Design, synthesis and in vitro cell-based evaluation of the anti-cancer activities of hispolon analogs

Abstract

Phytochemicals play an important role in cancer therapy. Hispolon and 26 of its analogs (9 known and 17 new) were synthesized and evaluated for their antiproliferative activities in a panel of six independent human cancer cell lines using the in vitro cell-based MTT assay. Among the hispolon analogs tested, Compound VA-2, the most potent overall, produced its most significant effect in the colon cancer cell lines HCT-116 (IC50 1.4±1.3 μM) and S1 (IC50 1.8±0.9 μM) compared to its activity in the normal HEK293/pcDNA3.1 cell line (IC50 15.8±3.7 μM; p<0.01 for each comparison). Based on our results, VA-2 was about 9- to 11-times more potent in colon cancer cells and 2- to 3-times more potent in prostate cancer cells compared to HEK293/pcDNA3.1 cells. Morphological analysis of VA-2 showed significant reduction of cell number, while the cells’ sizes were also markedly increased and were obvious at 68 h of treatment with 1 μM in HCT-116 (colon) and PC-3 (prostate) cancer cells. A known analog, Compound VA-4, prepared by simple modifications on the aromatic functional groups of hispolon, inhibited prostate and colon cancer cell lines with IC50 values < 10 μM. In addition, hispolon isoxazole and pyrazole analogs, VA-7 and VA-15 (known), respectively, have shown significant activity with the mean IC50 values in the range 3.3 to 10.7 μM in all the cancer cell lines tested. Activity varied among the analogs in which aromatic functional groups and β-diketone functional groups are modified. But the activity of analogs VA-16 to VA-27 was completely lost when the side chain double-bond was hydrogenated indicating the crucial role of this functionality for anticancer activity. Furthermore, many of the compounds synthesized were not substrates for the ABCB1-transporter, the most common cause of multidrug resistance in anti-cancer drugs, suggesting they may be more effective anticancer agents.

Toxicity and Antigenotoxic Effect of Hispolon Derivatives: Role of Structure in Modulating Cellular Redox State and Thioredoxin Reductase

“…HS, HME, HP, and HMEP were synthesized, purified, and characterized as reported previously. 21 DMSO, GSH, β-nicotinamide adenine dinucleotide 2′-phosphate reduced tetra sodium salt hydrate (NADPH), GSH reductase, cumene hydroperoxide, cytochalasin B, diethyl pyrocarbonate, acridine orange, CelLytic- reagent, paraformaldehyde, o -phthalaldehyde, N -ethylmaleimide, meta -phosphoric acid, TRI reagent, high and low melting point agarose, di-potassium hydrogen phosphate, potassium dihydrogen phosphate, sodium chloride, potassium chloride, SYBR Green-II dye, protease inhibitor cocktail, and amplification grade DNase from Sigma Chemical Company (St. Louis, MO, USA) were purchased from local agents. The cDNA synthesis kit and ProLong Gold antifade mountant with DAPI from Thermo Scientific (USA), 2X SYBR green PCR mix from Roche Chemical Co (Indianapolis, USA), and 2′,7′-dichlorofluorescin diacetate (DCFDA) from Molecular Probes (USA) were procured through local agents.…”

“…Considering the importance of HS as a pharmacological agent, several of its new derivatives have been synthesized and evaluated for antiproliferative and antitubercular effects. 20 , 21 On similar lines, recently our group reported the abilities of HS and its derivatives such as hispolon pyrazole (HP), hispolon monomethyl ether (HME), and hispolon monomethyl ether pyrazole (HMEP) to scavenge reactive oxygen species (ROS) and to exhibit antioxidant activity in cell-free systems. 22 The exposure of carcinogenic agents such as radiation, pollutants, and xenobiotics are known to increase the intracellular levels of ROS, leading to oxidative damages.…”

A Flexible Strategy for Modular Synthesis of Curcuminoid‐BF2/Curcuminoid Pairs and Their Comparative Antiproliferative Activity in Human Cancer Cell Lines

“…The general synthetic sequence outlined below (Scheme 1), provides a reliable method for the synthesis of symmetrical curcuminoid-BF 2 adducts 3-BF 2 , from which the corresponding CURs 3 are obtained by decomplexation, typically in high yields. [8][9][10] Thus, reaction of acetylacetone-BF 2 adduct, (AA-BF 2 ) 1, with two equivalents of the selected aldehyde 2 in the presence of a mild base (usually n-BuNH 2 ) leads to a double-aldol condensation followed by dehydration to form the corresponding CUR-BF 2 adduct 3-BF 2 which typically falls out of ethyl acetate used as solvent. [8][9][10] Previously reported methods for decomplexation of curcumin-BF 2 adducts employed NaOH in MeOH under heating, [9a] or aq.…”

Dehydroxyhispolon Methyl Ether, A Hispolon Derivative, Inhibits WNT/β-Catenin Signaling to Elicit Human Colorectal Carcinoma Cell Apoptosis

“…In particular, the anticancer action of hispolon involves antiproliferation via the arrest of cell-cycle progression, induction of apoptosis, and inhibition of metastasis [ 15 , 16 , 17 ]. Given the potential of hispolon as an anticancer agent, Balaji et al designed and chemically synthesized a panel of hispolon derivatives that were subjected to an evaluation of in vitro cytotoxicity, in the hope of finding lead molecules with more potent anticancer activity [ 18 ].…”