Synthesis of N4-(Substituted phenyl)-N4-alkyl/desalkyl-9H-pyrimido[4,5-b]indole-2,4-diamines and Identification of New Microtubule Disrupting Compounds that are Effective against Multidrug Resistant Cells1

A series of fourteen N 4 -(substituted phenyl)- N 4 -methyl/desmethyl-9 H -pyrimido[4,5- b ]indole-2,4-diamines was synthesized as potential microtubule targeting agents. The synthesis involved a Fisher indole cyclization of 2-amino-6-hydrazinylpyrimidin-4(3 H )-one with cyclohexanone, followed by o...

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Published in:Bioorganic & medicinal chemistry 2012-12, Vol.21 (4), p.891-902
Main Authors: Gangjee, Aleem, Zaware, Nilesh, Devambatla, Ravi Kumar Vyas, Raghavan, Sudhir, Westbrook, Cara D., Dybdal-Hargreaves, Nicholas F., Hamel, Ernest, Mooberry, Susan L.
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Language:English
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Summary:A series of fourteen N 4 -(substituted phenyl)- N 4 -methyl/desmethyl-9 H -pyrimido[4,5- b ]indole-2,4-diamines was synthesized as potential microtubule targeting agents. The synthesis involved a Fisher indole cyclization of 2-amino-6-hydrazinylpyrimidin-4(3 H )-one with cyclohexanone, followed by oxidation, chlorination and displacement with appropriate anilines. Compounds 6 , 14 and 15 had low nanomolar potency against MDA-MB-435 tumor cells and depolymerized microtubules. Compound 6 additionally had nanomolar GI 50 values against 57 of the NCI 60-tumor panel cell lines. Mechanistic studies showed that 6 inhibited tubulin polymerization and [ 3 H]colchicine binding to tubulin. The most potent compounds were all effective in cells expressing P-glycoprotein or the βIII isotype of tubulin, which have been associated with clinical drug reisistence. Modeling studies provided the potential interactions of 6 , 14 and 15 within the colchicine site.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2012.12.010