Design, synthesis and evaluation of progesterone-adenine hybrids as bivalent inhibitors of P-glycoprotein-mediated multidrug efflux

Waël Zeinyeh; Ghina Alameh; Sylvie Radix; Catherine Grenot; Charles Dumontet; Nadia Walchshofer

doi:10.1016/j.bmcl.2010.03.085

Design, synthesis and evaluation of progesterone-adenine hybrids as bivalent inhibitors of P-glycoprotein-mediated multidrug efflux

Bioorg Med Chem Lett. 2010 May 15;20(10):3165-8. doi: 10.1016/j.bmcl.2010.03.085. Epub 2010 Mar 28.

Authors

Waël Zeinyeh¹, Ghina Alameh, Sylvie Radix, Catherine Grenot, Charles Dumontet, Nadia Walchshofer

Affiliation

¹ Université de Lyon, Université Lyon 1, ISPB-Faculté de Pharmacie, INSERM U863, F-69373 Lyon cedex 08, France.

PMID: 20399647
DOI: 10.1016/j.bmcl.2010.03.085

Abstract

Steroidal bivalent ligands were designed on the basis of the described closer proximity of the ATP-site and the putative steroid-binding site of P-glycoprotein (ABCB1). The syntheses of seven progesterone-adenine hybrids were described. Their abilities to inhibit P-glycoprotein-mediated daunorubicin efflux in K562/R7 human leukemic cells overexpressing P-glycoprotein were evaluated versus progesterone.

MeSH terms

ATP Binding Cassette Transporter, Subfamily B
ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors*
ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
Adenine / chemistry*
Antibiotics, Antineoplastic / pharmacology
Antineoplastic Agents / chemical synthesis*
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology
Binding Sites
Cell Line, Tumor
Daunorubicin / pharmacology
Drug Design
Humans
Progesterone / chemistry*

Substances

ABCB1 protein, human
ATP Binding Cassette Transporter, Subfamily B
ATP Binding Cassette Transporter, Subfamily B, Member 1
Antibiotics, Antineoplastic
Antineoplastic Agents
Progesterone
Adenine
Daunorubicin