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 cells

Aleem Gangjee, Nilesh Zaware, Ravi Kumar Vyas Devambatla, Sudhir Raghavan, Cara D. Westbrook, Nicholas F. Dybdal-Hargreaves, Ernest Hamel, Susan L Mooberry

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

A series of fourteen N4-(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 GI50 values against 57 of the NCI 60-tumor panel cell lines. Mechanistic studies showed that 6 inhibited tubulin polymerization and [3H]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.

Original languageEnglish (US)
Pages (from-to)891-902
Number of pages12
JournalBioorganic and Medicinal Chemistry
Volume21
Issue number4
DOIs
StatePublished - Feb 15 2013

Fingerprint

Diamines
Tubulin
Microtubules
Cells
Colchicine
Tumors
Aniline Compounds
Chlorination
Halogenation
Cyclization
P-Glycoprotein
Tumor Cell Line
Drug Resistance
Polymerization
Oxidation
Pharmaceutical Preparations
indole
Neoplasms

Keywords

  • Microtubules
  • Multidrug resistance
  • Pyrimido[4,5-b]indole-2,4-diamines

ASJC Scopus subject areas

  • Pharmaceutical Science
  • Drug Discovery
  • Organic Chemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry
  • Biochemistry

Cite this

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 cells. / Gangjee, Aleem; Zaware, Nilesh; Devambatla, Ravi Kumar Vyas; Raghavan, Sudhir; Westbrook, Cara D.; Dybdal-Hargreaves, Nicholas F.; Hamel, Ernest; Mooberry, Susan L.

In: Bioorganic and Medicinal Chemistry, Vol. 21, No. 4, 15.02.2013, p. 891-902.

Research output: Contribution to journalArticle

Gangjee, Aleem ; Zaware, Nilesh ; Devambatla, Ravi Kumar Vyas ; Raghavan, Sudhir ; Westbrook, Cara D. ; Dybdal-Hargreaves, Nicholas F. ; Hamel, Ernest ; Mooberry, Susan L. / 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 cells. In: Bioorganic and Medicinal Chemistry. 2013 ; Vol. 21, No. 4. pp. 891-902.
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