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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.

ABSTRACT: To identify the structural features of 9H-pyrimido[4,5-b]indoles as microtubule depolymerizers, pyrimido[4,5-b]indoles 2-8 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 compounds 2-8. Compounds 2 and 6 had two-digit nanomolar potency (IC50) against MDA-MB-435, SK-OV-3 and HeLa cancer cells in vitro. Compounds 2 and 6 also depolymerized microtubules comparable to the lead compound 1. Compounds 2, 3, 6 and 8 were effective in cells expressing P-glycoprotein or the ?III 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.

SUBMITTER: Devambatla RKV 

PROVIDER: S-EPMC5603926 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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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.

Devambatla Ravi Kumar Vyas RKV   Li Wei W   Zaware Nilesh N   Choudhary Shruti S   Hamel Ernest E   Mooberry Susan L SL   Gangjee Aleem A  

Bioorganic & medicinal chemistry letters 20170527 15

To identify the structural features of 9H-pyrimido[4,5-b]indoles as microtubule depolymerizers, pyrimido[4,5-b]indoles 2-8 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 compounds 2-8. Compounds 2 and 6 had two-digit nanomolar potency (IC<sub>50</sub>) against MDA-MB-435, SK-OV-3 and HeLa cancer cell  ...[more]

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