Mei-Zhen Luo

Synthesis of several pyrimidine l-nucleoside analogues as potential antiviral agents

Abstract β- l -5-Iodo-2′-deoxyuridine (β- l -IUdR, 7) and 1-[(β- l - arabinofuranosyl )-E-5-(2- bromovinyl)]uracil (β- l -BV-ara-U, 10) have been synthesized via a multi-step synthesis from l -arabinose. 2′,3′-Dideoxy-β- l -5-azacytidine (18), 2′,3′-dideoxy-β- l -2-thiocytidine (20) and their respective α-anomers, compounds 19 and 21, also were synthesized by direct coupling of 1-O- acetyl -5-O-(tert- butyldimethylsilyl )-2,3-dideoxy- l - ribofuranose (13) with the corresponding silylated bases, in the presence of EtAlCl2 in CH2Cl2, followed by separation of the α- and β-isomers and deblocking of the 5′-protecting groups. In addition, 2′,3′-dideoxy-β- l -5-fluorocytidine (34), a potent anti-HIV and anti-HBV agent, was synthesized by an alternative methodology from 2′,3′-dideoxy-β- l -5-fluorouridine (31) via a 4-triazolylpyrimidinone intermediate. These l -nucleoside analogues were tested in vitro against HIV, HBV, HSV-1, and HSV-2. Among these compounds, 2′,3′-dideoxy-β- l -5-azacytidine (18) was found to show significant activity against HBV in vitro at approximately the same level as 2′,3′-dideoxy-β- d -cytidine (ddC), which is a known potent anti-HBV agent.

Synthesis and biological evaluation of l- and d-configuration 1,3-dioxolane 5-azacytosine and 6-azathymine nucleosides

Novel L- and D-configuration dioxolane 5-azacytosine and 6-azathymine nucleosides have been synthesized and evaluated for biological activity. (-)-(2S,4S)-1-[2-(Hydroxymethyl)-1,3-dioxolan-4-yl]-5-azacytosine (6) showed significant activity against HBV, whereas the D-configuration analogue (14) has been found to exhibit potent anti-HIV activity.

4-nitrobenzyloxycarbonyl derivatives of O(6)-benzylguanine as hypoxia-activated prodrug inhibitors of O(6)-alkylguanine-DNA alkyltransferase (AGT), which produces resistance to agents targeting the O-6 position of DNA guanine.

A series of 4-nitrobenzyloxycarbonyl prodrug derivatives of O(6)-benzylguanine (O(6)-BG), conceived as prodrugs of O(6)-BG, an inhibitor of the resistance protein O(6)-alkylguanine-DNA alkyltransferase (AGT), were synthesized and evaluated for their ability to undergo bioreductive activation by reductase enzymes under oxygen deficiency. Three agents of this class, 4-nitrobenzyl (6-(benzyloxy)-9H-purin-2-yl)carbamate (1) and its monomethyl (2) and gem-dimethyl analogues (3), were tested for activation by reductase enzyme systems under oxygen deficient conditions. Compound 3, the most water-soluble of these agents, gave the highest yield of O(6)-BG following reduction of the nitro group trigger. Compound 3 was also evaluated for its ability to sensitize 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)-2-[(methylamino)carbonyl]hydrazine (laromustine)-resistant DU145 human prostate carcinoma cells, which express high levels of AGT, to the cytotoxic effects of this agent under normoxic and oxygen deficient conditions. While 3 had little or no effect on laromustine cytotoxicity under aerobic conditions, significant enhancement occurred under oxygen deficiency, providing evidence for the preferential release of the AGT inhibitor O(6)-BG under hypoxia.

SYNTHESIS OF HALOGEN-SUBSTITUTED 3-DEAZAADENOSINE AND 3-DEAZAGUANOSINE ANALOGUES AS POTENTIAL ANTITUMOR/ANTIVIRAL AGENTS

Various 2-halogen-substituted analogues (38, 39, 43 and 44), 3-halogen- substituted analogues (51 and 52), and 2′, 3′-dihalogen-substituted analogues (57–60) of 3-deazaadenosine and 3-halogen-substituted analogues (61 and 62) of 3-deazaguanosine have been synthesized as potential anticancer and/or antiviral agents. Among these compounds, 3-deaza-3-bromoguanosine (62) showed significant cytotoxicity against L1210, P388, CCRF-CEM and B16F10 cell lines in vitro, producing IC50 values of 3, 7, 9 and 7,μM, respectively. Several 3-deazaadenosine analogues (38, 51, 57 and 59) showed moderate to weak activity against hepatitis B virus. †Deceased.

A stereospecific synthesis of 2′,3′-dideoxy-β-l-cytidine (β-l-ddC), a potent inhibitor against human hepatitis B virus (HBV) and human immunodeficiency virus (HIV)

Abstract 2′,3′-Dideoxy-β- l -cytidine (β- l -ddC), a potent inhibitor against human hepatitis B virus (HBV) and human immunodeficiency virus (HIV), has been stereospecifically synthesized from l -arabinose in 9 steps.

SYNTHESIS OF A SERIES OF PURINE 2',3'-DIDEOXY-L-NUCLEOSIDE ANALOGUES AS POTENTIAL ANTIVIRAL AGENTS

Abstract Various 2′,3′-dideoxy-L-nucleoside analogues, 6-amino-9-(2,3-dideoxy-β-L-ribofuranosyl) purine (19), 2-chloro-6-amino-9-(2,3-dideoxy-β-L-ribofuranosyl)-purine (20), 2-chloro-6-amino-9-(2,3-dideoxy-4-thio-β-L-ribofuranosyl) purine (21), 2,6-diamino-9-(2,3-dideoxy-β-L-ribofuranosyl) purine (26), 2,6-diamino-9-(2,3-dideoxy-β-thio-β-L-ribofuranosyl)-purine (27), 2-amino-6-chloro-9-(2,3-dideoxy-β-L-ribofuranosyl) purine (28), 6-chloro-9-(2,3-dideoxy-4-thio-β-L-ribofuranosyl) purine (29), and 6-amino-9-(2,3-dideoxy-4-thio-β-L-ribofuran-osyl) purine (30) have been synthesized by coupling of the sodium salt of 2-amino-6-chloropurine (1), 6-chloropurine (2), and 2,6-dichloropurine (3) with 1-O-acetyl-5-O-(tert-butyldimethylsilyl)-2,3-dideoxy-L-ribofuranose (4) or 1-O-acetyl-5-O-(tert-butyldimethylsilyl)-2,3-dideoxy-4-thio-L-ribofuranose (5) in anhydrous MeCN in the presence of either EtAlCl2 or Et2AlCl followed by separation of the α/β-anomers and deprotection of the blocking groups. However, the synthesi...

Synthesis and biological evaluation of 2- and 7-substituted 9-deazaadenosine analogues.

A series of 2-halogen and 7-alkyl substituted analogues of 9-deazaadenosine and 2′-deoxy-9-deazaadenosine was synthesized by new efficient methodology involving transformation of corresponding 9-deazaguanosine and 2′-deoxyguanosine, which in turn were synthesized by direct C-glycosylation of 1-benzyl-9-deazaguanine with 1-O -acetyl-2,3,5-tri-O -benzoyl-d-ribofuranose and methyl 2-deoxy-3,5-di-O -(p -toluoyl)-d-ribofuranoside, respectively. Deoxychlorination of C6 and diazotization/chloro- or fluoro-dediazoniation of the sugar-protected 9-deazaguanosine, followed by selective ammonolysis at C6 and deprotection of the sugar moiety, gave 2-chloro- and 2-fluoro-9-deazaadenosine (6 and 9). Substitution of the 7-position of the dihalogen-intermediate with alkyl groups, followed by ammonolysis and deprotection, provided 2-chloro-7-alkyl-9-deazaadenosines (13a–e) and 2-fluoro-7-benzyl-9-deazaadenosine (13f). Catalytic hydrogenation of 13a–e gave 7-alkyl-9-deazaadenosines 14a–e. Similarly, 2-chloro-2′-deoxy-9-deazaadenosine (21), 2-chloro-2′-deoxy-7-methyl-9-deazaadenosine (25), 2′-deoxy-9-deazaadenosine (22), and 2′-deoxy-7-methyl-9-deazaadenosine (26) were prepared from sugar-protected 2′-deoxy-9-deazaguanosine. Among these compounds, 7-benzyl-9-deazaadenosine (14b) showed the most potent cytotoxic activity, with IC50 values of 0.07, 0.1, 0.2 and 1.5 µM, while both 7-methyl-9-deazaadenosine (14a) and 2-fluoro-9-deazaadenosine (9) also demonstrated significant cytotoxic activity with IC50 values of 0.4, 0.7, 0.3, and 1.5 µM, and 1.5, 0.9, 0.3, and 5 µM against L1210 leukemia, P388 leukemia, CCRF-CEM lymphoblastic leukemia, and B16F10 melanoma cells, respectively.

An improved synthesis of 9-deazaguanine

ABSTRACT A new, improved synthesis of 9-deazaguanine is described. The method involves use of the benzyloxymethyl group to protect the N 3-position of 2-[(dimethylaminomethylene)- amino]-6-methyl-5-nitro-4(3H)-pyrimidinone, followed by treatment with DMF-dimethylacetal, reductive cyclization, treatment with ethanolic ammonia and removal of the protecting group by catalytic hydrogenation.

Synthesis and Biological Evaluation of 1,3-Oxathiolane 5-Azapyrimidine, 6-Azapyrimidine, and Fluorosubstituted 3-Deazapyrimidine Nucleosides

Abstract (2R,5S)-5-Amino-2-[2-(hydroxymethyl)-1,3-oxathiolan-5-y1]-1,2,4-triazine-3(2H)-one (8) and (2R,5R)-5-amino-2-[2-(hydroxymethyl)-1,3-oxathiolan-5-y1]-1,2,4-triazine-3(2H)-one (9) have been synthesized via a multi-step procedure from 6-azauridine. (2R,5S)-4-Amino-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-y1]-1,3,5-triazine-2(1H)-one (11) and (2R,5R)-4-amino-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-y1]-1,3,5-triazine-2(1H)-one (12), and the fluorosubstituted 3-deazanucleosides (19–24) have been synthesized by the transglycosylation of (2R,5S)-1-{2-[[(tert-butyldiphenylsilyl) oxy]methyl]-1,3-oxathiolan-5-y1} cytosine (2) with silylated 5-azacytosine and the corresponding silylated fluorosubstituted 3-deazacytosines, respectively, in the presence of trimethylsilyl trifluoromethanesulfonate as the catalyst in anhydrous dichloroethane, followed by deprotection of the blocking groups. These compounds were tested in vitro for cytotoxicity against L1210, B16F10, and CCRF-CEM tumor cell lines and for antiviral activity against HIV-1 and HBV.

Synthesis of 1-β-L-Arabinofuranosylcytosine (β-L-Ara-C) and 2′-Deoxy-2′-methylene-β-L-cytidine (β-L-DMDC) as Potential Antineoplastic Agents

Abstract 1-β-L-Arabinofuranosylcytosine (β-L-Ara-C, 7) and 2′-deoxy-2′-methylene-β-L-cytidine (β-L-DMDC, 14) have been synthesized via a multi-step synthesis from L-arabinose. These compounds were tested in vitro against L1210, P388, Sarcoma 180, and CEM cells, and found not to be active at a concentration up to 100 μM. β-L-Ara-C and β-L-DMDC were also tested against HSV-1 and HSV-2 and yielded ID50 values of 100 μM.