Janus compounds, 5-chloro-N4-methyl-N4-aryl-9hpyrimido[4,5-b]indole-2,4-diamines, cause both microtubule depolymerizing and stabilizing effects

Cristina C. Rohena, April L Risinger, Ravi Kumar Vyas Devambatla, Nicholas F. Dybdal-Hargreaves, Roma Kaul, Shruti Choudhary, Aleem Gangjee, Susan L Mooberry

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

While evaluating a large library of compounds designed to inhibitmicrotubule polymerization, we identified four compounds that have unique effects on microtubules. These compounds cause mixed effects reminiscent of both microtubule depolymerizers and stabilizers. Immunofluorescence evaluations showed that each compound initially caused microtubule depolymerization and, surprisingly, with higher concentrations, microtubule bundles were also observed. There were subtle differences in the propensity to cause these competing effects among the compounds with a continuum of stabilizing and destabilizing effects. Tubulin polymerization experiments confirmed the differential effects and, while each of the compounds increased the initial rate of tubulin polymerization at high concentrations, total tubulin polymer was not enhanced at equilibrium, likely because of the dueling depolymerization effects. Modeling studies predict that the compounds bind to tubulin within the colchicine site and confirm that there are differences in their potential interactions that might underlie their distinct effects on microtubules. Due to their dual properties of microtubule stabilization and destabilization, we propose the name Janus for these compounds after the two-faced Roman god. The identification of synthetically tractable, small molecules that elicit microtubule stabilizing effects is a significant finding with the potential to identify new mechanisms of microtubule stabilization.

Original languageEnglish (US)
Article number21121661
JournalMolecules
Volume21
Issue number12
DOIs
StatePublished - Dec 1 2016

Fingerprint

Janus
Diamines
indoles
Tubulin
diamines
Microtubules
Depolymerization
causes
Polymerization
Stabilization
depolymerization
polymerization
Colchicine
Polymers
colchicine
stabilization
Molecules
indole
destabilization
bundles

Keywords

  • Cancer
  • Colchicine site
  • Microtubule
  • Microtubule destabilizer
  • Microtubule stabilizer

ASJC Scopus subject areas

  • Medicine(all)
  • Organic Chemistry

Cite this

Janus compounds, 5-chloro-N4-methyl-N4-aryl-9hpyrimido[4,5-b]indole-2,4-diamines, cause both microtubule depolymerizing and stabilizing effects. / Rohena, Cristina C.; Risinger, April L; Devambatla, Ravi Kumar Vyas; Dybdal-Hargreaves, Nicholas F.; Kaul, Roma; Choudhary, Shruti; Gangjee, Aleem; Mooberry, Susan L.

In: Molecules, Vol. 21, No. 12, 21121661, 01.12.2016.

Research output: Contribution to journalArticle

Rohena, Cristina C. ; Risinger, April L ; Devambatla, Ravi Kumar Vyas ; Dybdal-Hargreaves, Nicholas F. ; Kaul, Roma ; Choudhary, Shruti ; Gangjee, Aleem ; Mooberry, Susan L. / Janus compounds, 5-chloro-N4-methyl-N4-aryl-9hpyrimido[4,5-b]indole-2,4-diamines, cause both microtubule depolymerizing and stabilizing effects. In: Molecules. 2016 ; Vol. 21, No. 12.
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