Synthesis of 3'-acetamidoadenosine derivatives as potential A3 adenosine receptor agonists.

On the basis of high binding affinity of 3'-aminoadenosine derivatives 2b at the human A3 adenosine receptor (AR), 3'-acetamidoadenosine derivatives 3a-e were synthesized from 1,2:5,6-di-O-isopropylidene-D-glucose via stereoselective hydroboration as a key step. Although all synthesized compounds were totally devoid of binding affinity at the human A3AR, our results revealed that 3'-position of adenosine can only be tolerated with small size of a hydrogen bonding donor like hydroxyl or amino group in the binding site of human A3AR.

Design, enantiopure synthesis, and biological evaluation of novel iso-D-2',3'-dideoxy-3'-fluorothianucleoside derivatives as a bioisostere of lamivudine.

Novel iso D-2',3'-dideoxythianucleoside derivatives 1-3 were designed and asymmetrically synthesized to search for new anti-HIV agents. Final compounds 1-3 were evaluated against a variety of viruses including HIV-1 and 2. Only cytosine analog 3 showed a potent anti-VSV activity (EC(50) = 9.43 microg/mL). This result implies that iso 2',3'-dideoxy sugar templates might play a role of a sugar surrogate of nucleosides for the development of anti-RNA virus agent.

Asymmetric synthesis of apio fluoroneplanocin A analogs as potential AdoHcy hydrolase inhibitor.

Apio fluoroneplanocin A (apio F-NPA, 3) and its uracil analogue 4 have been designed and asymmetrically synthesized starting from D-ribose. Introduction of fluoro group into vinylic position of 5 was accomplished successfully over 5 steps employing key reactions such as iodination according to an addition-elimination reaction mechanism, stereo- and regioselective reduction of alpha,beta-unsaturated ketone, and electrophilic fluorination. This methodology can be adapted to the synthesis of fluoro compounds extensively.

Synthesis of enantiopure pseudo-L-vinylcyclopropyl nucleosides bearing quaternary carbon as potential anti-herpesvirus agent.

Pseudo-L-vinylcyclopropyl adenine and guanine nucleosides 11 and 12 were designed and enantiopurely synthesized starting from (S)-epichlorohydrin using tandem alkylation, regioselective oxirane-ring opening, and chemoselective reduction as key steps.

Asymmetric synthesis of novel pseudo-D-vinylcyclopropyl nucleosides bearing quaternary carbon as potential anti-herpesvirus agent.

Pseudo-D-vinylcyclopropyl nucleosides 10-12 bearing a quaternary carbon were designed and synthesized starting from (R)-epichlorohydrin using a tandem reaction of double alkylation and lactonization via oxirane-ring opening reaction, a Wittig reaction, and chemoselective reduction as potential anti-herpesvirus agent.

Asymmetric synthesis and biological activity of L-bicyclocarba-d4T.

Novel L-bicyclocarba-d4T (1), an enantiomer of D-N-MCd4T has been enantiopurely synthesized as a potent anti-HIV agent starting from (R)-epichlorohydrin using tandem alkylation, chemoselective reduction of ester in the presence of lactone functional group, Grignard reaction, RCM reaction, and Mitsunobu reaction as key steps. L-N-MCd4T (1) was found to be very potent anti-HIV-1 (EC(50) = 6.76 microg/mL) agent with no cytotoxicity.

Stereoselective synthesis of 1'-functionalized-4'-thionucleosides.

Stereoselective functionalization of the 1'-position of 4'-thionucleosides was achieved using a stereoselective S(N)2 reaction controlled by 5-membered ring coordination.

Asymmetric synthesis of cyclopropyl-fused 2'-C-methylcarbanucleosides as potential anti-HCV agents.

Novel 2'-C-methyl-cyclopropyl-fused carbocyclic nucleosides as potential anti-HCV agents were stereoselectively synthesized, utilizing regioselective cleavage of the isopropylidene group and cyclic sulfate chemistry as key steps.

Synthesis of N6-substituted 3'-ureidoadenosine derivatives as highly potent agonists at the mutant A3 adenosine receptor.

Several N6-substituted 3 '-ureidoadenosine derivatives were efficiently synthesized starting from D-glucose for the development of H272E mutant A3 adenosine receptor (AR) agonists. Among compounds tested, 3 '-ureido-N6-(3-iodobenzyl)adenosine (2c) exhibited the highest binding affinity (Ki = 0.22 micro M) at the H272E mutant A3 AR without binding to the natural A3AR.

Synthesis and antitumor activity of fluorocyclopentenyl-pyrimidines.

Synthesis of fluorocyclopentenyl pyrimidine nucleosides 6-9 was enantiopurely accomplished employing oxidative rearrangement, RCM reaction and electrophilic fluorination starting from d-ribose. Cytosine analog 8 was found to exhibit significant anticancer activity in various human tumor cell lines.

Asymmetric synthesis of novel apio carbocyclic nucleoside analogues as potential antiviral and antitumor agent.

Novel apio carbocyclic nucleosides 18-21 were asymmetrically synthesized as potential antiviral and antitumor agent, starting from D-ribose employing aldol reaction, RCM reaction and Mitsunobu reaction as key reactions.

Stereoselective synthesis of homo-apioneplanocin A as potential inhibitor of S-adenosylhomocysteine hydrolase.

Homo-apioneplanocin A (1) as a potential inhibitor of S-adenosylhomocysteine hydrolase was synthesized from D-ribose, employing stereoselective hydroxymethylation, regioselective oxidation, and regio- and chemoselective hydroboration as key steps.

Design, synthesis, and anti-tumor activity of 4'-thionucleosides as potent and selective agonists at the human A3 adenosine receptor.

On the basis of potent and selective binding affinity of Cl-IB-MECA to the human A(3) adenosine receptor, its 4'-thioadenosine derivatives were efficiently synthesized starting from D-gulonic gamma-lactone. Among compounds tested, 2-chloro-N(6)-(3-iodobenzyl)- and 2-chloro-N(6)-methyl-4' -thioadenosine-5' -methyluronamides (7a and 7b) exhibited nanomolar range of binding affinity (K(i) = 0.38 nM and 0.28 nM, respectively) at the human A(3)AR. These compounds showed anti-growth effects on HL-60 leukemia cell, which resulted from the inhibition of Wnt signaling pathway.

Structure-activity relationships of 2-chloro-N6-substituted-4'-thioadenosine-5'-uronamides as highly potent and selective agonists at the human A3 adenosine receptor.

We have established structure-activity relationships of novel 4'-thionucleoside analogues as the A(3) adenosine receptor (AR) agonists. Binding affinity, selectivity toward other AR subtypes, and efficacy in inhibition of adenylate cyclase were studied. From this study, 2-chloro-N(6)-methyl-4'-thioadenosine-5'-methyluronamide (36a) emerged as the most potent and selective agonist at the human A(3) AR. We have also revealed that, similar to 4'-oxoadenosine analogues, at least one hydrogen on the 5'-uronamide moiety was necessary for high-affinity binding at the human A(3) AR, presumably to allow this group to donate a H bond within the binding site. Furthermore, bulky substituents on the 5'-uronamide reduced binding affinity, but in some cases large 5'-uronamide substituents, such as substituted benzyl and 2-phenylethyl groups, maintained moderate affinity with reduced efficacy, leading to A(3) AR partial agonists or antagonists. In several cases for which the corresponding 4'-oxonucleosides have been studied, the 4'-thionucleosides showed higher binding affinity to the A(3) AR.

Induction of apoptosis in human leukemia cells by MCS-C2 via caspase-dependent Bid cleavage and cytochrome c release.

The purpose of the present study was to investigate the anti-proliferative and apoptotic effects of MCS-C2, a novel synthetic analogue of the pyrrolo[2,3-d]pyrimidine nucleoside toyocamycin and sangivamycin, in human promyelocytic leukemia (HL-60) cells. When treated with 5 microM MCS-C2, inhibited proliferation associated with apoptotic induction was found in the HL-60 cells in a concentration-dependent and time-dependent manner, plus nuclear DAPI staining revealed the typical nuclear features of apoptosis. However, MCS-C2 showed almost no antiproliferative effect and no apoptotic induction in normal lymphocyte cells used as a control when compared with those in HL-60 cancer cells. Moreover, a flow cytometric analysis of the HL-60 cells using FITC-dUTP and propidium iodide (PI) showed that the apoptotic cell population increased gradually from <1% at 0 h to 34% at 12 h after exposure to 5 microM MCS-C2. This apoptotic induction was associated with the cleavage of Bid and a release of cytochrome c from mitochondria into the cytosol, followed by the activation of caspase-3 and inactivation of poly(ADP-ribose) polymerase (PARP). However, there was no significant change in any other mitochondrial membrane proteins, such as Bcl-2 and Bax. Consequently, the current findings suggest that the mitochondrial pathway was primarily involved in the MCS-C2-induced apoptosis in the human promyelocytic leukemia HL-60 cells.

Synthesis of 3'-deoxy-3'-C-hydroxymethyl analogues of tiazofurin and ribavirin.

On the basis of potent biological activity of 3'-branched-3'-deoxynucleoside analogues, novel ribavirin and tiazofurin derivatives with 3'-C-hydroxymethyl substituent were synthesized, starting from D-xylose.

Synthesis of homo-N-nucleoside with 1,2,4-triazole-3-carboxamide.

On the basis of potent biological activities of ribavirin and homo-N-nucleosides, a novel homo-N-1,2,4-triazole-3-carboxamide derivative 1 was synthesized starting from 2,3,5-tri-O-benzoylribofuranosyl-1-acetate as a potential antiviral agent.

Stereoselective synthesis of novel thioiso dideoxy nucleosides with exocyclic methylene as potential antiviral agents.

Novel thioiso pyrimidine and purine nucleosides substituted with exocyclic methylene have been synthesized, starting from D-xylose. Cyclization of the dimesylate to the 4-thiosugar 6a proceeded in pure SN2 reaction in the presence of allylic functional group.

D-4'-thioadenosine derivatives as highly potent and selective agonists at the human A3 adenosine receptor.

4'-Thionucleoside derivatives as potent and selective A3 adenosaine receptor agonists were synthesized, starting from D-gulono-gamma-lactone via D-thioribosyl acetate as a key intermediate, among which the 2-chloro-N6-methyladenosine-5-methyluronamide showed the most potent and selective binding affinity (Ki = 0.28 +/- 0.09 nM) at the human A3 adenosine receptor.

Structure-activity relationship of 5'-substituted fluoro-neplanocin a analogues as potent inhibitors of S-adenosylhomocysteine hydrolase.

Four 5'-substituted fluoro-neplanocin A analogues la-d were designed and synthesized, and the inhibitory activity against SAH was in the following order: NH2 > SH > F, N3, indicating a hydrogen bonding donor is essential for inhibitory activity.