Ducho_2007_J.Med.Chem_50_1335

Reference

Title : Bis-cycloSal-d4T-monophosphates: drugs that deliver two molecules of bioactive nucleotides - Ducho_2007_J.Med.Chem_50_1335
Author(s) : Ducho C , Gorbig U , Jessel S , Gisch N , Balzarini J , Meier C
Ref : Journal of Medicinal Chemistry , 50 :1335 , 2007
Abstract :

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 31P 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 6 and 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 1 in HIV-2-infected TK-deficient CEM cells, indicating an efficient TK-bypass.

PubMedSearch : Ducho_2007_J.Med.Chem_50_1335
PubMedID: 17328534

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Citations formats

Ducho C, Gorbig U, Jessel S, Gisch N, Balzarini J, Meier C (2007)
Bis-cycloSal-d4T-monophosphates: drugs that deliver two molecules of bioactive nucleotides
Journal of Medicinal Chemistry 50 :1335

Ducho C, Gorbig U, Jessel S, Gisch N, Balzarini J, Meier C (2007)
Journal of Medicinal Chemistry 50 :1335