Analogs of Estrogen Metabolites as Probes of Estrogen-Induced Tumorigenesis
Annual summary rept. 1 Jul 96-30 Jun 99
OHIO STATE UNIV COLUMBUS
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A series of C-4 hydroxyalkylestradiol analogs were synthesized as metabolically stable analogs of 4-hydroxyestradiol 4-OHE2 in order to separate the receptor activation and redox cycling properties. The Stille cross-coupling and the carboxymethylation reactions were used for the synthesis of these analogs. The 4-hydroxyalkyl estrogens and catechol estrogens were compared in potentiometric and DNA-damaging studies. The non-redox cycling estrogen analogs were unable to induce DNA damage, whereas catechol estrogens produced DNA damage. A novel synthetic route was developed for synthesis of catechol estrogens from 2- and 4-substituted formyl estradiols. In addition, several estrogen analogs were synthesized as potential inhibitors of estrogen hydroxylases, the enzymes responsible for catechol estrogen biosynthesis. 2-Methoxymethylestradiol 2MME2 was identified as a novel inhibitor of tubulin polymerization in vitro. Finally, a novel synthetic route was developed for constructing benzopyrones, present in various natural products that interact with enzymes and receptors of therapeutic importance in breast and prostate cancer. Readily available salicylic acids and terminal alkynes were used as building blocks for the benzopyrone ring system. This synthetic approach utilizes readily available starting materials, mild and high yielding reactions with good functional group tolerance, and is ideal for developing combinatorial libraries of the benzopyrone ring system.
- Medicine and Medical Research