Abstract
Cancer is the second leading cause of death, after cardiovascular diseases. Different strategies have been developed to treat cancer; however, chemotherapy with cytotoxic agents is still the most widely used treatment approach. Nevertheless, drug resistance to available chemotherapeutic agents is still a serious problem, and the development of new active compounds remains a constant need. Taking advantage of the molecular hybridization approach, in the present work we designed, synthesized, and tested the cytotoxic activity of two hybrid compounds and seven derivatives based on the structure of combretastatin A-4 and 2,3-diphenyl-2H-indazole. Practical modifications of reported synthetic protocols for 2-pheny-2H-indazole and 2,3-dipheny-2H-indazole derivatives under microwave irradiation were implemented. The cytotoxicity assays showed that our designed hybrid compounds possess strong activity, especially compound 5, which resulted even better than the reference drug cisplatin against HeLa and SK-LU-1 cells (IC50 of 0.16 and 6.63 µM, respectively), and it had similar potency to the reference drug imatinib against K562 cells. Additionally, in silico and in vitro studies strongly suggest tubulin as the molecular target for hybrid compound 5.
Highlights
Cancer is “a group of diseases characterized by uncontrollable growth and spread of abnormal cells, which can invade adjoining parts of the body and spread to other organs” [1,2]
Compounds 5 and 6 decreased the polymerization Vmax, 3.8 and 1.3 times, respectively, in comparison to vehicle (8 and 24 vs. 31 mOD/min). These results suggest that hybrid compound 5 is a potential inhibitor of tubulin polymerization that displays an effect similar to that of CA-4 at 10 μM
Two hybrid compounds of CA-4 and 2,3-diphenyl-2H-indazole (5 and 6) and seven related derivatives were synthesized with microwave assisted chemistry showing short reaction times and good yields
Summary
Cancer is “a group of diseases characterized by uncontrollable growth and spread of abnormal cells, which can invade adjoining parts of the body and spread to other organs” [1,2]. Pharmaceuticals 2021, 14, 815 with cytotoxic agents is still the most widely used treatment approach. Previous studies focused on the search of antiprotozoal compounds showed that 2,3-diphenyl-2H-indazole (4) exhibits cytotoxic activity against HeLa cells (IC50 = 125 μM) [8]. CA-4, isolated from the bushwillow tree Combretum caffrum, is a well-known cytotoxic stilbenoid that acts as a tubulin polymerization inhibitor by binding to the colchicine site [9]. The hybridization of both molecules, 2,3-diphenyl-2H-indazole and CA-4, was pursued to increase the cytotoxic effect by combination of two biologically active structures [8,9,10]. The stabilization of the cis-diphenyl pattern, that can isomerize into the trans isomer in CA-4
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
