title: Antiandrogenic activity of anthranilic acid ester derivatives as novel lead structures to inhibit prostate cancer cell proliferation.
abstract: A plant extract from the fruits of saw palmetto, which is currently used to treat the androgen-dependent benign prostatic hyperplasia and PCa, served as source for new structure variants. We investigated the antiandrogenic potential of an ethanolic total extract and one of its main aromatic components anthranilic acid. An androgen receptor-antagonistic (antiandrogenic) effect of the extract was evident, and although anthranilic acid itself revealed no remarkable effect, its methyl ester, methyl anthranilate, exhibited antiandrogenic potential. Based on this chemical structure, we synthesized and investigated the antiandrogenic activity of four AnA ester derivatives, which were either novel or only little described in literature. These AnA esters inhibit the androgen-dependent transactivation of both the wild-type (wt) androgen receptor and the androgen receptor point mutant T877A, which often occurs in refractory PCa. Moreover, they inhibit the androgen receptor-induced expression of the endogenous prostate-specific antigen. Importantly, AnA esters repress the growth of human PCa cells. Deletion analyses of androgen receptor propose that the antiandrogenic effect of anthranilic acid esters is mediated by the ligand-binding domain, most likely through direct binding, without affecting androgen receptor protein levels. Taken together, the data suggest antiandrogenic potential of anthranilic acid ester derivatives, which can serve as lead structures for novel antiandrogens.
authors: Institute of Human Genetics, Jena University Hospital, Germany.
authors: Daniela
authors: D
authors: Roell
authors: Thomas W
authors: TW
authors: Rösler
authors: Stephanie
authors: S
authors: Degen
authors: Rudolf
authors: R
authors: Matusch
authors: Aria
authors: A
authors: Baniahmad
mesh_terms: D000726:Androgen Antagonists / Q000737:chemistry / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000494:pharmacology*; D002277:Carcinoma / Q000188:drug therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D008297:Male; D009154:Mutation / Q000187:drug effects; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism; D028024:Serenoa / Q000737:chemistry*; D062367:ortho-Aminobenzoates / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C410798:AR protein, human; D000726:Androgen Antagonists; D000972:Antineoplastic Agents, Phytogenic; D010936:Plant Extracts; D011944:Receptors, Androgen; D062367:ortho-Aminobenzoates; C031385:anthranilic acid; C040972:saw palmetto extract