title: Silibinin derivatives as anti-prostate cancer agents: Synthesis and cell-based evaluations.
abstract: This study aims to systematically explore the alkylation effect of 7-OH in silibinin and 2,3-dehydrosilibinin on the antiproliferative potency toward three prostate cancer cell lines. Eight 7-O-alkylsilibinins, eight 7-O-alkyl-2,3-dehydrosilibinins, and eight 3,7-O-dialkyl-2,3-dehydrosilibinins have been synthesized from commercially available silibinin for the in vitro cell-based evaluation. The WST-1 cell proliferation assay indicates that nineteen out of twenty-four silibinin derivatives have significantly improved antiproliferative potency when compared with silibinin. 7-O-Methylsilibinin (2) and 7-O-ethylsilibinin (3) have been identified as the most potent compounds with 98- and 123-fold enhanced potency against LNCaP human androgen-dependent prostate cancer cell line. Among 2,3-dehydrosilibinin derivatives, 7-O-methyl-2,3-dehydrosilibinin (10) and 7-O-ethyl-2,3-dehydrosilibinin (11) have been identified as the optimal compounds with the highest potency towards both androgen-dependent LNCaP and androgen-independent PC-3 prostate cancer cell lines. 7-O-Ethyl-2,3-dehydrosilibinin (11) was demonstrated to arrest PC-3 cell cycle at the G0/G1 phase and to induce PC-3 cell apoptosis. The findings in this study suggest that antiproliferative potency of silibinin and 2,3-dehydrosilibinin can be appreciably enhanced through suitable chemical modifications on the phenolic hydroxyl group at C-7 and that introduction of a chemical moiety with the potential to improve bioavailability through a linker to 7-OH in silibinin and 2,3-dehydrosilibinin would be a feasible strategy for the development of silibinin derivatives as anti-prostate cancer agents.
authors.affiliation: Department of Chemistry, California State University, Fresno, 2555 E. San Ramon Avenue, M/S SB70, Fresno, CA 93740, USA.
authors.forename: Bao
authors.initials: B
authors.lastname: Vue
authors.affiliation: Department of Chemistry, California State University, Fresno, 2555 E. San Ramon Avenue, M/S SB70, Fresno, CA 93740, USA.
authors.forename: Sheng
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Chemistry, California State University, Fresno, 2555 E. San Ramon Avenue, M/S SB70, Fresno, CA 93740, USA.
authors.forename: Xiaojie
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Chemistry, California State University, Fresno, 2555 E. San Ramon Avenue, M/S SB70, Fresno, CA 93740, USA.
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Parisis
authors.affiliation: RCMI Cancer Research Center Xavier University of Louisiana, 1 Drexel Drive, New Orleans, LA 70125, USA.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: RCMI Cancer Research Center Xavier University of Louisiana, 1 Drexel Drive, New Orleans, LA 70125, USA.
authors.forename: Shilong
authors.initials: S
authors.lastname: Zheng
authors.affiliation: RCMI Cancer Research Center Xavier University of Louisiana, 1 Drexel Drive, New Orleans, LA 70125, USA; Department of Chemistry, Xavier University of Louisiana, 1 Drexel Drive, New Orleans, LA 70125, USA.
authors.forename: Guangdi
authors.initials: G
authors.lastname: Wang
authors.affiliation: Department of Chemistry, California State University, Fresno, 2555 E. San Ramon Avenue, M/S SB70, Fresno, CA 93740, USA. Electronic address: qchen@csufresno.edu.
authors.forename: Qiao-Hong
authors.initials: QH
authors.lastname: Chen
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D008297:Male; D011467:Prostate / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000077385:Silybin; D012838:Silymarin / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D012838:Silymarin; D000077385:Silybin
keywords: Anti-proliferative activity; Cell apoptosis; Prostate cancer; Silibinin derivatives; Structure–activity relationship