Publications

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The synthesis of 3'-fluoro analogues of recently discovered highly potent anti-VZV furanopyrimidine deoxynucleosides (BCNAs) is herein reported, for both the alkyl and alkylphenyl series. The compounds are tested against a range of herpes viruses and display poor activity, strongly supporting the notion of the importance of the presence of a 3'-OH for antiviral activity.

A series of 3,5-bis(benzylidene)-4-piperidones 3 were converted into the corresponding 3,5-bis(benzylidene)-1-phosphono-4-piperidones 5 via diethyl esters 4. The analogues in series 4 and 5 displayed marked growth inhibitory properties toward human Molt 4/C8 and CEM T-lymphocytes as well as murine leukemia L1210 cells. In general, the N-phosphono compounds 5, which are more hydrophilic than the analogues in series 3 and 4, were the most potent cluster of cytotoxins, and, in particular, 3,5-bis-(2-nitrobenzylidene)-1-phosphono-4-piperidone 5 g had an average IC(50) value of 34 nM toward the two T-lymphocyte cell lines. Four of the compounds displayed potent cytotoxicity toward a panel of nearly 60 human tumor cell lines, and nanomolar IC(50) values were observed in a number of cases. The mode of action of 5 g includes the induction of apoptosis and inhibition of cellular respiration. Most of the members of series 4 as well as several analogues in series 5 are potent multi-drug resistance (MDR) reverting compounds. Various correlations were noted between certain molecular features of series 4 and 5 and cytotoxic properties, affording some guidelines in expanding this study.

In order to determine if the potent antiviral properties of (+/-)-5'-noraristeromycin reside in one of its enantiomers, an analysis of each enantiomer has been carried out. A five-step route to the (+)-stereoisomer is described from (+)-(1R,4S)-4-hydroxy-2-cyclopenten-1-yl acetate, whereas the synthesis of the (-)-enantiomer had been reported previously from the same starting material. The (-)-2 and (+)-2 enantiomers were evaluated for antiviral activity against a large number of viruses and found to display an antiviral activity spectrum characteristic of (S)-adenosyl-L-homocysteine hydrolase inhibitors. The (-)-enantiomer retained the significant anticytomegalovirus properties previously reported for the racemic 2 and was, on the average, 10-fold more potent than (+)-2 in inhibiting virus replication, tumor cell growth, and (S)-adenosyl-L-homocysteine hydrolase activity.

Abstract The substitution of methoxy groups of nitrosobis(methoxy)pyrimidine (I) by various aliphatic and aromatic amines is studied.

3,5-Disubstituted hydantoin (1,3-imidazolidinedione) derivatives 5a-h were prepared by base induced cyclization of the corresponding N-(1-benzotriazolecarbonyl)-L- and D-amino acid amides 4a-h. Compounds 5a-h were evaluated for their cytostatic and antiviral activities. Among all the compounds evaluated, 3-benzhydryl-5-isopropyl hydantoin (5a) showed a weak but selective inhibitory effect against vaccinia virus (EC(50) = 16 microg/mL; selectivity index: 25). 3-Cyclohexyl-5-phenyl hydantoin (5g) showed inhibitory activity against cervical carcinoma (HeLa, IC(50) = 5.4 microM) and breast carcinoma (MCF-7, IC(50) = 2 microM), but also cytotoxic effects towards human normal fibroblasts (WI 38). On the contrary, the 3-benzhydryl-5-phenyl substituted hydantoin derivative 5h showed moderate inhibitory activity towards HeLa, MCF-7, pancreatic carcinoma (MiaPaCa-2), lung carcinoma (H 460) and colon carcinoma (SW 620) (IC(50) = 20-23 microM), but no effect on WI 38.