Rational drug design of multifunctional phosphoramidate substituted nucleoside analogs.
This review focuses on our approach to the study of the effect of a series of phosphoramidate substituted nucleoside analogs on model systems for cancer, HIV and fertility. This approach allowed the development of compound WHI-07, an arylphosphoramidate derivative of zidavudine. This compound is a multifunctional agent showing potent activity in the above mentioned model systems. Our rational drug design provided such a powerful derivative with all the necessary characteristic of a drug candidate. Importantly, we have experimental evidence that each of the groups associated with the molecular frame of WHI-07 imparts the multifunctional ability for this agent. In addition, we have also suggested a possible biological pathway for WHI-07 including various products with their therapeutic targets that are formed during the course of its metabolism inside the cell. We also propose which individual moieties in the structure of WHI-07 are responsible for the biological activity from the formation of these metabolites. A detailed structure-activity relationship is presented in the review in connection with various structural modifications of the agent. Application of this active agent in animal models shows the potential usefulness of this agent as a drug candidate. We further plan to utilize gene-chip technology to identify new targets and modes of action using microarrays to measure expression changes in thousands of gene products. In conclusion, we have demonstrated the power of multifunctional drug design to discover drugs to combat various diseases. We believe this is the future direction of the drug discovery process.
Venkatachalam
T K
TK
Department of Chemistry, Virology Paradigm Pharmaceuticals LLC, 2685 Patton Road, Roseville, MN 55119, USA. tvenku@ih.org
Goodman
P A
PA
Qazi
S
S
D'Cruz
O
O
Uckun
F M
FM
D000577:Amides / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D054306:Dideoxynucleotides; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D005299:Fertility Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy; D009705:Nucleosides / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D010756:Phosphoric Acids / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D013938:Thymidine Monophosphate / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D015215:Zidovudine / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use
C114570:5-bromo-6-methoxy-5, 6-dihydro-3'-azidothymidine-5'-(p-bromophenyl) methoxyalaninyl phosphate; D000577:Amides; D054306:Dideoxynucleotides; D005299:Fertility Agents; D009705:Nucleosides; D010756:Phosphoric Acids; D013938:Thymidine Monophosphate; D015215:Zidovudine; C011067:phosphoramidic acid