In vitro activity of novel dual action MDR anthranilamide modulators with inhibitory activity at CYP-450.
Synthesis and in vitro cytotoxicity assays of new anthranilamide MDR modulators have been performed to assess their inhibition potency of the P-glycoprotein (P-gp) transporter. The aromatic spacer group between nitrogen atoms (N1 and N2) in the known inhibitor XR9576 was replaced with a flexible alkyl chain of 2 to 6 carbon atoms in length. 6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinoline and their open-chain N-methylhomoveratrylamine counterparts were shown to be potent P-gp inhibitors. The maximal inhibition was obtained when using an ethyl or propyl spacer. Several compounds were more potent than verapamil and intrinsically less cytotoxic than XR9576. In addition, in vitro metabolism studies of 23a with a subset of human CYP-450 isoforms revealed that, unlike XR9576, 23a inhibited CYP3A4, an enzyme that colocalizes with P-gp in the intestine and contributes to tumor cell chemoresistance by enhancing the biodisposition of anticancer drugs such as paclitaxel toward metabolism. In this context, 22a might be a suitable candidate for further drug development.
Labrie
Philippe
P
Instituts de Biomateriaux et des Biotechnologies, Hopital St-François d'Assise, Laval University, Que., Canada G1L 3L5. plabrie16@hotmail.com
Maddaford
Shawn P
SP
Lacroix
Jacques
J
Catalano
Concettina
C
Lee
David K H
DK
Rakhit
Suman
S
Gaudreault
René C
RC
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D006801:Humans; D011804:Quinolines; D013329:Structure-Activity Relationship; D062367:ortho-Aminobenzoates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D065607:Cytochrome P-450 Enzyme Inhibitors; D011804:Quinolines; D062367:ortho-Aminobenzoates; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; C402343:tariquidar; C000219:anthranilamide