Synthesis, Biological Evaluation, and Molecular Modeling Studies of 1-Aryl-1 H -pyrazole-Fused Curcumin Analogues as Anticancer Agents.

Autor: Doan NQH; Faculty of Pharmacy, Van Lang University, Ho Chi Minh City 700000, Vietnam., Nguyen NTK; Department of Organic Chemistry, Faculty of Pharmacy, University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh City 700000, Vietnam., Duong VB; Department of Organic Chemistry, Faculty of Pharmacy, University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh City 700000, Vietnam., Nguyen HTT; School of Biomedical Engineering, International University, Vietnam National University Ho Chi Minh City, Ho Chi Minh City 700000, Vietnam., Vong LB; School of Biomedical Engineering, International University, Vietnam National University Ho Chi Minh City, Ho Chi Minh City 700000, Vietnam., Duong DN; Immunology Lab, Vaccines and Biologicals Production Department, Pasteur Institute in Ho Chi Minh City, Ho Chi Minh City 700000, Vietnam., Nguyen NT; Immunology Lab, Vaccines and Biologicals Production Department, Pasteur Institute in Ho Chi Minh City, Ho Chi Minh City 700000, Vietnam., Nguyen TLT; Saigon Pharmaceutical Sciences and Technologies Center, Ho Chi Minh City 700000, Vietnam., Do TTH; Department of Pharmacology, Faculty of Pharmacy, University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh City 700000, Vietnam., Truong TN; Department of Organic Chemistry, Faculty of Pharmacy, University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh City 700000, Vietnam.
Jazyk: angličtina
Zdroj: ACS omega [ACS Omega] 2022 Sep 16; Vol. 7 (38), pp. 33963-33984. Date of Electronic Publication: 2022 Sep 16 (Print Publication: 2022).
DOI: 10.1021/acsomega.2c02933
Abstrakt: Addressing the growing burden of cancer and the shortcomings of chemotherapy in cancer treatment are the current research goals. Research to overcome the limitations of curcumin and to improve its anticancer activity via its heterocycle-fused monocarbonyl analogues (MACs) has immense potential. In this study, 32 asymmetric MACs fused with 1-aryl-1 H -pyrazole ( 7a-10h ) were synthesized and characterized to develop new curcumin analogues. Subsequently, via initial screening for cytotoxic activity, nine compounds exhibited potential growth inhibition against MDA-MB-231 (IC 50 2.43-7.84 μM) and HepG2 (IC 50 4.98-14.65 μM), in which seven compounds showing higher selectivities on two cancer cell lines than the noncancerous LLC-PK1 were selected for cell-free in vitro screening for effects on microtubule assembly activity. Among those, compounds 7d , 7h , and 10c showed effective inhibitions of microtubule assembly at 20.0 μM (40.76-52.03%), indicating that they could act as microtubule-destabilizing agents. From the screening results, three most potential compounds, 7d , 7h , and 10c , were selected for further evaluation of cellular effects on breast cancer MDA-MB-231 cells. The apoptosis-inducing study indicated that these three compounds could cause morphological changes at 1.0 μM and could enhance caspase-3 activity (1.33-1.57 times) at 10.0 μM in MDA-MB-231 cells, confirming their apoptosis-inducing activities. Additionally, in cell cycle analysis, compounds 7d and 7h at 2.5 μM and 10c at 5.0 μM also arrested MDA-MB-231 cells in the G 2 /M phase. Finally, the results from in silico studies revealed that the predicted absorption, distribution, metabolism, excretion, and the toxicity (ADMET) profile of the most potent MACs might have several advantages in addition to potential disadvantages, and compound 7h could bind into (Δ G -10.08 kcal·mol -1 ) and access wider space at the colchicine-binding site (CBS) than that of colchicine or nocodazole via molecular docking studies. In conclusion, our study serves as a basis for the design of promising synthetic compounds as anticancer agents in the future.
Competing Interests: The authors declare no competing financial interest.
(© 2022 The Authors. Published by American Chemical Society.)
Databáze: MEDLINE
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