2. Academic Validation
  3. Synthesis of novel C5-curcuminoid-fatty acid conjugates and mechanistic investigation of their anticancer activity

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

  • Bioorg Med Chem Lett. 2015;25(10):2174-80. doi: 10.1016/j.bmcl.2015.03.065.
David J Sanabria-Ríos 1,  Yaritza Rivera-Torres 2,  Joshua Rosario 2,  Camille Ríos 2,  Ricardo Gutierrez 2,  Néstor M Carballeira 3,  Christian Vélez 4,  Beatriz Zayas 4,  Félix Álvarez-Colón 5,  Gabriela Ortiz-Soto 5,  Victor Serrano 5,  Joanne Altieri-Rivera 5,  Eddy Ríos-Olivares 5,  José W Rodríguez 5
Affiliations

Affiliations

  • 1 Faculty of Science and Technology, Inter American University of Puerto Rico, Metropolitan Campus, PO Box 191293, San Juan, PR 00919, United States. Electronic address: [email protected].
  • 2 Faculty of Science and Technology, Inter American University of Puerto Rico, Metropolitan Campus, PO Box 191293, San Juan, PR 00919, United States.
  • 3 Department of Chemistry, University of Puerto Rico, Rio Piedras Campus, PO Box 23346, San Juan, PR 00931-3346, United States.
  • 4 School of Environmental Affairs, Universidad Metropolitana, PO Box 21150, San Juan, PR 00928, United States.
  • 5 Department of Microbiology and Immunology, Universidad Central del Caribe School of Medicine, PO Box 60327, Bayamón, PR 00960, United States.
PMID: 25881826 DOI: 10.1016/j.bmcl.2015.03.065
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 56.1μg/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=18.2μg/mL. In addition, it was demonstrated that 5c displayed significant apoptotic effect at GI50=46.0μg/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 250μg/mL. Our results strongly support the hypothesis that the inhibition of both NFκB and DNA Topoisomerase I by C5-Curc-FA conjugates is associated with their Anticancer activity.

Keywords

Anticancer agents; Apoptosis; C5-curcuminoids synthesis; DNA topoisomerase I; NFκB.

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