Design, Synthesis and Cancer Cell Growth Inhibition Evaluation of New Aminoquinone Hybrid Molecules

• Published in: Molecules (Basel, Switzerland) Switzerland), 2019-06, Vol.24 (12), p.2224
• Main Authors: Defant, Andrea, Mancini, Ines
• Format: Article
• Language: English
• Subjects: 3,4,5-trimethoxyphenyl group; Amides - pharmacology; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; antitumor activity; Apoptosis; Cancer; Cancer therapies; Cell adhesion & migration; Cell cycle; Cell Line, Tumor; Cell Proliferation - drug effects; Chromatography; Clinical trials; cytotoxicity; Deoxyribonucleic acid; Design; DNA; DNA Topoisomerases, Type II - chemistry; DNA Topoisomerases, Type II - genetics; docking calculation; Dose-Response Relationship, Drug; Drug dosages; Drug Screening Assays, Antitumor; Enzymes; Humans; hybrid molecules; Hybridization; Kinases; Molecular Docking Simulation; Molecular Structure; Naphthoquinones - chemical synthesis; Naphthoquinones - chemistry; naphtoquinones; Neoplasms - drug therapy; Neoplasms - genetics; Podophyllotoxin - pharmacology; Polymerization; Proteins; Pyridines - pharmacology; quinolinequinones; Quinolines - chemical synthesis; Quinolines - chemistry; Quinones; rho-Associated Kinases - antagonists & inhibitors; rho-Associated Kinases - chemistry; rho-Associated Kinases - genetics; Stilbenes - pharmacology; Structure-Activity Relationship; Topoisomerase II Inhibitors - chemical synthesis; Topoisomerase II Inhibitors - chemistry; Topoisomerase II Inhibitors - pharmacology; Tubulin - chemistry; Tubulin - genetics; Tubulin Modulators - chemical synthesis; Tubulin Modulators - chemistry; Tubulin Modulators - pharmacology; Tumor cell lines
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules24122224

Molecular hybridization has proven to be a successful multi-target strategy in the design and development of new antitumor agents. Based on this rational approach, we have planned hybrid molecules containing covalently linked pharmacophoric units, present individually in compounds acting as inhibitors of the cancer protein targets tubulin, human topoisomerase II and ROCK1. Seven new molecules, selected by docking calculation of the complexes with each of the proteins taken into consideration, have been efficiently synthesized starting from 2,3-dichloro-1,4-naphtoquinone or 6,7-dichloro-5,8-quinolinquinone. By screening the full National Cancer Institute (NCI) panel, including 60 human cancer cell lines, four molecules displayed good and sometimes better growth inhibition GI than the ROCK inhibitor Y-27632, the Topo II inhibitor podophyllotoxin and the tubulin inhibitor combretastatin A-4. The relative position of heteroatoms in the structures of the tested compounds was crucial in affecting bioactivity and selectivity. Furthermore, compound (2-(4-(2-hydroxyethyl)piperazin-1-yl)-3-(3,4,5-trimethoxyphenoxy)naphthalene-1,4-dione) emerged as the most active in the series, showing a potent and selective inhibition of breast cancer BT-549 cells (GI < 10 nM).