| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
a Drug Discovery Program,
b Departments of Reproductive Biology,
c Chemistry, and
d Virology, Wayne Hughes Institute, St. Paul, Minnesota 55113
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 µM) but lacked SIA (EC50 > 300 µM), 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-07 cause a complete and irreversible loss of sperm motility in a concentration- and time-dependent fashion without concomitantly affecting the sperm acrosomal membrane integrity. In experiments designed to assess the fertilizing capacity of treated sperm, preincubation of sperm with either compound resulted in a concentration-dependent loss of the ability to adhere to and penetrate zona-free hamster eggs as well as inhibition of binding to human zona. WHI-07 applied intravaginally prior to artificial insemination of epididymal sperm drastically reduced fertility in hormonally primed CD-1 mice. Unlike the intravaginal application of N-9, repetitive intravaginal application of WHI-07 did not damage the vaginal epithelium or cause local inflammation. Structure-function relationship analyses showed that the addition of bromo-methoxy functional groups to AZT was essential for, and the aryl phosphate derivatization contributory to, the SIA of both compounds. Compounds WHI-05 and WHI-07 may be useful as dual-function vaginal contraceptives for women who are at high risk for acquiring HIV/acquired immunodeficiency virus syndrome by heterosexual vaginal transmission.
This article has been cited by other articles:
|
|
 |
|
  O. J. D'Cruz and F. M. Uckun Preclinical Evaluation of a Dual-Acting Microbicidal Prodrug WHI-07 in Combination with Vanadocene Dithiocarbamate in the Female Reproductive Tract of Rabbit, Pig, and Cat Toxicol Pathol, December 1, 2007; 35(7): 910 - 927. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. F. Doncel Exploiting common targets in human fertilization and HIV infection: development of novel contraceptive microbicides Hum. Reprod. Update, March 1, 2006; 12(2): 103 - 117. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K V R Reddy, C Aranha, S M Gupta, and R D Yedery Evaluation of antimicrobial peptide nisin as a safe vaginal contraceptive agent in rabbits: in vitro and in vivo studies Reproduction, July 1, 2004; 128(1): 117 - 126. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. J. D'Cruz, B. Waurzyniak, and F. M. Uckun Antiretroviral Spermicide WHI-07 Prevents Vaginal and Rectal Transmission of Feline Immunodeficiency Virus in Domestic Cats Antimicrob. Agents Chemother., April 1, 2004; 48(4): 1082 - 1088. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. J. D'Cruz, B. Waurzyniak, and F. M. Uckun Mucosal Toxicity Studies of a Gel Formulation of Native Pokeweed Antiviral Protein Toxicol Pathol, February 1, 2004; 32(2): 212 - 221. [Abstract] [PDF]
|
|
|
|
 |
|
 O. J. D'Cruz, P. Samuel, B. Waurzyniak, and F. M. Uckun Development and Evaluation of a Thermoreversible Ovule Formulation of Stampidine, a Novel Nonspermicidal Broad-Spectrum Anti-Human Immunodeficiency Virus Microbicide Biol Reprod, December 1, 2003; 69(6): 1843 - 1851. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. J. D'Cruz and F. M. Uckun Pre-clinical safety evaluation of novel nucleoside analogue-based dual-function microbicides (WHI-05 and WHI-07) J. Antimicrob. Chemother., December 1, 2002; 50(6): 793 - 803. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. J. D'Cruz, T. K. Venkatachalam, C. Mao, S. Qazi, and F. M. Uckun Structural Requirements for Potent Anti-Human Immunodeficiency Virus (HIV) and Sperm-Immobilizing Activities of Cyclohexenyl Thiourea and Urea Non-Nucleoside Inhibitors of HIV-1 Reverse Transcriptase Biol Reprod, December 1, 2002; 67(6): 1959 - 1974. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. J. D'Cruz, B. Waurzyniak, and F. M. Uckun A 13-Week Subchronic Intravaginal Toxicity Study of the Novel Broad-Spectrum Anti-HIV and Spermicidal Agent, N-[2-(1-cyclohexenyl)ethyl]-N'-[2-(5-bromopyridyl)]-thiourea (PHI-346) in Mice Toxicol Pathol, October 1, 2002; 30(6): 687 - 695. [Abstract] [PDF]
|
|
|
|
 |
|
 O. J. D'Cruz and F. M. Uckun Short-Term (13-week) Toxicity Study of 5-Bromo-6-methoxy-5,6- dihydro-3'-azidothymidine-5'-(p-bromophenyl) Methoxyalaninyl Phosphate (WHI-07), a Novel Anti-HIV and Contraceptive Agent, in B6C3F1 Mice Toxicol. Sci., April 1, 2001; 60(2): 373 - 378. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. J. D'Cruz, T. K. Venkatachalam, and F. M. Uckun Thymidine Kinase-Independent Intracellular Delivery of Bioactive Nucleotides by Aryl Phosphate Derivatives of Bromo-Methoxy Zidovudine (Compounds WHI-05 and WHI-07) in Normal Human Female Genital Tract Epithelial Cells and Sperm Biol Reprod, January 1, 2001; 64(1): 51 - 59. [Abstract] [Full Text]
|
|
|
|
|
|
O. J. D'Cruz, T. K. Venkatachalam, and F. M. Uckun Novel Thiourea Compounds as Dual-Function Microbicides Biol Reprod, July 1, 2000; 63(1): 196 - 205. [Abstract] [Full Text]
|
|
|
|
|
|
O. J. D'Cruz, A. Vassilev, and F. M. Uckun Studies in Humans on the Mechanism of Potent Spermicidal and Apoptosis-Inducing Activities of Vanadocene Complexes Biol Reprod, April 1, 2000; 62(4): 939 - 949. [Abstract] [Full Text]
|
|
|
|
|
|
O. J. D'Cruz, T. K. Venkatachalam, and F. M. Uckun Structural Requirements for Potent Human Spermicidal Activity of Dual-Function Aryl Phosphate Derivative of Bromo-Methoxy Zidovudine (Compound WHI-07) Biol Reprod, January 1, 2000; 62(1): 37 - 44. [Abstract] [Full Text]
|
|
|
|
|
|
O. J. D'Cruz and F. M. Uckun Novel Derivatives of Phenethyl-5-Bromopyridylthiourea and Dihydroalkoxybenzyloxopyrimidine Are Dual-Function Spermicides with Potent Anti-Human Immunodeficiency Virus Activity Biol Reprod, June 1, 1999; 60(6): 1419 - 1428. [Abstract] [Full Text]
|
|
|
|
 |
|
 O. J. D'Cruz, M.-J. Shih, S. H. Yiv, C.-L. Chen, and F. M. Uckun Synthesis, characterization and preclinical formulation of a dual-action phenyl phosphate derivative of bromo-methoxy zidovudine (compound WHI-07) with potent anti-HIV and spermicidal activities Mol. Hum. Reprod., May 1, 1999; 5(5): 421 - 432. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. E. Tibbles, A. Vassilev, H. Wendorf, D. Schonhoff, D. Zhu, D. Lorenz, B. Waurzyniak, X.-P. Liu, and F. M. Uckun Role of a JAK3-dependent Biochemical Signaling Pathway in Platelet Activation and Aggregation J. Biol. Chem., May 18, 2001; 276(21): 17815 - 17822. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
