共查询到20条相似文献,搜索用时 0 毫秒
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Lydia Pouga Maria Mercedes Santoro Charlotte Charpentier Domenico Di Carlo Isabella Romeo Anna Artese Stefano Alcaro Andrea Antinori Marc Wirden Carlo Federico Perno Francesca Alessandra Ambrosio Vincent Calvez Diane Descamps Anne‐Genevive Marcelin Francesca Ceccherini‐Silberstein Sidonie Lambert‐Niclot 《Chemical biology & drug design》2019,93(1):50-59
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Sluis-Cremer N Hamamouch N San Félix A Velazquez S Balzarini J Camarasa MJ 《Journal of medicinal chemistry》2006,49(16):4834-4841
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P Wang B Gullen M G Newton Y C Cheng R F Schinazi C K Chu 《Journal of medicinal chemistry》1999,42(17):3390-3399
Asymmetric syntheses of L-carbocyclic 2',3'-didehydro-2',3'-dideoxy- and 2',3'-dideoxypyrimidine and purine nucleoside analogues were accomplished, and their anti-HIV and anti-HBV activities were evaluated. The key intermediate, (1S, 4R)-1-benzoyloxy-4-(tert-butoxymethyl)cyclopent-2-ene (7), was prepared by benzoylation of the alcohol 2, selective deprotection of the isopropylidene group of 3, followed by thermal elimination via cyclic ortho ester or deoxygenation via cyclic thionocarbonate. The target compounds were also synthesized by thermal elimination via cyclic ortho esters from protected nucleosides. It was found that L-carbocyclic 2',3'-didehydro-2',3'-dideoxyadenosine (34) exhibited potent anti-HBV activity (EC(50) = 0.9 microM) and moderate anti-HIV activity (EC(50) = 2.4 microM) in vitro without cytotoxicity up to 100 microM. 相似文献
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Synthesis and anti-HIV activity of carbocyclic 2',3'-didehydro-2',3'-dideoxy 2,6-disubstituted purine nucleosides 总被引:2,自引:0,他引:2
(+-)-cis-[4-[(2,5-Diamino-6-chloropyrimidinyl)amino]-2- cyclopentenyl]carbinol (5a) was synthesized from 2-amino-4,6-dichloropyrimidine and cis-4-(hydroxymethyl)cyclopentenylamine (2a) by subsequent preparation of the 5-[(4-chlorophenyl)azo] derivative of the resulting pyrimidine (3a) and reduction of the azo moiety with zinc and acetic acid. The carbocyclic analogue of 2',3'-didehydro-2',3'-dideoxy 2-amino-6-chloropurine (6a) and the corresponding 8-azapurine (9a) were prepared from 5a. The carbocyclic 2',3'-didehydro-2',3'-dideoxy analogues of guanine (7a) and 2,6-diaminopurine (8a), and 8-azaguanine (10a) and 8-aza-2,6-diaminopurine (11a) were prepared from 6a and 9a, respectively. The corresponding 2',3'-saturated series of 2-amino-6-substituted-purine carbocyclic nucleosides was prepared following the same scheme starting with cis-4-(hydroxymethyl)cyclopentylamine (2b). Carbocyclic 2',3'-didehydro-2',3'-dideoxyguanosine (carbovir, 7a) emerged as a potent and selective anti-HIV agent. Its hydrolytic stability and its ability to inhibit the infectivity and replication of HIV in T-cells at concentrations of approximately 200-400-fold below toxic concentrations make carbovir an excellent candidate for development as a potential antiretroviral agent. 相似文献
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K B Mullah T S Rao J Balzarini E De Clercq W G Bentrude 《Journal of medicinal chemistry》1992,35(15):2728-2735
The preparations and antiviral activities of a series (4-17) of potential prodrug forms of the antivirals 2',3'-didehydro-2',3'-dideoxyadenosine (D4A) and 2',3'-didehydro-2',3'-dideoxycytosine (D4C) are reported. The 5'-phenyl- and 5'-methylphosphonates (4, 6, 8, and 10) and their phosphonothionate congeners (5, 7, 9, and 11), with the exception of 10, were inactive in vitro against HIV-1 and HIV-2. However, the 5'-phenyl, 5'-methyl, and 5'-(3'-thymidyl) phosphate diesters (12-17) demonstrated inhibition of the cytopathic effect of HIV-1 and HIV-2 (EC50 approximately 1-60 microM) and cytotoxicities (CC50 approximately 35-200 microM) at concentration levels comparable to those of their parent compounds, D4A and D4C. This strongly suggests that the diesters are hydrolyzed to the nucleosides D4A and D4C and/or their 5'-monophosphates. The facile hydrolysis of 12 and 13 to these products was demonstrated in a medium containing 10% fetal calf serum. The molecules can serve as ready prodrug sources of the free nucleosides and their 5'-monophosphates. Evidently, the phosphonates and phosphonothionates are not similarly cleaved, nor are they phosphorylated to form antivirally active or cytotoxic products. The importance of intracellular formation of these products in the activation of 12-17 is less clear. Potential prodrugs 4-17 are all stable in aqueous solution for hours with the exception of 14. Conjugates 4-17 showed no activity against a series of DNA and RNA viruses. 相似文献
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Núbia Boechat Warner B. Kover Mônica M. Bastos Nelilma C. Romeiro Alessa S. C. Silva Fernanda C. Santos Alessandra L. Valverde Maria L. G. Azevedo Wagner Wollinger Thiago M. L. Souza Silmara Lúcia Oliveira de Souza Izabel Christina P. P. de Frugulhetti 《Medicinal chemistry research》2007,15(9):492-510
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Chong Y Choo H Choi Y Mathew J Schinazi RF Chu CK 《Journal of medicinal chemistry》2002,45(22):4888-4898
As 2',3'-didehydro-2',3'-dideoxy-2'-fluoronucleosides have exhibited interesting antiviral effects against HIV-1 as well as HBV, it is of interest to synthesize the isosterically substituted 4'-thionucleosides in which 4'-oxygen is replaced by a sulfur atom. To study structure-activity relationships, various pyrimidine and purine nucleosides were synthesized from the key intermediate (2R,4S)-1-O-acetyl-5-O-(tert-butyldiphenylsilyl)-2,3-dideoxy-2-fluoro-2-phenylselenyl-4-thio-beta-D-ribofuranoside 8, which was prepared from the 2,3-O-isopropylidene-D-glyceraldehyde 1 in 13 steps. The antiviral activity of the synthesized compounds were evaluated against HIV-1 in human peripheral blood mononuclear (PBM) cells, among which cytidine 17, 5-fluorocytidine 18, adenosine 24, and 2-fluoroadenosine 32 showed moderate to potent anti-HIV activities (EC(50) 1.3, 11.6, 8.1, and 1.2 microM, respectively). It is noteworthy that 2-fluoroadenosine analogue 32 showed antiviral potency as well as high cytotoxicity (IC(50) 1.5, 1.1, and 7.6 microM for PBM, CEM, and Vero, respectively) whereas no other compound showed cytotoxicity up to 100 microM. The cytidine 17 and 5-fluorocytidine 18 analogues showed significantly decreased antiviral activity against the clinically important lamivudine-resistant variants (HIV-1(M184V)), whereas the corresponding D-2'-Fd4 nucleosides showed limited cross-resistance. Molecular modeling studies demonstrated that the larger van der Waals radius as well as the close proximity to Met184 of the 4'-sulfur atom of D-2'-F-4'-Sd4C (17) may be the reasons for the decreased antiviral potency of synthesized 4'-thio nucleosides against the lamivudine-resistant variants (HIV-1(M184V)). 相似文献
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J Balzarini G J Kang M Dalal P Herdewijn E De Clercq S Broder D G Johns 《Molecular pharmacology》1987,32(1):162-167
A series of 2',3'-didehydro-2',3'-dideoxyribonucleosides (ddeNs) [i.e., 2',3'-dideoxythymidinene (ddeThd), 2',3'-dideoxyuridinene (ddeUrd), 2',3'-dideoxycytidinene (ddeCyd), and 2',3'-dideoxyadenosinene (ddeAdo)] has been synthesized and the individual members compared in terms of their in vitro antiviral, antimetabolic, and cytostatic properties to their 2',3'-saturated counterparts (ddNs) (i.e., ddThd, ddUrd, ddCyd and ddAdo). All ddeNs except ddeUrd are potent and/or selective inhibitors of human immunodeficiency virus (HIV) in vitro, ddeCyd being the most potent (MIC50, 0.30 microM). The inhibitory effect of ddeCyd on ATH8 cell proliferation and HIV-induced cytopathogenicity is comparable to that of ddCyd. ddeThd is a more potent anti-HIV agent than ddThd (MIC50, 3.4 microM and 84 microM, respectively), but also more cytostatic (ID50, 172 microM and greater than 2000 microM, respectively). However, its in vitro chemotherapeutic index is higher than that of 3'-azido-2',3'-dideoxythymidine, a drug which has recently proven effective in the treatment of acquired immunodeficiency syndrome. ddeAdo has a weaker anti-HIV and a stronger cytostatic effect than ddAdo. Neither ddeUrd nor ddUrd shows significant anti-retroviral activity at 500 microM. In contrast to their anti-retroviral activity, both ddNs and ddeNs lack any appreciable inhibitory activity against a series of nononcogenic RNA and DNA viruses, pointing to their selectivity as anti-retroviral agents. All ddeNs show a progressive loss of anti-retroviral effect upon prolonged incubation with virus-infected cells. This phenomenon is most likely due to the chemical instability of these compounds, and not to a preferential enzymatic phosphorolytic cleavage of the ddeNs. Evidence is presented that ddeCyd and ddCyd, and ddeThd and ddThd are phosphorylated by cellular dCyd kinase and dThd kinase, respectively. However, the Ki values as alternate substrate inhibitors for their respective kinases are high (greater than 500 microM), indicating poor substrate activity and, thus, poor anabolism in ATH8 cells. 相似文献
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