Indolizine-phenothiazine hybrids as the first dual inhibitors of tubulin polymerization and farnesyltransferase with synergistic antitumor activity.

Abstract

In the incessant search for innovative cancer control strategies, this study was devoted to the design, synthesis and pharmacological evaluation of dual inhibitors of farnesyltransferase and tubulin polymerization (FTI/MTIs). A series of indolizine-phenothiazine hybrids 16 (amides) and 17 (ketones) has been obtained in a 4-step procedure. The combination of the two heterocycles provided potent tubulin polymerization inhibitors with similar efficiency as the reference phenstatin and (-)-desoxypodophyllotoxin. Ketones 17 were also able to inhibit human farnesyltransferase (FTase) in vitro. Interestingly, three molecules 17c, 17d and 17f were very effective against both considered biological targets. Next, nine indolizine-phenothiazine hybrids 16c, 16f, 17a-f and 22b were evaluated for their cell growth inhibition potential on the NCI-60 cancer cell lines panel. Ketones 17a-f were the most active and displayed promising cellular activities. Not only they arrested the cell growth of almost all tested cancer cells, but they displayed cytotoxicity potential with GI50 values in the low nanomolar range. The most sensitive cell lines upon treatment with indolizine-phenothiazine hybrids were NCI-H522 (lung cancer), COLO-205 and HT29 (colon cancer), SF-539 (human glioblastoma), OVCAR-3 (ovarian cancer), A498 (renal cancer) and especially MDA-MB-435 (melanoma). Demonstrating the preclinical effectiveness of these dual inhibitors can be crucial. A single dual molecule could induce a synergy of antitumor activity, while increasing the effectiveness and reducing the toxicity of the classical combo treatments currently used in chemotherapy.

• Authors: Iuliana-Monica Moise, Elena Bîcu, Amaury Farce, Joëlle Dubois, Alina Ghinet
• Journal: Bioorganic chemistry (Bioorg Chem) Vol. 103 Pg. 104184 (10 2020) ISSN: 1090-2120 [Electronic] United States
• PMID: 32891861 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents
• Enzyme Inhibitors
• Indolizines
• Phenothiazines
• Tubulin
• Tubulin Modulators
• Farnesyltranstransferase

Topics

• Antineoplastic Agents (chemical synthesis, metabolism, pharmacology)
• Binding Sites
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Drug Design
• Drug Screening Assays, Antitumor
• Enzyme Inhibitors (chemical synthesis, metabolism, pharmacology)
• Farnesyltranstransferase (antagonists & inhibitors, chemistry, metabolism)
• Humans
• Indolizines (chemical synthesis, metabolism, pharmacology)
• Molecular Docking Simulation
• Molecular Structure
• Phenothiazines (chemical synthesis, metabolism, pharmacology)
• Protein Binding
• Structure-Activity Relationship
• Tubulin (chemistry, metabolism)
• Tubulin Modulators (chemical synthesis, metabolism, pharmacology)