ARYL PHOSPHATE DERIVATIVES OF BROMO-METHOXY-AZIDOTHYMIDINE ARE DUAL-FUNCTION SPERMICIDES WITH POTENT ANTI-HUMAN-IMMUNODEFICIENCY-VIRUS

Detergent-based vaginal microbicides, in addition to their high contra ceptive failure rates, cause mucosal erosion and local inflammation th at might increase the risk of heterosexual human immunodeficiency viru s (HIV) transmission. In a systematic effort to identify a microbicide contraceptive potentially capable of preventing the sexual transmissi on of HIV as well as providing fertility control, a series of novel ar yl phosphate derivatives of 5-bromo-6-methoxy-3'-azido-3'-deoxythymidi ne (AZT; zidovudine) were synthesized and examined for dual anti-HIV a nd sperm-immobilizing activity (SIA). Whereas AZT displayed potent ant i-HIV activity (IC50 = 0.006 mu M) but lacked SIA (EC50 > 300 mu M), t wo 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-fol d lower, respectively, than those for the detergent-based virucidal sp ermicide, non-oxynol-9 (N-9). Sperm motion kinematics using computer-a ssisted sperm motion analysis combined with confocal laser scanning mi croscopy, high-resolution low-voltage scanning, and transmission elect ron microscopy demonstrated that both WHI-05 and WHI-07 cause a comple te and irreversible loss of sperm motility in a concentration- and tim e-dependent fashion without concomitantly affecting the sperm acrosoma l membrane integrity. In experiments designed to assess the fertilizin g capacity of treated sperm, preincubation of sperm with either compou nd resulted in a concentration-dependent loss of the ability to adhere to and penetrate zona-free hamster eggs as well as inhibition of bind ing to human zona. WHI-07 applied intravaginally prior to artificial i nsemination of epididymal sperm drastically reduced fertility in hormo nally primed CD-1 mice. Unlike the intravaginal application of N-9, re petitive intravaginal application of WHI-07 did not damage the vaginal epithelium or cause local inflammation. Structure-function relationsh ip analyses showed that the addition of bromo-methoxy functional group s to AZT was essential for, and the aryl phosphate derivatization cont ributory to, the SIA of both compounds. Compounds WHI-05 and WHI-07 ma y be useful as dual-function vaginal contraceptives for women who are at high risk for acquiring HIV/acquired immunodeficiency virus syndrom e by heterosexual vaginal transmission.