Design, synthesis, and structure–activity relationships of pyrimido[4, 5-b]indole-4-amines as microtubule depolymerizing agents that are effective against multidrug resistant cells. Issue 15 (1st August 2017)

• Record Type: Journal Article
• Authors: Devambatla, Ravi Kumar Vyas; Li, Wei; Zaware, Nilesh; Choudhary, Shruti; Hamel, Ernest; Mooberry, Susan L.; Gangjee, Aleem
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 27:Issue 15(2017)
• Page Start: 3423
• Page End: 3430
• Publication Date: 2017-08-01
• Subjects: NCI National Cancer Institute -- MTAs microtubule targeting agents -- CA-4 combretastatin A-4 -- DMSO dimethyl sulfoxide -- PDB Protein Data Bank -- Pgp P-glycoprotein -- Rr relative resistance -- NMR nuclear magnetic resonance; Microtubules -- Pyrimido[4, 5-b]indoles -- Microtubule depolymerizing agents -- Multidrug resistance -- Conformational restriction; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2017.05.085
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: To identify the structural features of 9 H -pyrimido[4, 5- b ]indoles as microtubule depolymerizers, pyrimido[4, 5- b ]indoles2 –8 with varied substituents at the 2-, 4- and 5-positions were designed and synthesized. Nucleophilic displacement of 2, 5-substituted-4-chloro-pyrimido[4, 5- b ]indoles with appropriate arylamines was the final step employed in the synthesis of target compounds2 –8 . Compounds2 and6 had two-digit nanomolar potency (IC50 ) against MDA-MB-435, SK-OV-3 and HeLa cancer cells in vitro. Compounds2 and6 also depolymerized microtubules comparable to the lead compound1 . Compounds2, 3, 6 and8 were effective in cells expressing P-glycoprotein or the βIII isotype of tubulin, mechanisms that are associated with clinical drug resistance to microtubule targeting drugs. Proton NMR and molecular modeling studies were employed to identify the structural basis for the microtubule depolymerizing activity of pyrimido[4, 5- b ]indoles.