A set of meta-substituted 3-arylisoquinolinones have been identified that show substantial cytotoxicity in breast, liver, lung and colon cancer cell lines; these are up to 700-fold more active than the corresponding para analogues. These compounds were initially proposed as inhibitors of N-ribosyl dihydronicotinamide (NRH): quinone oxidoreductase 2 (NQO2) but were found to be inactive against the enzyme. Instead, COMPARE analysis suggested that 6-fluoro-3-(meta-fluorophenyl)isoquinolin-1(2H)-one (4) could mimic colchicine and interact with microtubules, a recognized target for cancer therapy. Subsequent docking, molecular dynamics simulations, and free energy analysis further suggested that compound 4 bound well into the colchicine-binding pocket of tubulin. Indeed, 4 suppressed tubulin polymerization, caused G2/M cell cycle arrest, and induced apoptosis. Also, 4 inhibited the formation of endothelial cell capillary-like tubes and further disrupted the structure of preestablished tubes; the effects were not observed with para analogue 5. In accordance with this, the computed free energy of binding of 5 to tubulin was lower in magnitude than that for 4 and appeared to arise in part from the inability of the para substituent to occupy a tubulin subpocket, which is possible in the meta orientation. In conclusion, the antiproliferative potential of the novel 3-arylisoquinolinones is markedly influenced by a subtle change in the structure (meta versus para). The meta-substituted isoquinolinone 4 is a microtubule-destabilizing agent with potential tumor-selectivity and antiangiogenic and vascular disrupting features.
Bibliographical noteFunding Information:
The authors acknowledge the financial support received from the Newton-Mosharafa Doctoral 2015 program, the Egyptian Ministry of Higher Education-Mission Sector, and the Libyan Ministry of Higher Education. Assistance from Research IT and the use of the Computational Shared Facility at the University of Manchester were also acknowledged. Gareth Smith, Department of Chemistry, University of Manchester is acknowledged for recording the MS data. Reynard Spiess, MIB, University of Manchester, was acknowledged for the HPLC-MS data.
© 2022 American Chemical Society.
- Antineoplastic Agents/chemistry
- Cell Line, Tumor
- Cell Proliferation
- Drug Screening Assays, Antitumor
- Molecular Structure
- Structure-Activity Relationship
- Tubulin Modulators/chemistry
ASJC Scopus subject areas
- Drug Discovery
- Molecular Medicine