title: Synthesis, characterization and biological evaluation of succinate prodrugs of curcuminoids for colon cancer treatment.
abstract: A novel series of succinyl derivatives of three curcuminoids were synthesized as potential prodrugs. Symmetrical (curcumin and bisdesmethoxycurcumin) and unsymmetrical (desmethoxycurcumin) curcuminoids were prepared through aldol condensation of 2,4-pentanedione with different benzaldehydes. Esterification of these compounds with a methyl or ethyl ester of succinyl chloride gave the corresponding succinate prodrugs in excellent yields. Anticolon cancer activity of the compounds was evaluated using Caco-2 cells. The succinate prodrugs had IC₅₀ values in the 1.8-9.6 μM range, compared to IC₅₀ values of 3.3-4.9 μM for the parent compounds. Curcumin diethyl disuccinate exhibited the highest potency and was chosen for stability studies. Hydrolysis of this compound in phosphate buffer at pH 7.4 and in human plasma followed pseudo first-order kinetics. In phosphate buffer, the k(obs) and t(½) for hydrolysis indicated that the compound was much more stable than curcumin. In human plasma, this compound was able to release curcumin, therefore our results suggest that succinate prodrugs of curcuminoids are stable in phosphate buffer, release the parent curcumin derivatives readily in human plasma, and show anti-colon cancer activity.
authors.affiliation: Pharmaceutical Technology (International) Program, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand.
authors.forename: Wisut
authors.initials: W
authors.lastname: Wichitnithad
authors.forename: Ubonthip
authors.initials: U
authors.lastname: Nimmannit
authors.forename: Sumrit
authors.initials: S
authors.lastname: Wacharasindhu
authors.forename: Pornchai
authors.initials: P
authors.lastname: Rojsitthisak
mesh_terms: D018938:Caco-2 Cells; D003110:Colonic Neoplasms / Q000188:drug therapy*; D003474:Curcumin / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D015394:Molecular Structure; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*; D013386:Succinates / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*
chemical_list: D011355:Prodrugs; D013386:Succinates; C000614237:curcumin diethyl disuccinate; D003474:Curcumin