Publications

Abstract A general method for the synthesis of unsaturated keto- nucleosides of a-L-rhamnose with 5-fluorouracil and their in vitro and in vivo anticancer activity evaluation results are discussed. The synthesis was effected by selective protection and deprotection of the sugar hydroxyls with acid and base labile groups following standard procedure. In the final step, oxidation of the 2′,3′ acylated nucleoside afforded the 4′-ketoenonucleoside. Two unsaturated ketonucleosides, 3′-O-benzoyl and 3′-O-acetyl were synthesized in this way and both these compounds show inhibition of tumor cell growth af murine leukemia L1210, murine mammary carcinoma FM3A, human B-lymphoblast Raji, human T-lymphoblast Molt/4F. Also one compound shows antitumor activity in the adenocarcinoma 755 model in BDF mice.

The R- and S-isomers of 6'-C-neplanocin A analogues, which are all known as inhibitors of S-adenosylhomocysteine (AdoHcy) hydrolase, were studied for their inhibitory effects on Human Immunodeficiency Virus type 1 (HIV-1) replication and HIV-1 Tat-mediated transactivation. The R-isomers showed much greater activity against AdoHcy hydrolase than the S-isomers. The same differential activity was observed against the HIV-1 replication and the Tat transactivation.

Enlightened by our previous efforts to modify diarylpyrimidines as HIV-1 non-nucleoside reverse transcriptase (RT) inhibitors (NNRTIs) and the reported crystallographic studies, we designed and synthesized novel 1,2,3-triazole-derived diarylpyrimidine derivatives via the CuAAC "click reaction", to make additional interactions with the hydrophobic channel in the NNRTI binding pocket. The newly synthesized compounds were evaluated for anti-HIV potency in MT-4 cells. All the compounds showed favorable activity against the wild-type HIV-1 strain with an EC50 of 0.013-5.62 μM. Interestingly, some compounds displayed remarkable potency in inhibiting K103N mutant virus, a key drug-resistant mutant to NNRTIs. Among them, meta-methylbenzoate (ZL2, EC50(IIIB) = 0.020 μM, EC50(K103N) = 0.043 μM, CC50 > 241.52 μM), para-methylbenzoate (ZL3, EC50(IIIB) = 0.013 μM, EC50 (K103N) = 0.022 μM, CC50 > 241.52 μM) and para-phenol (ZL7, EC50(IIIB) = 0.014 μM, EC50 (K103N) = 0.054 μM, CC50 = 2.1 μM) derivatives are the three most promising compounds which are superior to the first-line antiretroviral drug efavirenz (EC50(IIIB) = 0.003 μM, EC50 (K103N) = 0.11 μM, CC50 > 6.34 μM) against the K103N mutant strain. More encouragingly, ZL2 and ZL3 exhibited much lower cytotoxicity and a high selection index of >10 000 compared with all the control drugs (AZT, 3TC, NVP, EFV, and ETV). The detailed structure-activity relationship (SAR), enzymatic inhibitory activity and docking study of the representative compounds are also discussed. Furthermore, the preliminary physicochemical properties and the early metabolic stability of representative compounds were examined to evaluate their drug-like properties.

Abstract Die Reaktion der entsprechenden Nucleoside (I) oder (III) mit Phosphorylchlorid und anschließend mit ,N‐Methylethanolamin oder N,N′‐Dimethylethylendiamin führt zu den cyclischen Phosphoramidaten (II) bzw. (IV) der Nucleoside.

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