title: Synthesis of N(4)-(substituted phenyl)-N(4)-alkyl/desalkyl-9H-pyrimido[4,5-b]indole-2,4-diamines and identification of new microtubule disrupting compounds that are effective against multidrug resistant cells.
abstract: A series of fourteen N(4)-(substituted phenyl)-N(4)-alkyl/desalkyl-9H-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(3H)-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 resistance. Modeling studies provided the potential interactions of 6, 14 and 15 within the colchicine site.
authors: Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, 600 Forbes Avenue, Pittsburgh, PA 15282, USA. gangjee@duq.edu
authors: Aleem
authors: A
authors: Gangjee
authors: Nilesh
authors: N
authors: Zaware
authors: Ravi Kumar Vyas
authors: RK
authors: Devambatla
authors: Sudhir
authors: S
authors: Raghavan
authors: Cara D
authors: CD
authors: Westbrook
authors: Nicholas F
authors: NF
authors: Dybdal-Hargreaves
authors: Ernest
authors: E
authors: Hamel
authors: Susan L
authors: SL
authors: Mooberry
mesh_terms: D000814:Aniline Compounds / Q000737:chemistry; D001665:Binding Sites; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003078:Colchicine / Q000737:chemistry / Q000378:metabolism; D003500:Cyclization; D003512:Cyclohexanones / Q000737:chemistry; D003959:Diamines / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007211:Indoles / Q000737:chemistry*; D008870:Microtubules / Q000737:chemistry* / Q000378:metabolism; D062105:Molecular Docking Simulation; D010084:Oxidation-Reduction; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011743:Pyrimidines / Q000737:chemistry*; D050257:Tubulin Modulators / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity
chemical_list: D000814:Aniline Compounds; D003512:Cyclohexanones; D003959:Diamines; D007211:Indoles; D011743:Pyrimidines; D050257:Tubulin Modulators; C036468:cyclohexanone; C030374:indole; C030986:pyrimidine; C023650:aniline; D003078:Colchicine