title: In vitro cytotoxicity of (-)-EGCG octaacetate on MDAMB-231 and SKHep-1 human carcinoma cells: a pharmacological consideration on prodrug design.
abstract: Esterification of acetate with generic pharmaceutical compound has been commonly employed to produce ester prodrug for improving its potency when compared with the mother compound. Acetate, on the other hand, has been recognized to have inhibitory effect on the respiratory biochemistry. Here we demonstrate that acetate at a concentration of 400 microM exhibited significant growth inhibitory activity on two human cancer cell lines, the MDAMB-231 breast cancer and the SKHep-1 hepatoma cell lines. To establish the ester prodrug with multi-acetate ester conjugates as our experimental model, one molecule of (-)-epigallocatechin gallate was required to conjugate with eight molecules of acetate forming the corresponding (-)-epigallocatechin gallate octaacetate prodrug. Chemical structure of this epigallocatechin gallate octaacetate ester prodrug was confirmed by both 13C and 1H nuclear magnetic resonance spectra and mass spectrometry. Further cytotoxic assay using both MDAMB-231 and SKHep-1 human carcinoma cell lines showed that acetate at a concentration of 400 microM exhibits an additional cytotoxic effect with (-)-epigallocatechin gallate at a concentration of 50 microM, although the additional effect was not as high as (-)-epigallocatechin gallate octaacetate ester prodrug alone at a concentration of 50 microM. Our results thus raise a pharmacological consideration of using multi-acetate conjugate as the ester prodrug where the release of free acetate by esterase could be part of the explanation for the improved in vitro cytotoxicity.
authors.affiliation: Department of Applied Biology and Chemical Technology, Hong Kong Polytechnic University, Hong Kong, PR China.
authors.forename: Stanton Hon Lung
authors.initials: SH
authors.lastname: Kok
authors.forename: Raymond Siu Ming
authors.initials: RS
authors.lastname: Wong
authors.forename: Roberto
authors.initials: R
authors.lastname: Gambari
authors.forename: Filly
authors.initials: F
authors.lastname: Cheung
authors.forename: Wing Sze
authors.initials: WS
authors.lastname: Lam
authors.forename: Fung Yi
authors.initials: FY
authors.lastname: Lau
authors.forename: Gregory Yin Ming
authors.initials: GY
authors.lastname: Cheng
authors.forename: Chor Hing
authors.initials: CH
authors.lastname: Cheng
authors.forename: Kim Hung
authors.initials: KH
authors.lastname: Lam
authors.forename: Sau Hing
authors.initials: SH
authors.lastname: Chan
authors.forename: Johnny Cheuk On
authors.initials: JC
authors.lastname: Tang
authors.forename: Chung Hin
authors.initials: CH
authors.lastname: Chui
authors.forename: Kwok Ping
authors.initials: KP
authors.lastname: Ho
mesh_terms: D000085:Acetates / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D002392:Catechin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D006801:Humans; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000085:Acetates; D000970:Antineoplastic Agents; D011355:Prodrugs; D002392:Catechin; C045651:epigallocatechin gallate