Inhibition of Human Topoisomerase II by N,N,N‐Trimethylethanammonium Iodide Alkylcarbazole Derivatives

• DOI: 10.1002/cmdc.201800546
• Publication Date: 2018-10-22T21:39:57Z
• Authors: Carmela Saturnino; Anna Caruso; Domenico Iacopetta; Camillo Rosano; Jessica Ceramella; Noemi Muià; Annaluisa Mariconda; Maria Grazia Bonomo; Marco Ponassi; Giuseppe Rosace; Maria Stefania Si...; Pasquale Longo
• Keywords: 0301 basic medicine; topoisomerase II; caspase; Carbazoles; Apoptosi; Antineoplastic Agents; Apoptosis; Breast Neoplasms; N-alkylcarbazole; 3. Good health; Molecular Docking Simulation; Quaternary Ammonium Compounds; Structure-Activity Relationship; 03 medical and health sciences; apoptosis; caspases; docking simulations; N-alkylcarbazoles; topoisomerase II; Biochemistry; Molecular Medicine; Pharmacology; Drug Discovery3003 Pharmaceutical Science; Pharmacology, Toxicology and Pharmaceutics (all); Organic Chemistry; DNA Topoisomerases, Type II; docking simulation; Cell Line, Tumor; Humans; Topoisomerase II Inhibitors; Female; Ellipticines; Drug Screening Assays, Antitumor; Cell Proliferation

Abstract Chemotherapy is used for the treatment of all stages breast cancer, including metastatic stage disease. Treatment regimens are generally tailored each patient′s particular situation. However, chemotherapeutic agents leading cause serious drug‐related adverse effects; moreover, drug resistance often occurs. In this study, we designed and synthesized a new series N ‐alkylcarbazoles derived from ellipticine, an alkaloid with carbazole skeleton initially in cancer later dismissed because poor aqueous solubility severe side effects. After evaluating binding modes our class newly compounds human topoisomerase II (hTopo II), performed hTopo decatenation assays, identifying compound 4 f (2‐(4‐((3‐chloro‐9 H ‐carbazol‐9‐yl)pentyl)piperazin‐1‐yl)‐ , ‐trimethylethanammonium iodide) as good inhibitor. Moreover, g ‐carbazol‐9‐yl)hexyl)piperazin‐1‐yl)‐ showed anti‐proliferative activity toward cells, causing apoptosis by activation caspase pathway. Interestingly, these two on triple‐negative MDA‐MB‐231 which tend to be highly aggressive, strictly connected observed inhibition II.