Aryl phosphate derivatives of bromo-methoxy-azidothymidine are dual-function spermicides with potent anti-human immunodeficiency virus

Biology of Reproduction
Osmond J D'CruzFatih M Uckun

Abstract

Detergent-based vaginal microbicides, in addition to their high contraceptive failure rates, cause mucosal erosion and local inflammation that might increase the risk of heterosexual human immunodeficiency virus (HIV) transmission. In a systematic effort to identify a microbicide contraceptive potentially capable of preventing the sexual transmission of HIV as well as providing fertility control, a series of novel aryl phosphate derivatives of 5-bromo-6-methoxy-3'-azido-3'-deoxythymidine (AZT; zidovudine) were synthesized and examined for dual anti-HIV and sperm-immobilizing activity (SIA). Whereas AZT displayed potent anti-HIV activity (IC50 = 0.006 microM) but lacked SIA (EC50 > 300 microM), two 5-bromo-6-methoxy-aryl phosphate derivatives of AZT, compounds WHI-05 and WHI-07, exhibited potent anti-HIV activity as well as SIA. The IC50 (HIV) and EC50 (SIA) values for WHI-07 were 439-fold and 13.5-fold lower, respectively, than those for the detergent-based virucidal spermicide, nonoxynol-9 (N-9). Sperm motion kinematics using computer-assisted sperm motion analysis combined with confocal laser scanning microscopy, high-resolution low-voltage scanning, and transmission electron microscopy demonstrated that both WHI-05 and WHI-0...Continue Reading

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Citations

Nov 13, 2001·Contraception·Osmond J D'Cruz, Fatih M Uckun
Feb 13, 2001·Fertility and Sterility·Osmond J D'Cruz, Fatih M Uckun
Jul 3, 2004·Reproduction : the Official Journal of the Society for the Study of Fertility·K V R ReddyR D Yedery
Aug 2, 2002·Expert Opinion on Investigational Drugs·Jim A Turpin
Feb 2, 2006·The European Journal of Contraception & Reproductive Health Care : the Official Journal of the European Society of Contraception·Gopal Gupta
Dec 7, 2010·Toxicology in Vitro : an International Journal Published in Association with BIBRA·G AhmadL Bujan
Mar 17, 2004·Fertility and Sterility·Osmond J D'Cruz, Fatih M Uckun
Oct 19, 2007·Bioorganic & Medicinal Chemistry·Amira ZairiKhaled Hani
Jun 22, 2000·Biology of Reproduction·Osmond J D'CruzFatih M Uckun
Jun 18, 2004·Toxicologic Pathology·Osmond J D'CruzFatih M Uckun
Mar 30, 2001·The Journal of Biological Chemistry·H E TibblesFatih M Uckun
Sep 8, 2006·BJOG : an International Journal of Obstetrics and Gynaecology·J Aggarwal, V Prabha

Related Concepts

WHI-05
WHI-07
Metazoa
Cricetus
Electron Microscopy
Sperm Motility
Sperm-Zona Pellucida Penetration
Vaginal Spermicides
Deoxythymidylate
Virus Replication

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