Bis-cycloSal-d4T-monophosphates: drugs that deliver two molecules of bioactive nucleotides.
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.
Ducho
Christian
C
Department of Chemistry, Organic Chemistry, Faculty of Science, University of Hamburg, Martin-Luther-King-Platz 6, D-20146 Hamburg, Germany.
Görbig
Ulf
U
Jessel
Sönke
S
Gisch
Nicolas
N
Balzarini
Jan
J
Meier
Chris
C
D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002091:Butyrylcholinesterase / Q000737:chemistry; D045744:Cell Line, Tumor; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D054306:Dideoxynucleotides; D015497:HIV-1 / Q000187:drug effects; D015498:HIV-2 / Q000187:drug effects; D006801:Humans; D006868:Hydrolysis; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018119:Stavudine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013938:Thymidine Monophosphate / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013942:Thymine Nucleotides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
C113124:2',3'-dideoxy-2',3'-didehydrothymidine monophosphate; D019380:Anti-HIV Agents; D002800:Cholinesterase Inhibitors; D054306:Dideoxynucleotides; D011355:Prodrugs; D013942:Thymine Nucleotides; C519108:bis(5-methylcyclosaligenyl)-3'-deoxy-2',3'-didehydrothymidine 5'-monophosphate; C519107:bis(cyclosaligenyl)-3'-deoxy-2',3'-didehydrothymidine 5'-monophosphate; D013938:Thymidine Monophosphate; D018119:Stavudine; D002091:Butyrylcholinesterase