Modified carbazoles destabilize microtubules and kill glioblastoma multiform cells

Philippe Diaz; Eric Horne; Cong Xu; Ernest Hamel; Michael Wagenbach; Ravil R Petrov; Benjamin Uhlenbruck; Brian Haas; Parvinder Hothi; Linda Wordeman; Rick Gussio; Nephi Stella

doi:10.1016/j.ejmech.2018.09.026

Modified carbazoles destabilize microtubules and kill glioblastoma multiform cells

Eur J Med Chem. 2018 Nov 5:159:74-89. doi: 10.1016/j.ejmech.2018.09.026. Epub 2018 Sep 11.

Authors

Affiliations

¹ Department of Biomedical and Pharmaceutical Sciences, The University of Montana, 32 Campus Drive, Missoula, MT, 59812, USA; DermaXon LLC, 32 Campus Drive, Missoula, MT, 59812, USA. Electronic address: Philippe.diaz@umontana.edu.
² Stella Therapeutics, Inc., Pacific Northwest Research Institute, 720 Broadway, Seattle, WA, 98122, USA.
³ Department of Pharmacology (CX, BH and NS), Department of Physiology and Biophysics (MW and LW), Department of Psychiatry and Behavioral Sciences (NS), The University of Washington, Seattle, WA, 98195, USA.
⁴ Screening Technologies Branch (EH) and Computational Drug Development Group (RG), Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, Frederick National Laboratory for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, 21702, USA.
⁵ Department of Biomedical and Pharmaceutical Sciences, The University of Montana, 32 Campus Drive, Missoula, MT, 59812, USA.
⁶ Ivy Center for Advance Brain Tumor Treatment, Swedish Neuroscience Institute, 550 17th Ave, Seattle, WA, 98122, USA.
⁷ Stella Therapeutics, Inc., Pacific Northwest Research Institute, 720 Broadway, Seattle, WA, 98122, USA; Department of Pharmacology (CX, BH and NS), Department of Physiology and Biophysics (MW and LW), Department of Psychiatry and Behavioral Sciences (NS), The University of Washington, Seattle, WA, 98195, USA. Electronic address: nstella@uw.edu.

Abstract

Small molecules that target microtubules (MTs) represent promising therapeutics to treat certain types of cancer, including glioblastoma multiform (GBM). We synthesized modified carbazoles and evaluated their antitumor activity in GBM cells in culture. Modified carbazoles with an ethyl moiety linked to the nitrogen of the carbazole and a carbonyl moiety linked to distinct biaromatic rings exhibited remarkably different killing activities in human GBM cell lines and patient-derived GBM cells, with IC₅₀ values from 67 to >10,000 nM. Measures of the activity of modified carbazoles with tubulin and microtubules coupled to molecular docking studies show that these compounds bind to the colchicine site of tubulin in a unique low interaction space that inhibits tubulin assembly. The modified carbazoles reported here represent novel chemical tools to better understand how small molecules disrupt MT functions and kill devastating cancers such as GBM.

Keywords: Carbazole; Colchicine; Gliomas; Microtubules.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Carbazoles / chemical synthesis
Carbazoles / chemistry
Carbazoles / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Survival / drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Glioblastoma / drug therapy*
Glioblastoma / pathology
Humans
Microtubules / drug effects*
Molecular Docking Simulation
Molecular Structure
Structure-Activity Relationship

Substances

Antineoplastic Agents
Carbazoles

Abstract

MeSH terms

Substances

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