Synthesis of novel C5-curcuminoid-fatty acid conjugates and mechanistic investigation of their anticancer activity

Abstract

The first synthesis of C5-Curcumin-Fatty Acid (C5-Curc-FA) conjugates was successfully performed. Through a two-step synthetic route, 10 analogs were synthesized for a structure-activity relationship (SAR) study. It was found that C5-Curc-FA conjugates containing either decanoic acid or palmitic acid moieties were cytotoxic against colorectal adenocarcinoma cell (CCL-229) at IC50s ranging from 22.5 to 56.1 µg/mL, being 5c the most active C5-Curc-FA conjugate. Our results strongly suggests that a decanoic acid moiety at the meta position in C5-Curc-FA conjugates is important for their anticancer activity effect. Possible mechanisms for the anticancer activity of C5-Curc-FA conjugates were also investigated including apoptosis induction, mitochondrial damage and caspases activation. It was shown that 5c inhibited the luminescence activity of NFκB, a key signaling molecule involved in cell apoptosis and cell proliferation, at IC50 = 18.2 µg/mL. In addition, it was demonstrated that 5c displayed significant apoptotic effect at GI50 = 46.0 µg/mL in colorectal adenocarcinoma cell line (ATCC CCL-222), which can be explained by the significant mitochondrial membrane permeabilization and caspases 3 and 7 activation effect of 5c. Finally, it was investigated that C5-Curc-FA conjugates can affect the replication process of cancer cells, since compounds 5c, 5e, and 6c inhibited the relaxing activity of the human DNA topoisomerase I at minimum inhibitory concentrations (MICs) that range from 50 to 500 µg/mL. Our results strongly support the hypothesis that the inhibition of both NFkB and DNA topoisomerase I by C5-Curc-FA conjugates is associated with their anticancer activity.

Biological activities of curcuminoids, other biomolecules from turmeric and their derivatives – A review

“…The studied active compounds were potent stimulators of apoptosis and can be useful for anticancer activity. Sanabria-Rios et al 145 have synthesized C5-curcumin-fatty acid conjugates (C5-CUR-FA) containing decanoic acid or palmitic acid moieties through a two-step synthetic route, 10 analogs in order to determine survey activity relationship (SAR) study using the colorectal adenocarcinoma cell (CCL-229). Decanoic acid moiety at the meta position in C5-CUR-FA conjugates is important for their anticancer activity effect.…”

The Therapeutic and Preventive Efficacy of Curcumin and Its Derivatives in Esophageal Cancer

“…In chronic myeloid leukemia and colon cancer cell line HCT116 the C5 Curcumin-Fatty Acid conjugates containing either a ten carbon decanoic acid or a sixteen carbon palmitic acid moieties (Sanabria-Ríos et al, 2015) analog of curcumin shows the good cytotoxic effect by inhibiting the TNF-α-induced NF-κB activation in these cancers than the curcumin. Research has been performed on the study of various analogs of C5 curcumin in cancer treatment because of its effective anti-inflammatory properties as compared to curcumin alone (Allegra et al, 2017).…”

Chemical conjugation of 2-hexadecynoic acid to C5-curcumin enhances its antibacterial activity against multi-drug resistant bacteria

“…Then, 2-HDA was conjugated to vanillin, using Steglich esterification conditions as described in the literature, 21-22 affording 5 in a 40% yield. Compound 5 was subsequently reacted with acetone and lithium hydroxide monohydrate to obtain 6 in a 45% yield.…”

“…Compound 5 was subsequently reacted with acetone and lithium hydroxide monohydrate to obtain 6 in a 45% yield. The synthetic strategy displayed in Scheme 1 was also used to prepare the C5-Curcumin-Palmitic Acid ( C5-Curc-PA ) conjugate as described by Sanabria-Ríos et al 22 …”

“…In addition to Vero cells, the toxicity of 2 and 6 was also determined in peripheral blood mononuclear cells (PBMCs) from healthy volunteers as described by Sanabria-Ríos et al 19,22 The cytotoxicity of 2 and 6 against both Vero cells and PBMCs are displayed in Table 2. Therapeutic Indexes (TIs) of the above-mentioned compounds were calculated as reported by Sanabria-Ríos.…”