TY - JOUR
T1 - 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
AU - Devambatla, Ravi Kumar Vyas
AU - Li, Wei
AU - Zaware, Nilesh
AU - Choudhary, Shruti
AU - Hamel, Ernest
AU - Mooberry, Susan L.
AU - Gangjee, Aleem
N1 - Funding Information:
This work was supported, in part, by a grant from the National Institutes of Health, National Cancer Institute (CA142868 (AG, SLM)); by the Duquesne University Adrian Van Kaam Chair in Scholarly Excellence (AG); and by an NSF equipment grant for NMR instrumentation (NMR: CHE 0614785).
Publisher Copyright:
© 2017 Elsevier Ltd
PY - 2017
Y1 - 2017
N2 - 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 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.
AB - 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 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.
KW - Conformational restriction
KW - Microtubule depolymerizing agents
KW - Microtubules
KW - Multidrug resistance
KW - Pyrimido[4,5-b]indoles
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U2 - 10.1016/j.bmcl.2017.05.085
DO - 10.1016/j.bmcl.2017.05.085
M3 - Article
C2 - 28610978
AN - SCOPUS:85020414157
VL - 27
SP - 3423
EP - 3430
JO - Bioorganic and Medicinal Chemistry Letters
JF - Bioorganic and Medicinal Chemistry Letters
SN - 0960-894X
IS - 15
ER -