Antileukemic activity and cellular metabolism of the aryl phosphate derivative of bromo-methoxy zidovudine (compound WHI-07).

Abstract

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.

• Authors: Fatih M Uckun, Hung-Liang Tai, Osmond J D'Cruz
• Journal: Arzneimittel-Forschung (Arzneimittelforschung) Vol. 55 Issue 1 Pg. 50-65 ( 2005) ISSN: 0004-4172 [Print] Germany
• PMID: 15727164 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• 5-bromo-6-methoxy-5, 6-dihydro-3'-azidothymidine-5'-(p-bromophenyl) methoxyalaninyl phosphate
• Antimetabolites, Antineoplastic
• Cholinesterase Inhibitors
• Dideoxynucleotides
• Nucleosides
• Tetrazolium Salts
• Thiazoles
• Rhodamine 123
• Thymidine Monophosphate
• Zidovudine
• Carboxylic Ester Hydrolases
• thiazolyl blue
• Glutathione
• Paraoxon

Topics

• Animals
• Antimetabolites, Antineoplastic (metabolism, pharmacology)
• Biotransformation
• Carboxylic Ester Hydrolases (antagonists & inhibitors, metabolism)
• Cell Division (drug effects)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Cholinesterase Inhibitors (pharmacology)
• Dideoxynucleotides
• Drug Resistance, Multiple
• Embryo, Nonmammalian
• Glutathione (metabolism)
• Humans
• Leukemia (drug therapy)
• Nucleosides (metabolism)
• Paraoxon (pharmacology)
• Rhodamine 123 (metabolism)
• Subcellular Fractions
• Tetrazolium Salts
• Thiazoles
• Thymidine Monophosphate (analogs & derivatives, metabolism, pharmacology)
• Tumor Stem Cell Assay
• Zebrafish
• Zidovudine (analogs & derivatives, metabolism, pharmacology)