title: Trimethoxybenzanilide-based P-glycoprotein modulators: an interesting case of lipophilicity tuning by intramolecular hydrogen bonding.
abstract: One of the principal reasons for the chemotherapy failure is the overexpression of drug efflux pumps, ABCB1 (also known as MDR1 or P-gp) and ABCC1 (also known as MRP1), whose inhibition remains a priority to circumvent drug resistance. We have recently shown a clear trend between lipophilicity and P-glycoprotein inhibitory activity for a class of galloyl-based modulators targeting P-glycoprotein and MRP1. Herein we report a new series of polymethoxy benzamides, whose lipophilicity was modulated through the establishment of an intramolecular hydrogen bond (IMHB) which allows reaching of P-gp inhibitory activity at the submicromolar IC50 level. The present study provides a strong rationale for candidates in the presence of IMHB as a key element for a high P-gp inhibitory activity.
authors.affiliation: Dipartimento di Farmacia-Scienze del Farmaco, Università di Bari "Aldo Moro" , Via Orabona 4, 70125 Bari, Italy.
authors.forename: Piero
authors.initials: P
authors.lastname: Tardia
authors.forename: Angela
authors.initials: A
authors.lastname: Stefanachi
authors.forename: Mauro
authors.initials: M
authors.lastname: Niso
authors.forename: Diana Antonella
authors.initials: DA
authors.lastname: Stolfa
authors.forename: Giuseppe Felice
authors.initials: GF
authors.lastname: Mangiatordi
authors.forename: Domenico
authors.initials: D
authors.lastname: Alberga
authors.forename: Orazio
authors.initials: O
authors.lastname: Nicolotti
authors.forename: Gianluca
authors.initials: G
authors.lastname: Lattanzi
authors.forename: Angelo
authors.initials: A
authors.lastname: Carotti
authors.forename: Francesco
authors.initials: F
authors.lastname: Leonetti
authors.forename: Roberto
authors.initials: R
authors.lastname: Perrone
authors.forename: Francesco
authors.initials: F
authors.lastname: Berardi
authors.forename: Amalia
authors.initials: A
authors.lastname: Azzariti
authors.forename: Nicola Antonio
authors.initials: NA
authors.lastname: Colabufo
authors.forename: Saverio
authors.initials: S
authors.lastname: Cellamare
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D000813:Anilides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability; D004285:Dogs; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D005452:Fluoresceins / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D061985:Madin Darby Canine Kidney Cells; D056004:Molecular Dynamics Simulation; D013329:Structure-Activity Relationship
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000813:Anilides; D000970:Antineoplastic Agents; D005452:Fluoresceins; D004317:Doxorubicin; C007740:fluorexon