title: Design and synthesis of novel 2-substituted 11-keto-boswellic acid heterocyclic derivatives as anti-prostate cancer agents with Pin1 inhibition ability.
abstract: A series of novel acetyl-11-keto-β-boswellic acid (AKBA) derivatives with a different electron-withdrawing group on ring A and a nitrogen heterocycle at C-24 were designed and synthesized. These semi-synthetic compounds showed improved anti-proliferative activity against prostate cancer cells over AKBA. Compound 8f bearing 2-cyano-3,11-dioxo moiety and piperazine was the most potent to inhibit growth of prostate cancer PC-3 (IC50= 0.04 μM) and LNCaP (IC50= 0.27 μM) cell lines. 8f caused cell cycle arrest in G2/M and induced apoptosis. 8f decreased the protein levels of anti-apoptosis protein Mcl-1, c-FLIP and cell cycle regulating protein cyclin D1. 8f inhibited the activity of Pin1, a peptidyl-prolyl cis-trans isomerase to stabilize cyclin D1. 8f represented a compound with improved anti-proliferative effects for prostate cancer therapy working through new mechanisms.
authors.affiliation: Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
authors.forename: Kun
authors.initials: K
authors.lastname: Li
authors.affiliation: School of Life Sciences and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang 110016, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Li
authors.affiliation: Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
authors.forename: Shuxiang
authors.initials: S
authors.lastname: Wang
authors.affiliation: Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Li
authors.affiliation: Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
authors.forename: Tianyi
authors.initials: T
authors.lastname: Ma
authors.affiliation: Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China. Electronic address: sammyld@163.com.
authors.forename: Dan
authors.initials: D
authors.lastname: Liu
authors.affiliation: School of Life Sciences and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang 110016, China. Electronic address: yongkjing@yahoo.com.
authors.forename: Yongkui
authors.initials: Y
authors.lastname: Jing
authors.affiliation: Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China. Electronic address: linxiang.zhao@vip.sina.com.
authors.forename: Linxiang
authors.initials: L
authors.lastname: Zhao
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D060326:Chemistry Techniques, Synthetic; D015195:Drug Design; D006801:Humans; D008297:Male; D062105:Molecular Docking Simulation; D000072340:NIMA-Interacting Peptidylprolyl Isomerase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000473:pathology*; D014315:Triterpenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
chemical_list: C447943:11-keto-boswellic acid; D000970:Antineoplastic Agents; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D014315:Triterpenes
keywords: Acetyl-11-keto-β-boswellic acid; Anti-proliferative activity; Cell cycle; Cyclin D1; Pin1