Janus Compounds, 5-Chloro-N4-methyl-N4-aryl-9H-pyrimido[4,5-b]indole-2,4-diamines, Cause Both Microtubule Depolymerizing and Stabilizing Effects
While evaluating a large library of compounds designed to inhibit microtubule 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 show...
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| Format: | Article |
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MDPI AG
2016-12-01
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| Series: | Molecules |
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| Online Access: | http://www.mdpi.com/1420-3049/21/12/1661 |
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| author | Cristina C. Rohena April L. Risinger Ravi Kumar Vyas Devambatla Nicholas F. Dybdal-Hargreaves Roma Kaul Shruti Choudhary Aleem Gangjee Susan L. Mooberry |
| author_facet | Cristina C. Rohena April L. Risinger Ravi Kumar Vyas Devambatla Nicholas F. Dybdal-Hargreaves Roma Kaul Shruti Choudhary Aleem Gangjee Susan L. Mooberry |
| author_sort | Cristina C. Rohena |
| collection | DOAJ |
| description | While evaluating a large library of compounds designed to inhibit microtubule 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. |
| first_indexed | 2024-04-12T18:28:08Z |
| format | Article |
| id | doaj.art-6703b455e5c74eb4bb7c78024318e1ec |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-04-12T18:28:08Z |
| publishDate | 2016-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-6703b455e5c74eb4bb7c78024318e1ec2022-12-22T03:21:10ZengMDPI AGMolecules1420-30492016-12-012112166110.3390/molecules21121661molecules21121661Janus Compounds, 5-Chloro-N4-methyl-N4-aryl-9H-pyrimido[4,5-b]indole-2,4-diamines, Cause Both Microtubule Depolymerizing and Stabilizing EffectsCristina C. Rohena0April L. Risinger1Ravi Kumar Vyas Devambatla2Nicholas F. Dybdal-Hargreaves3Roma Kaul4Shruti Choudhary5Aleem Gangjee6Susan L. Mooberry7Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USADepartment of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USADivision of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA 15282, USADepartment of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USADepartment of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USADivision of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA 15282, USADivision of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA 15282, USADepartment of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USAWhile evaluating a large library of compounds designed to inhibit microtubule 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.http://www.mdpi.com/1420-3049/21/12/1661microtubulemicrotubule stabilizermicrotubule destabilizercancercolchicine site |
| spellingShingle | Cristina C. Rohena April L. Risinger Ravi Kumar Vyas Devambatla Nicholas F. Dybdal-Hargreaves Roma Kaul Shruti Choudhary Aleem Gangjee Susan L. Mooberry Janus Compounds, 5-Chloro-N4-methyl-N4-aryl-9H-pyrimido[4,5-b]indole-2,4-diamines, Cause Both Microtubule Depolymerizing and Stabilizing Effects Molecules microtubule microtubule stabilizer microtubule destabilizer cancer colchicine site |
| title | Janus Compounds, 5-Chloro-N4-methyl-N4-aryl-9H-pyrimido[4,5-b]indole-2,4-diamines, Cause Both Microtubule Depolymerizing and Stabilizing Effects |
| title_full | Janus Compounds, 5-Chloro-N4-methyl-N4-aryl-9H-pyrimido[4,5-b]indole-2,4-diamines, Cause Both Microtubule Depolymerizing and Stabilizing Effects |
| title_fullStr | Janus Compounds, 5-Chloro-N4-methyl-N4-aryl-9H-pyrimido[4,5-b]indole-2,4-diamines, Cause Both Microtubule Depolymerizing and Stabilizing Effects |
| title_full_unstemmed | Janus Compounds, 5-Chloro-N4-methyl-N4-aryl-9H-pyrimido[4,5-b]indole-2,4-diamines, Cause Both Microtubule Depolymerizing and Stabilizing Effects |
| title_short | Janus Compounds, 5-Chloro-N4-methyl-N4-aryl-9H-pyrimido[4,5-b]indole-2,4-diamines, Cause Both Microtubule Depolymerizing and Stabilizing Effects |
| title_sort | janus compounds 5 chloro n4 methyl n4 aryl 9h pyrimido 4 5 b indole 2 4 diamines cause both microtubule depolymerizing and stabilizing effects |
| topic | microtubule microtubule stabilizer microtubule destabilizer cancer colchicine site |
| url | http://www.mdpi.com/1420-3049/21/12/1661 |
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