C-7 analogues of progesterone as potent inhibitors of the P-glycoprotein efflux pump.
The 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.
Leonessa
Fabio
F
Department of Oncology and Lombardi Cancer Center, Georgetown University School of Medicine, 3970 Reservoir Road Northwest, Washington, DC 20007, USA.
Kim
Ji-Hyun
JH
Ghiorghis
Alem
A
Kulawiec
Robert J
RJ
Hammer
Charles
C
Talebian
Abdelhossein
A
Clarke
Robert
R
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000970:Antineoplastic Agents / Q000378:metabolism; D001667:Binding, Competitive; D002455:Cell Division / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology; D004317:Doxorubicin / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D006801:Humans; D011282:Pregnenediones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011374:Progesterone / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D011980:Receptors, Progesterone / Q000187:drug effects; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D014700:Verapamil / Q000494:pharmacology; D014747:Vinblastine / Q000378:metabolism
C446055:7-(4'-(N-alpha-methylbenzylaminoacylaminophenyl)thio)pregna-4-ene-3,20-dione; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D011282:Pregnenediones; D011980:Receptors, Progesterone; D011374:Progesterone; D014747:Vinblastine; D004317:Doxorubicin; D016572:Cyclosporine; D014700:Verapamil