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

Der-Yen Lee,Hui-Yi Lin,Kuo-Hsiung Lee,Min-Tsang Hsieh,Sheng-Chu Kuo,Jai-Sing Yang,Tsu-Yuan Chang,Yu-Chi Hou

doi:10.3390/molecules25030479

Abstract

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 2–6 are 4,4-dimethylated, 4,4-diethylated, 4,4-dibenzylated, 4,4-dipropargylated and 4,4-diallylated compound 1, respectively. Compounds 2m–6m, the ester hydrolysis products of compounds 2–6, 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.

Highlights

Curcumin [(1E,6E)-1,7-bis(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-dione, the structureCurcumin [(1E,6E)-1,7-bis(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-dione, the structure of which is shown in Scheme 1], the naturally occurring phytochemical from the rhizome of Curcuma of which is shown in Scheme 1], the naturally occurring phytochemical from the rhizome of Curcuma longa L., is a polyphenol with a symmetrical structure composed of two ortho-methoxyphenol rings longa L., is a polyphenol with a symmetrical structure composed of two ortho-methoxyphenol rings connected to each other through a flexible conjugated hydrocarbon chain
Structural modifications at the C-4 position of compound 1, a 2,2-bis(hydroxymethyl)propionate curcumin prodrug, with polar and nonpolar functional groups were performed to form a series of 4,4-disubstituted analogs of 1 and dimethyl curcumin (DMC)
The in vitro anti-proliferative assay of these derivatives elucidated an obvious SAR in which the enhancement of polarity on C-4 resulted in the erosion of anticancer activity

Summary

Introduction

Curcumin [(1E,6E)-1,7-bis(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-dione, the structureCurcumin [(1E,6E)-1,7-bis(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-dione, the structure of which is shown in Scheme 1], the naturally occurring phytochemical from the rhizome of Curcuma of which is shown in Scheme 1], the naturally occurring phytochemical from the rhizome of Curcuma longa L., is a polyphenol with a symmetrical structure composed of two ortho-methoxyphenol rings longa L., is a polyphenol with a symmetrical structure composed of two ortho-methoxyphenol rings connected to each other through a flexible conjugated hydrocarbon chain. Similar to some phenolic natural products, curcumin is a gene expression [7] and protein binding [8]. Similar to some phenolic natural products, curcumin is multi-target anticancer agent [9] with the ability to interfere with several signaling pathways associated a multi-target anticancer agent [9] with the ability to interfere with several signaling pathways with tumor progression, metastasis, apoptosis, and angiogenesis [10].

Methods

Results

Conclusion