partially deprotecting the hydrazines 5, 9 , and 15 , and these were prepared by coupling the hydrazines 3 and 14 with the carboxylic acids 4 and 8 . The crystal structure analysis of the fully protected UU dimer 5 showed the formation of an antiparallel cyclic duplex with the uracil units H‐bonded via H? N(3) and O?C(2). Stacking interactions were observed between the uracil units with a buckle twist of 30.9°, and between the uracil unit II and the fluoren‐9‐yl group of Fmoc (=9H‐fluoren‐9‐yl)methoxycarbonyl). The hydrazide H? N(3′) and the C?O group of Fmoc form an intramolecular H‐bond. The uracil‐ and adenine‐derived, water‐soluble hydrazide‐linked self‐complementary octamers 23 – 32 and the non‐self‐complementary uracil derived decamer 33 were obtained by coupling the carboxylic acids 4 and 8 on a solid support. 1H‐NMR Analysis in CDCl3, mixtures of CDCl3 and (D6)DMSO, and (D8)THF showed that the partially deprotected dimers 5, 6, 12 , and 13 form weakly associated linear duplexes. The partially deprotected tetramers 17 and 18 do not associate. The hydrazide‐linked octamers 23 – 32 do not stack in aqueous solution, and the non‐self‐complementary decamer 33 does not stack with the complementary strands of DNA 43 and RNA 42 . The Cbz‐protected amide‐linked octamers 51 – 56 derived from uracil, adenine, cytosine, and guanine were obtained as the main products by solid‐phase synthesis from the carboxylic acids 46 – 49 . The fully deprotected amide‐linked octamers proved insoluble, and could neither be purified nor analysed. 相似文献
12.
The self‐complementary (Z)‐configured U*[ce]A(*) dinucleotide analogues 6, 8, 10, 12, 14 , and 16 , and the A*[ce]U(*) dimers 19, 21, 23, 25, 27 , and 29 were prepared by partial hydrogenation of the corresponding ethynylene linked dimers. Photolysis of 14 led to the (E)‐alkene 17 . These dinucleotide analogues associate in CDCl3 solution, as evidenced by NMR and CD spectroscopy. The thermodynamic parameters of the duplexation were determined by van't Hoff analysis. The (Z)‐configured U*[ce]A(*) dimers 14 and 16 form cyclic duplexes connected by Watson–Crick H‐bonds, the (E)‐configured U*[ce]A dimer 17 forms linear duplexes, and the U*[ce]A(*) allyl alcohols 6, 8, 10 , and 12 form mixtures of linear and cyclic duplexes. The C(6/I)‐unsubstituted A*[ce]U allyl alcohols 19 and 23 form linear duplexes, whereas the C(6/I)‐substituted A*[ce]U* allyl alcohols 21 and 25 , and the C(5′/I)‐deoxy A*[ce]U(*) dimers 27 and 29 also form minor amounts of cyclic duplexes. The influence of intra‐ and intermolecular H‐bonding of the allyl alcohols and the influence of the base sequence upon the formation of cyclic duplexes are discussed. 相似文献
13.
14.
15.
Bruno Bernet Zeena Johar Anne Ritter Bernhard Jaun Andrea Vasella 《Helvetica chimica acta》2009,92(12):2596-2630
The tritylated and silylated self‐complementary A*[s]U*[s]A*[s]U* and U*[s]A*[s]U*[s]A* tetramers 18 and 24 , linked by thiomethylene groups (abbreviated as [s]) between a nucleobase and C(5′) of the neighbouring nucleoside unit were prepared by a linear synthesis based on S‐alkylation of 5′‐thionucleosides by 6‐(chloromethyl)uridines, 7 or 10 , or 8‐(chloromethyl)adenosines, 12 or 15 . The tetramers 18 and 24 were detritylated to the monoalcohols 19 and 25 , and these were desilylated to the diols 20 and 26 , respectively. The association of the tetramers 18 – 21 and 24 – 26 in CDCl3 or in CDCl3/(D6)DMSO 95 : 5 was investigated by the concentration dependence of the chemical shifts for H? N(3) or H2N? C(6). The formation of cyclic duplexes connected by four base pairs is favoured by the presence of one and especially of two OH groups. The diol 20 with the AUAU sequence prefers reverse‐Hoogsteen, and diol 26 with the UAUA sequence Watson–Crick base pairing. The structure of the cyclic duplex of 26 in CDCl3 at 2° was derived by a combination of AMBER* modeling and simulated annealing with NMR‐derived distance and torsion‐angle restraints resulting in a Watson–Crick base‐paired right‐handed antiparallel helix showing large roll angles, especially between the centre base pairs, leading to a bent helix axis. 相似文献
16.
Martina Schulze‐Adams David Touboul Bruno Bernet Andrea Vasella 《Helvetica chimica acta》2014,97(8):1037-1054
The self‐complementary guanosine‐ and cytidine‐derived aminomethylene‐linked C*[n ]G dinucleoside 9 was synthesized by reductive amination of aldehyde 3 with an iminophosphorane derived from azide 7 . Deacylation of 9 gave the isopropylidene‐protected dinucleoside 10 . The sequence‐isomeric G*[n ]C dinucleoside 11 was similarly prepared from aldehyde 8 and azide 5 , and deacylated to 12 . The association of 10 and 12 in CHCl3 or in CHCl3/DMSO mixtures, and the structure of the associates were studied by 1H‐NMR, ESI‐MS, CD, and vapor pressure osmometry (VPO). Broad 1H‐NMR signals of dinucleosides 10 and 12 evidence an equilibrium between duplexes and quadruplexes (Hoogsteen base pairing between the Watson? Crick base‐paired duplexes). The quadruplex dominates for the G*[n ]C dinucleoside 12 between ?50° and room temperature. The sequence‐isomeric C*[n ]G 10 forms mostly only a cyclic duplex in CDCl3 and in CDCl3/(D6)DMSO 9 : 1. 相似文献
17.
The thiomethylene‐linked U*[s]U(*) dimers 9 – 14 were synthesized by substitution of the 6‐[(mesyloxy)methyl]uridine 6 by the thiolate derived from the uridine‐5′‐thioacetates 7 and 8 followed by O‐deprotection. Similarly, the thiomethylene‐linked A*[s]A(*) dimers 9 – 14 were obtained from the 8‐(bromomethyl)adenosine 15 and the adenosine‐5′‐thioacetates 16 and 17 . The concentration dependence of both H? N(3) of the U*[s]U(*) dimers 9 – 14 evidences the formation of linear and cyclic duplexes, and of linear higher associates, C(8 or 6)CH2OH and/or C(5′/II)OH groups favouring the formation of cyclic duplexes. The concentration dependence of the chemical shift for both H2N? C(6) of the A*[s]A(*) dimers 18 – 23 evidences the formation of mainly linear associates. The heteroassociation of U*[s]U(*) to A*[s]A(*) dimers is stronger than the homoassociation of U*[s]U(*) dimers, as evidenced by diluting equimolar mixtures of 11 / 20 and 13 / 22 . A 1 : 1 stoichiometry of the heteroassociation is evidenced by a Job's plot for 11 / 20 , and by mole ratio plots for 9 / 18, 10 / 19, 12 / 21, 13 / 22 , and 14 / 23 . 相似文献
18.
Martina Schulze‐Adams Bruno Bernet David Touboul Daniel Egli Lorenz Herdeis Andrea Vasella 《Helvetica chimica acta》2014,97(9):1244-1268
The G[s ]G dinucleoside 6 and the G[s ]G* dinucleoside 8 were prepared by alkylation of the guanosine thiols derived from 2 and 5 , respectively, by the C(8)‐chloromethylated guanosine 4 that was obtained from alcohol 3 . Dinucleosides 6 and 8 were deacylated to 7 and 9 , and fully deprotected to 10 and 11 , respectively. The G[n ]G dinucleoside 16 was obtained by reductive amination of aldehyde 13 with an iminophosphorane derived from azide 14 and deprotection of the resulting dimer 15 . In the solid state of 6 , and in a solution of 6 and 8 in CDCl3, H? N(1/I) and H? N(1/II) are engaged in intramolecular H‐bonds to the C?O of the isobutyryl protecting groups, and HN of the isobutyryl group of unit I forms an interresidue, intramolecular H‐bond to N(7/II), leading to a syn orientation of the nucleobase at unit I, to a tg orientation of the sulfanyl moiety, and to an orthogonal orientation of the nucleobases, preventing any base pairing. The silylated and isopropylidenated dinucleosides 7 and 9 are present in DMSO solution as solvated monoplexes. Broad 1H‐NMR signals of the nucleosides 7 and 16 in CHCl3 solution evidence equilibrating G‐quadruplexes. The quadruplex formation of 7 and 16 was established by 1H‐NMR spectroscopy (only of 16 ), vapour pressure osmometry, mass spectrometry, and CD spectroscopy. The C(6(I))‐hydroxymethylated analogue 9 in CDCl3 and the fully deprotected dinucleosides 10 and 11 in H2O form only weakly π? π stacked associates, but no G‐quadruplexes, as evidenced by CD spectroscopy. 相似文献
19.