期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 50, 期 6, 页码 1335-1346出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm0611713
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Bis-cycloSal-d4T-monophosphates have been synthesized as potentially anti-HIV active dimeric prodrugs of 2',3'-dideoxy-2',3'-didehydrothymidine monophosphate (d4TMP). These pronucleotides display a mask-drug ratio of 1:2, a novelty in the field of pronucleotides. Both bis-cycloSal-d4TMP 6 and bis-5-methyl-cycloSal-d4TMP 7 showed increased hydrolytic stability as compared to their monomeric counterparts and a completely selective hydrolytic release of d4TMP. The hydrolysis pathway was investigated via P-31 NMR spectroscopy. Moreover, due to the steric bulkiness, compound 6 already displayed strongly reduced inhibitor potency toward human butyrylcholinesterase (BChE), while compound 7 turned out to be devoid of any inhibitory activity against BChE. Partial separation of the diastereomeric mixture of 6 revealed strong dependence of the pronucleotides' properties on the stereochemistry at the phosphorus centers. Both 6and 7 showed good activity against HIV-1 and HIV-2 in wild-type CEM cells in vitro. These compounds were significantly more potent than the parent nucleoside d4T 1in HIV-2-infected TK-deficient CEM cells, indicating an efficient TK-bypass.
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