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Chemical Compound Review

WHI-07     methyl(2S)-2-[[[(2R,3S,5R)-3- azido-5-(5...

Synonyms: AC1NUK89
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Disease relevance of WHI-07


High impact information on WHI-07

  • Pretreatment of the vagina or rectum with 2% WHI-07 alone or in combination with 0.25% VDDTC significantly (P = 0.004) protected cats from genital transmission by the highly infectious inoculum (7 million FIV(Bangston)-infected feline T cells) [1].
  • WHI-05 and WHI-07 differ fundamentally from currently used surfactant microbicides that are cytotoxic to genital tract epithelial cells at spermicidal concentrations [2].
  • The time- and concentration-dependent intracellular formation of ZDV metabolites following addition of WHI-05 and WHI-07 to normal human vaginal, ectocervical, and endocervical epithelial cells as well as motile sperm was studied by analytical HPLC [5].
  • 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) [6].
  • Unlike the intravaginal application of N-9, repetitive intravaginal application of WHI-07 did not damage the vaginal epithelium or cause local inflammation [6].

Chemical compound and disease context of WHI-07

  • 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 [6].

Biological context of WHI-07

  • 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 [6].
  • WHI-07 caused cessation of sperm motility in a concentration- and time-dependent fashion [7].
  • Furthermore, the 2% WHI-07 gel-microemulsion provided >90% inhibition of fertility even when insemination was delayed until 60 minutes after intravaginal application [8].
  • Repeated intravaginal exposure of mice to WHI-07 for 13 weeks had no toxicologically significant effect on organ weights, and did not cause any adverse changes in hematology parameters or blood chemistry profiles [4].
  • RESULT(S): Exposure of semen to WHI-07 at the time of artificial insemination completely inhibited pregnancy rates (WHI-07-pretreated, 0%, vs. control, 60%) and embryo implantation (WHI-07-pretreated, 0/175 vs. control, 68/170) [8].

Anatomical context of WHI-07

  • Addition of WHI-05 and WHI-07 to vaginal and cervical epithelial cells resulted in their concentration- and time-dependent conversion to alaninyl ZDV monophosphate (Ala-ZDV-MP) and 5'-ZDV monophosphate as the major metabolites [5].
  • In Experiment I, ovulated does in subgroups of 15 were artificially inseminated with semen mixed with WHI-07 or vehicle [8].
  • External, and skeletal examinations of fetuses for malformations and variations did not reveal any evidence of teratogenicity in any WHI-07-treated groups [9].
  • Repeated intravaginal exposure of mice to 2% WHI-07 had no adverse effects on ovulation response, mean number of eggs recovered or the percentage of eggs fertilized or cleaved [10].
  • Prior studies of repeated intravaginal administration of WHI-07 gel-microemulsion revealed lack of local toxicity to rabbit vaginal mucosa [9].

Associations of WHI-07 with other chemical compounds


Gene context of WHI-07

  • The anti-HIV activity of WHI-07 was tested by measuring viral p24 antigen production and reverse transcriptase activity as markers of viral replication in HIV-1 infected human peripheral blood mononuclear cells (PBMC) [7].
  • The effects of WHI-07 on human sperm motion kinematics were analysed by computer-assisted sperm analysis (CASA), and its effects on sperm membrane integrity were examined by confocal laser scanning microscopy (CLSM), and high-resolution low-voltage scanning electron microscopy (HR-LVSEM) [7].
  • On a molar basis, these concentrations of WHI-07 are 1400- to 5700-times higher than its spermicidal EC(50) and 1.4 x 10(6) to 5.7 x 10(6) times higher than its in vitro anti-HIV IC(50) [4].
  • Reproductive indices, ie, pregnancy rate, gravid uterine weights, litter size, number of corpora lutea, implantation sites, pre- and postimplantation losses, viable fetuses, resorptions, fetal body weights, and fetal sex ratio, were not affected by intravaginal exposure to WHI-07 [9].
  • 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) [11].

Analytical, diagnostic and therapeutic context of WHI-07


  1. Antiretroviral spermicide WHI-07 prevents vaginal and rectal transmission of feline immunodeficiency virus in domestic cats. D'Cruz, O.J., Waurzyniak, B., Uckun, F.M. Antimicrob. Agents Chemother. (2004) [Pubmed]
  2. Pre-clinical safety evaluation of novel nucleoside analogue-based dual-function microbicides (WHI-05 and WHI-07). D'Cruz, O.J., Uckun, F.M. J. Antimicrob. Chemother. (2002) [Pubmed]
  3. Structural requirements for potent human spermicidal activity of dual-function aryl phosphate derivative of bromo-methoxy zidovudine (compound WHI-07). D'Cruz, O.J., Venkatachalam, T.K., Uckun, F.M. Biol. Reprod. (2000) [Pubmed]
  4. 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. D'Cruz, O.J., Uckun, F.M. Toxicol. Sci. (2001) [Pubmed]
  5. 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. D'Cruz, O.J., Venkatachalam, T.K., Uckun, F.M. Biol. Reprod. (2001) [Pubmed]
  6. Aryl phosphate derivatives of bromo-methoxy-azidothymidine are dual-function spermicides with potent anti-human immunodeficiency virus. D'Cruz, O.J., Venkatachalam, T.K., Zhu, Z., Shih, M.J., Uckun, F.M. Biol. Reprod. (1998) [Pubmed]
  7. 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. D'Cruz, O.J., Shih, M.J., Yiv, S.H., Chen, C.L., Uckun, F.M. Mol. Hum. Reprod. (1999) [Pubmed]
  8. Contraceptive activity of a spermicidal aryl phosphate derivative of bromo-methoxy-zidovudine (compound WHI-07) in rabbits. D'Cruz, O.J., Uckun, F.M. Fertil. Steril. (2003) [Pubmed]
  9. Developmental toxicology studies of WHI-07, a novel nucleoside analogue-based dual-function microbicide, administered intravaginally to rabbits. D'Cruz, O.J., Erbeck, D., Uckun, F.M. Toxicologic pathology. (2003) [Pubmed]
  10. Lack of adverse effects on fertility of female CD-1 mice exposed to repetitive intravaginal gel-microemulsion formulation of a dual-function anti-HIV agent: aryl phosphate derivative of bromo-methoxy-zidovudine (compound WHI-07). D'Cruz, O.J., Uckun, F.M. Journal of applied toxicology : JAT. (2001) [Pubmed]
  11. Antileukemic activity and cellular metabolism of the aryl phosphate derivative of bromo-methoxy zidovudine (compound WHI-07). Uckun, F.M., Tai, H.L., D'Cruz, O.J. Arzneimittel-Forschung. (2005) [Pubmed]
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