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 language | English (US) |
|---|---|
| Article number | 21121661 |
| Journal | Molecules |
| Volume | 21 |
| Issue number | 12 |
| DOIs | |
| State | Published - Dec 1 2016 |
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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 journal › Article
}
TY - JOUR
T1 - Janus compounds, 5-chloro-N4-methyl-N4-aryl-9hpyrimido[4,5-b]indole-2,4-diamines, cause both microtubule depolymerizing and stabilizing effects
AU - Rohena, Cristina C.
AU - Risinger, April L
AU - Devambatla, Ravi Kumar Vyas
AU - Dybdal-Hargreaves, Nicholas F.
AU - Kaul, Roma
AU - Choudhary, Shruti
AU - Gangjee, Aleem
AU - Mooberry, Susan L
PY - 2016/12/1
Y1 - 2016/12/1
N2 - 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.
AB - 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.
KW - Cancer
KW - Colchicine site
KW - Microtubule
KW - Microtubule destabilizer
KW - Microtubule stabilizer
UR - http://www.scopus.com/inward/record.url?scp=85002922795&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85002922795&partnerID=8YFLogxK
U2 - 10.3390/molecules21121661
DO - 10.3390/molecules21121661
M3 - Article
C2 - 27918450
AN - SCOPUS:85002922795
VL - 21
JO - Molecules
JF - Molecules
SN - 1420-3049
IS - 12
M1 - 21121661
ER -