title: 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 56.1μg/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.
authors.affiliation: Faculty of Science and Technology, Inter American University of Puerto Rico, Metropolitan Campus, PO Box 191293, San Juan, PR 00919, United States. Electronic address: dsanabria@intermetro.edu.
authors.forename: David J
authors.initials: DJ
authors.lastname: Sanabria-Ríos
authors.affiliation: Faculty of Science and Technology, Inter American University of Puerto Rico, Metropolitan Campus, PO Box 191293, San Juan, PR 00919, United States.
authors.forename: Yaritza
authors.initials: Y
authors.lastname: Rivera-Torres
authors.affiliation: Faculty of Science and Technology, Inter American University of Puerto Rico, Metropolitan Campus, PO Box 191293, San Juan, PR 00919, United States.
authors.forename: Joshua
authors.initials: J
authors.lastname: Rosario
authors.affiliation: Faculty of Science and Technology, Inter American University of Puerto Rico, Metropolitan Campus, PO Box 191293, San Juan, PR 00919, United States.
authors.forename: Camille
authors.initials: C
authors.lastname: Ríos
authors.affiliation: Faculty of Science and Technology, Inter American University of Puerto Rico, Metropolitan Campus, PO Box 191293, San Juan, PR 00919, United States.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Gutierrez
authors.affiliation: Department of Chemistry, University of Puerto Rico, Rio Piedras Campus, PO Box 23346, San Juan, PR 00931-3346, United States.
authors.forename: Néstor M
authors.initials: NM
authors.lastname: Carballeira
authors.affiliation: School of Environmental Affairs, Universidad Metropolitana, PO Box 21150, San Juan, PR 00928, United States.
authors.forename: Christian
authors.initials: C
authors.lastname: Vélez
authors.affiliation: School of Environmental Affairs, Universidad Metropolitana, PO Box 21150, San Juan, PR 00928, United States.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Zayas
authors.affiliation: Department of Microbiology and Immunology, Universidad Central del Caribe School of Medicine, PO Box 60327, Bayamón, PR 00960, United States.
authors.forename: Félix
authors.initials: F
authors.lastname: Álvarez-Colón
authors.affiliation: Department of Microbiology and Immunology, Universidad Central del Caribe School of Medicine, PO Box 60327, Bayamón, PR 00960, United States.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Ortiz-Soto
authors.affiliation: Department of Microbiology and Immunology, Universidad Central del Caribe School of Medicine, PO Box 60327, Bayamón, PR 00960, United States.
authors.forename: Victor
authors.initials: V
authors.lastname: Serrano
authors.affiliation: Department of Microbiology and Immunology, Universidad Central del Caribe School of Medicine, PO Box 60327, Bayamón, PR 00960, United States.
authors.forename: Joanne
authors.initials: J
authors.lastname: Altieri-Rivera
authors.affiliation: Department of Microbiology and Immunology, Universidad Central del Caribe School of Medicine, PO Box 60327, Bayamón, PR 00960, United States.
authors.forename: Eddy
authors.initials: E
authors.lastname: Ríos-Olivares
authors.affiliation: Department of Microbiology and Immunology, Universidad Central del Caribe School of Medicine, PO Box 60327, Bayamón, PR 00960, United States.
authors.forename: José W
authors.initials: JW
authors.lastname: Rodríguez
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D003474:Curcumin / Q000737:chemistry*; D005227:Fatty Acids / Q000737:chemistry*; D006801:Humans
chemical_list: D000970:Antineoplastic Agents; D005227:Fatty Acids; D003474:Curcumin
keywords: Anticancer agents; Apoptosis; C5-curcuminoids synthesis; DNA topoisomerase I; NFκB