Isomeric N,N-bis(cyclohexanol)amine aryl esters: the discovery of a new class of highly potent P-glycoprotein (Pgp)-dependent multidrug resistance (MDR) inhibitors

Elisabetta Teodori; Cecilia Martelli; Milena Salerno; Nacira Darghal; Silvia Dei; Arlette Garnier-Suillerot; Fulvio Gualtieri; Dina Manetti; Serena Scapecchi; Maria Novella Romanelli

doi:10.1021/jm0614432

Isomeric N,N-bis(cyclohexanol)amine aryl esters: the discovery of a new class of highly potent P-glycoprotein (Pgp)-dependent multidrug resistance (MDR) inhibitors

J Med Chem. 2007 Feb 22;50(4):599-602. doi: 10.1021/jm0614432. Epub 2007 Jan 26.

Authors

Elisabetta Teodori¹, Cecilia Martelli, Milena Salerno, Nacira Darghal, Silvia Dei, Arlette Garnier-Suillerot, Fulvio Gualtieri, Dina Manetti, Serena Scapecchi, Maria Novella Romanelli

Affiliation

¹ Dipartimento di Scienze Farmaceutiche, Università di Firenze, via U. Schiff 6, 50019 Sesto Fiorentino (FI), Italy.

PMID: 17256837
DOI: 10.1021/jm0614432

Abstract

A new series of P-glycoprotein (Pgp)-dependent multidrug resistance (MDR) inhibitors having a N,N-bis(cyclohexanol)amine scaffold have been designed, following the frozen analog approach. With respect to the parent flexible molecules, the new compounds show improved potency and efficacy. Among them, compound 1d, on anthracycline-resistant erythroleukemia K562 cells, is able to completely reverse Pgp-dependent MDR at low nanomolar concentration.

MeSH terms

ATP Binding Cassette Transporter, Subfamily B / physiology*
Antineoplastic Agents / pharmacology
Cell Line, Tumor
Cyclohexanols / chemical synthesis*
Cyclohexanols / chemistry
Cyclohexanols / pharmacology
Doxorubicin / analogs & derivatives
Doxorubicin / pharmacology
Drug Resistance, Multiple / drug effects*
Drug Resistance, Neoplasm / drug effects*
Esters
Humans
Stereoisomerism

Substances

ATP Binding Cassette Transporter, Subfamily B
Antineoplastic Agents
Cyclohexanols
Esters
Doxorubicin
pirarubicin