title: [d4U]-spacer-[HI-236] double-drug inhibitors of HIV-1 reverse-transcriptase.
abstract: Four double-drug HIV NRTI/NNRTI inhibitors 15a-d of the type [d4U]-spacer-[HI-236] in which the spacer is varied as 1-butynyl (15a), propargyl-1-PEG (15b), propargyl-2-PEG (15c) and propargyl-4-PEG (15d) have been synthesized and biologically evaluated as RT inhibitors against HIV-1. The key step in their synthesis involved a Sonogashira coupling of 5-iodo d4U's benzoate with an alkynylated tethered HI-236 precursor followed by introduction of the HI-236 thiourea functionality. Biological evaluation in both cell-culture (MT-2 cells) as well as using an in vitro RT assay revealed 15a-c to be all more active than d4T. However, overall the results indicate the derivatives are acting as chain-extended NNRTIs in which for 15b-d the nucleoside component is likely situated outside of the pocket but with no evidence for any synergistic double binding between the NRTI and NNRTI sites. This is attributed, in part, to the lack of phosphorylation of the nucleoside component of the double-drug as a result of kinase recognition failure, which is not improved upon with the phosphoramidate of 15d incorporating a 4-PEG spacer.
authors.affiliation: Department of Chemistry, University of Cape Town, Rondebosch 7701, Cape Town, South Africa.
authors.forename: Yassir
authors.initials: Y
authors.lastname: Younis
authors.forename: Roger
authors.initials: R
authors.lastname: Hunter
authors.forename: Clare I
authors.initials: CI
authors.lastname: Muhanji
authors.forename: Ian
authors.initials: I
authors.lastname: Hale
authors.forename: Rajinder
authors.initials: R
authors.lastname: Singh
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Bailey
authors.forename: Todd J
authors.initials: TJ
authors.lastname: Sullivan
authors.forename: Karen S
authors.initials: KS
authors.lastname: Anderson
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D001665:Binding Sites; D002460:Cell Line; D003198:Computer Simulation; D015195:Drug Design; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015497:HIV-1 / Q000201:enzymology*; D006801:Humans; D011092:Polyethylene Glycols / Q000737:chemistry; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013890:Thiourea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D019380:Anti-HIV Agents; C121245:HI 236; D011725:Pyridines; D018894:Reverse Transcriptase Inhibitors; D011092:Polyethylene Glycols; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase; D013890:Thiourea