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

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:27

Article

Devambatla, Ravi Kumar Vyas¹  Li, Wei¹  Zaware, Nilesh¹  Choudhary, Shruti¹  Hamel, Ernest²  Mooberry, Susan L.³  Gangjee, Aleem¹ 

[1] Duquesne Univ, Grad Sch Pharmaceut Sci, Div Med Chem, 600 Forbes Ave, Pittsburgh, PA 15282 USA

[2] NIH, Screening Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diag,Frederick Natl Lab Canc, Frederick, MD 21702 USA

[3] Univ Texas Hlth Sci Ctr San Antonio, Canc Therapy & Res Ctr, Dept Pharmacol, 7703 Floyd Curl Dr, San Antonio, TX 78229 USA

关键词: Microtubules;    Pyrimido[4,5-b]indoles;    Microtubule depolymerizing agents;    Multidrug resistance;    Conformational restriction;   

DOI  :  10.1016/j.bmcl.2017.05.085

来源: Elsevier

【 摘 要 】

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 beta 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. (C) 2017 Elsevier Ltd. All rights reserved.

【 授权许可】

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