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

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.

Synthesis and Characterization of the Ethylene-Carbonate-Linked L-Valine Derivatives of 4,4-Dimethylcurcumin with Potential Anticancer Activities

“…Visualization was performed under UV irradiation at 254 nm followed by staining with aqueous potassium permanganate [KMnO 4 (3 g) and K 2 CO 3 (20 g) in 300 mL of H 2 O containing 5 mL of an aqueous solution of NaOH (5%, w/v)] and charring by heat gun. 1 H and 13 C NMR spectra were recorded on 500 or 400 FT NMR (Bruker, Billerica, MA, USA). Copies of 1 H, 13 C NMR and mass spectra of the synthetic products (5, 6, 7, 8, 1-TFA and 2-TFA) could be found in Supplementary Materials.…”

“…1 H and 13 C NMR spectra were recorded on 500 or 400 FT NMR (Bruker, Billerica, MA, USA). Copies of 1 H, 13 C NMR and mass spectra of the synthetic products (5, 6, 7, 8, 1-TFA and 2-TFA) could be found in Supplementary Materials. Chloroform-d, methanol-d and d-DMSO were used as solvents and TMS (δ = 0.00 ppm) as an internal standard.…”

“…The crude product was purified by chromatography with ethyl acetate to get the tert-butyl (S)-(1-((2-hydroxyethyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (5) (3.930 g, 82%) as a colorless oil. 1 H NMR (500 MHz, CDCl 3 ): 5.54 (br s, 1H), 4.00 (br s, 1H), 3.87 (t, J = 7.5 Hz, 1H), 3.63-3.60 (m, 2H), 3.37-3.28 (m, 2H), 1.99-1.97 (m, 1H), 1.36 (s, 9H), 0.90-0.86 (m, 6H); 13…”

“…DMCU-HMP is expected to convert into DMCU in vivo because the 2,2bis(hydroxymethyl) propionate group of DMCU-HMP could readily cleave upon treatment with a considerable amount of esterase that usually exists in plasma, gastrointestinal tract, and liver, respectively. Shortly thereafter, our pharmacokinetic evaluations of DMCU-HMP illustrated that DMCU appeared in serum of mice after oral administration of DMCU-HMP and both DMCU-HMP and DMCU are contributors to in vivo antitumor efficacy [13]. A formulation study of DMCU-HMP is still ongoing in our lab with the intention of increasing oral bioavailability.…”

Food and Drug Analysis

“…Curcumin is the naturally occurring phytochemical from the rhizome of Curcuma longa L. It is a polyphenol with a symmetrical structure composed of two ortho-methoxyphenol rings connected to each other through a flexible conjugated hydrocarbon chain. Lee et al [9] reported a series of derivatives modified from the 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. The established structure-activity relationship and pharmacokinetic outcomes are the guidance for future development of 4,4-disubstituted curcuminoid 2,2-bis(hydroxymethyl)-propionate derivatives as anticancer drug candidates.…”