Antileukemic activity and cellular metabolism of the aryl phosphate derivative of bromo-methoxy zidovudine (compound WHI-07).
The novel aryl phosphate derivative of bromo-methoxy zidovudine (ZDV/AZT) (compound WHI-07, CAS 213982-96-8) was found to be a potent antileukemic agent against human leukemia, lymphoma, and multiple myeloma cell lines in MTT and clonogenic assays with low micromolar IC50 values. In addition, WHI-07 was antimitotic, leading to cell fusion and developmental arrest in the Zebrafish model of rapid cell proliferation. WHI-07 was cytotoxic to drug-sensitive (NALM-6, MOLT-3, HL-60, P388) and multi-drug resistant (MDR) leukemia cell lines (HL-60/VCR, HL-60/ADR, P388/ ADR). Treatment of leukemia cells with WHI-07 showed rapid and dramatic depletion of all cellular nucleoside diphosphate and triphosphate (NDP/NTP) pools, which would contribute to the overall reduction of nucleic acid synthesis and cell death. WHI-07 was rapidly metabolized to alaninyl ZDV monophosphate (Ala-ZDV-MP), the levels of which inversely correlated with cytotoxic IC50 values of WHI-07. Glutathione was found to mediate the in vitro and in vivo detoxification pathway of WHI-07 to 3'-azidothymidine-5'-p-bromophenylmethoxyalaninyl phosphate and Ala-ZDV-MP, respectively. The proposed intracellular metabolic pathway for WHI-07 involves a thiol-mediated dehalogenation step followed by the paraoxon-sensitive carboxylesterase-mediated reaction leading to the formation of Ala-ZDV-MP as the major intracellular metabolite.
Uckun
Fatih M
FM
Drug Discovery Program, Departments of Virology, Parker Hughes Institute, St Paul, Minnesota 55113, USA. faith_uckun@ih.org
Tai
Hung-Liang
HL
D'Cruz
Osmond J
OJ
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000378:metabolism / Q000494:pharmacology*; D001711:Biotransformation; D002265:Carboxylic Ester Hydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D054306:Dideoxynucleotides; D018432:Drug Resistance, Multiple; D004625:Embryo, Nonmammalian; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D007938:Leukemia / Q000188:drug therapy*; D009705:Nucleosides / Q000378:metabolism; D010261:Paraoxon / Q000494:pharmacology; D020112:Rhodamine 123 / Q000378:metabolism; D013347:Subcellular Fractions; D013778:Tetrazolium Salts; D013844:Thiazoles; D013938:Thymidine Monophosphate / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology*; D014410:Tumor Stem Cell Assay; D015027:Zebrafish; D015215:Zidovudine / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology*
C114570:5-bromo-6-methoxy-5, 6-dihydro-3'-azidothymidine-5'-(p-bromophenyl) methoxyalaninyl phosphate; D000964:Antimetabolites, Antineoplastic; D002800:Cholinesterase Inhibitors; D054306:Dideoxynucleotides; D009705:Nucleosides; D013778:Tetrazolium Salts; D013844:Thiazoles; D020112:Rhodamine 123; D013938:Thymidine Monophosphate; D015215:Zidovudine; D002265:Carboxylic Ester Hydrolases; C022616:thiazolyl blue; D005978:Glutathione; D010261:Paraoxon