title: Studies in polyphenol chemistry and bioactivity. 4.(1) Synthesis of trimeric, tetrameric, pentameric, and higher oligomeric epicatechin-derived procyanidins having all-4beta,8-interflavan connectivity and their inhibition of cancer cell growth through cell cycle arrest.
abstract: We report an improved synthesis of bis(5,7,3',4'-tetra-O-benzyl)epicatechin 4beta,8-dimer (3) from 5,7,3',4'-tetra-O-benzylepicatechin (1) and 5,7,3',4'-tetra-O-benzyl-4-(2-hydroxyethoxy)epicatechin (2) by replacing the previously employed Lewis acid, titanium tetrachloride, with the clay mineral Bentonite K-10. Under the same conditions, the benzyl-protected all-4beta,8-trimer, -tetramer, and -pentamer were obtained regioselectively from their lower homologues, albeit in rapidly decreasing yields. Reaction of 2 with an organoaluminum thiolate generated from 2-mercaptobenzothiazole and trimethylaluminum followed by acetylation produced 3-O-acetyl-4-[(2-benzothiazolyl)thio]-5,7,3',4'-tetra-O-benzylepicatechin (12). Medium-sized protected oligomers with 4beta,8-interflavan linkages are obtained in improved yields by using this compound as the electrophile and silver tetrafluoroborate as activator and are isolated by reversed-phase HPLC. Their deprotection by ester saponification followed by hydrogenolysis yielded the free procyanidins, which were characterized as their peracetates. The synthetic procyanidins are identical by normal-phase HPLC with fractions isolated from cocoa. The principle of chain extension by two members was demonstrated using a dimeric electrophile obtained by self-condensation of compound 12. Both the synthetic and natural pentamer 32 inhibit the growth of several breast cancer cell lines. Using the MDA MB 231 line, it was established that this outcome is based on the induction of cell cycle arrest in the G0/G1 phase. Subsequent cell death is more likely necrotic rather than apoptotic. Control experiments demonstrate that the polyphenol itself, rather than hydrogen peroxide potentially formed by its autoxidation, is the causative agent.
authors.affiliation: Georgetown University Medical Center, Department of Neurology, Drug Discovery Laboratory, 3900 Reservoir Road NW, Washington, DC 20007, USA. kozikowa@georgetown.edu
authors.forename: Alan P
authors.initials: AP
authors.lastname: Kozikowski
authors.forename: Werner
authors.initials: W
authors.lastname: Tückmantel
authors.forename: Gesine
authors.initials: G
authors.lastname: Böttcher
authors.forename: Leo J
authors.initials: LJ
authors.lastname: Romanczyk
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D044946:Biflavonoids; D001943:Breast Neoplasms; D002384:Catalysis; D002392:Catechin / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D004354:Drug Screening Assays, Antitumor; D005260:Female; D005419:Flavonoids; D005434:Flow Cytometry; D006801:Humans; D015394:Molecular Structure; D010084:Oxidation-Reduction; D010636:Phenols / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011108:Polymers / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D044945:Proanthocyanidins; D013237:Stereoisomerism; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D044946:Biflavonoids; D005419:Flavonoids; D010636:Phenols; D011108:Polymers; D044945:Proanthocyanidins; C017674:procyanidin; D002392:Catechin