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.
abstract: 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.
authors.affiliation: Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA. crohena@ucsd.edu.
authors.forename: Cristina C
authors.initials: CC
authors.lastname: Rohena
authors.affiliation: Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA. risingera@uthscsa.edu.|Cancer Therapy & Research Center, San Antonio, TX 78229, USA. risingera@uthscsa.edu.
authors.forename: April L
authors.initials: AL
authors.lastname: Risinger
authors.affiliation: Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA 15282, USA. drkvyas@gmail.com.
authors.forename: Ravi Kumar Vyas
authors.initials: RK
authors.lastname: Devambatla
authors.affiliation: Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA. hargreavesnd@livemail.uthscsa.edu.
authors.forename: Nicholas F
authors.initials: NF
authors.lastname: Dybdal-Hargreaves
authors.affiliation: Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA. kaulr@livemail.uthscsa.edu.
authors.forename: Roma
authors.initials: R
authors.lastname: Kaul
authors.affiliation: Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA 15282, USA. choudharys@duq.edu.
authors.forename: Shruti
authors.initials: S
authors.lastname: Choudhary
authors.affiliation: Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA 15282, USA. gangjee@duq.edu.
authors.forename: Aleem
authors.initials: A
authors.lastname: Gangjee
authors.affiliation: Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA. mooberry@uthscsa.edu.|Cancer Therapy & Research Center, San Antonio, TX 78229, USA. mooberry@uthscsa.edu.
authors.forename: Susan L
authors.initials: SL
authors.lastname: Mooberry
mesh_terms: D001665:Binding Sites; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D003959:Diamines / Q000138:chemical synthesis* / Q000737:chemistry*; D006367:HeLa Cells; D006801:Humans; D008870:Microtubules / Q000187:drug effects* / Q000378:metabolism; D008958:Models, Molecular; D014404:Tubulin / Q000737:chemistry* / Q000378:metabolism; D050257:Tubulin Modulators / Q000737:chemistry*
chemical_list: D003959:Diamines; D014404:Tubulin; D050257:Tubulin Modulators
keywords: cancer; colchicine site; microtubule; microtubule destabilizer; microtubule stabilizer