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Open AccessFeature PaperArticle

Synthesis, Anticancer Activity, and Preliminary Pharmacokinetic Evaluation of 4,4-Disubstituted Curcuminoid 2,2-bis(Hydroxymethyl)Propionate Derivatives

1
Graduate Institute of Integrated Medicine, China Medical University, No. 91, Hsueh-Shih Road, Taichung 40402, Taiwan
2
School of Pharmacy, China Medical University, Taichung 40402, Taiwan
3
Department of Medical Research, China Medical University Hospital, China Medical University, Taichung 40447, Taiwan
4
Research Center for Chinese Herbal Medicine, China Medical University, Taichung 404, Taiwan
5
Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA
6
Chinese Medicinal Research and Development Center, China Medical University Hospital, Taichung 40447, Taiwan
*
Authors to whom correspondence should be addressed.
Academic Editor: Ping-Chung Kuo
Molecules 2020, 25(3), 479; https://doi.org/10.3390/molecules25030479
Received: 13 January 2020 / Revised: 21 January 2020 / Accepted: 22 January 2020 / Published: 22 January 2020
(This article belongs to the Special Issue Food and Drug Analysis)
Compound 1 is a curcumin di-O-2,2-bis(hydroxymethyl)propionate that shows significant in vitro and in vivo inhibitory activity against MDA-MB-231 cells with eight to ten-fold higher potency than curcumin. Here, we modified the α-position (C-4 position) of the central 1,3-diketone moiety of 1 with polar or nonpolar functional groups to afford a series of 4,4-disubstituted curcuminoid 2,2-bis(hydroxymethyl)propionate derivatives and evaluated their anticancer activities. A clear structure–activity relationship of compound 1 derivatives focusing on the functional groups at the C-4 position was established based on their anti-proliferative effects against the MDA-MB-231 and HCT-116 cell lines. Compounds 26 are 4,4-dimethylated, 4,4-diethylated, 4,4-dibenzylated, 4,4-dipropargylated and 4,4-diallylated compound 1, respectively. Compounds 2m6m, the ester hydrolysis products of compounds 26, respectively, were synthesized and assessed for anticancer activity. Among all compound 1 derivatives, compound 2 emerged as a potential chemotherapeutic agent for colon cancer due to the promising in vivo anti-proliferative activities of 2 (IC50 = 3.10 ± 0.29 μM) and its ester hydrolysis product 2m (IC50 = 2.17 ± 0.16 μM) against HCT-116. The preliminary pharmacokinetic evaluation of 2 implied that 2 and 2m are main contributors to the in vivo efficacy. Compound 2 was further evaluated in an animal study using HCT-116 colon tumor xenograft bearing nude mice. The results revealed a dose-dependent efficacy that led to tumor volume reductions of 27%, 45%, and 60% at 50, 100, and 150 mg/kg doses, respectively. The established structure–activity relationship and pharmacokinetic outcomes of 2 is the guidance for future development of 4,4-disubstituted curcuminoid 2,2-bis(hydroxymethyl)- propionate derivatives as anticancer drug candidates. View Full-Text
Keywords: curcuminoid derivatives; prodrug; colon cancer; breast cancer; active metabolites curcuminoid derivatives; prodrug; colon cancer; breast cancer; active metabolites
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MDPI and ACS Style

Lee, D.-Y.; Hou, Y.-C.; Yang, J.-S.; Lin, H.-Y.; Chang, T.-Y.; Lee, K.-H.; Kuo, S.-C.; Hsieh, M.-T. Synthesis, Anticancer Activity, and Preliminary Pharmacokinetic Evaluation of 4,4-Disubstituted Curcuminoid 2,2-bis(Hydroxymethyl)Propionate Derivatives. Molecules 2020, 25, 479.

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