Fabio Leonessa, Ji-Hyun Kim, Alem Ghiorghis, Robert J Kulawiec, Charles Hammer, Abdelhossein Talebian, Robert Clarke
Department of Oncology and Lombardi Cancer Center, Georgetown University School of Medicine, 3970 Reservoir Road Northwest, Washington, DC 20007, USA.
Journal of medicinal chemistry 2002 Jan 17The P-glycoprotein product (Pgp) of the MDR1 gene has been implicated in the multiple drug resistance phenotype expressed by many cancers. Functioning as an efflux pump, P-glycoprotein prevents the accumulation of high intracellular concentrations of substrates. We have taken a rational approach to designing inhibitors of P-glycoprotein function, selecting a natural substrate (progesterone) as our lead compound. We hypothesized that progesterone, substituted at C-7 with an aromatic moiety(s), would exhibit reduced Pgp affinity, significantly increased antiPgp activity, and reduced affinity for progesterone receptors (PGR). We synthesized 7 alpha-[4'-(aminophenyl)thio]pregna-4-ene-3,20-dione (2), which comprises a C-7 alpha thiol bridge linking an aminophenyl moiety to progesterone, from pregna-4,6-diene-3,20-dione (1). The subsequent addition reaction of 2 with the appropriate isocyanate produced an initial series of compounds (3-6). Compounds 3-5 (respectively, -CH(2)CH(2)Cl; -CH(2)CH(3); and -CH(CH(3))C(6)H(5)) exhibit a significantly increased ability to inhibit P-glycoprotein. Potency for restoring doxorubicin accumulation in MDR1-transduced human breast cancer cells is increased up to 60-fold as compared with progesterone. Compound 5 has greater potency than verapamil and is equipotent with cyclosporin A, for inhibiting P-glycoprotein function. Furthermore, 5 does not bind to PGR, implying a potential reduction in in vivo toxicity. These data identify C-7-substituted progesterone analogues and 5, in particular, as rationally designed antiPgp compounds worthy of further evaluation/development.
Fabio Leonessa, Ji-Hyun Kim, Alem Ghiorghis, Robert J Kulawiec, Charles Hammer, Abdelhossein Talebian, Robert Clarke. C-7 analogues of progesterone as potent inhibitors of the P-glycoprotein efflux pump. Journal of medicinal chemistry. 2002 Jan 17;45(2):390-8
PMID: 11784143
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