title: Investigations on cytotoxicity and anti-inflammatory potency of licofelone derivatives.
abstract: A series of C5-substituted licofelone ([2,2-dimethyl-6-(4-chlorophenyl)-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl]acetic acid) derivatives were developed by a parallel synthesis approach and investigated for cytotoxicity against MCF-7 and MDA-MB-231 cells as well as for anti-inflammatory potency in vitro and in vivo. Dependent on the C5-substituent, the compounds showed high selectivity for MCF-7 cells. Especially 2-oxoethyl benzoate derivatives were inactive at the MDA-MB-231 cell line and as active as 5-FU at MCF-7 cells. C5-acetyl (8a), -2-oxoethyl formiate (8e), -2-oxoethyl acetate (8f) and -2-oxoethyl propionate (8g) derivatives showed growth inhibition at both cell lines, comparable with cisplatin. Modifications significantly reduced the inhibitory potency at COX-1 and COX-2 in vitro and in the xylene-induced ear swelling assay in mice. Only compound 8a was equipotent to licofelone, ibuprofen and celecoxibe in vivo.
authors.affiliation: Department of Medicinal Chemistry, China Pharmaceutical University, Tongjia Xiang 24, 210009 Nanjing, PR China.
authors.forename: Wukun
authors.initials: W
authors.lastname: Liu
authors.forename: Jinpei
authors.initials: J
authors.lastname: Zhou
authors.forename: Kerstin
authors.initials: K
authors.lastname: Bensdorf
authors.forename: Huibin
authors.initials: H
authors.lastname: Zhang
authors.forename: Haoran
authors.initials: H
authors.lastname: Liu
authors.forename: Yubin
authors.initials: Y
authors.lastname: Wang
authors.forename: Hai
authors.initials: H
authors.lastname: Qian
authors.forename: Yanchun
authors.initials: Y
authors.lastname: Zhang
authors.forename: Anja
authors.initials: A
authors.lastname: Wellner
authors.forename: Gerhard
authors.initials: G
authors.lastname: Rubner
authors.forename: Wenlong
authors.initials: W
authors.lastname: Huang
authors.forename: Cancheng
authors.initials: C
authors.lastname: Guo
authors.forename: Ronald
authors.initials: R
authors.lastname: Gust
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry* / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D016861:Cyclooxygenase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D005260:Female; D008297:Male; D051379:Mice; D011758:Pyrroles / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000893:Anti-Inflammatory Agents; D000970:Antineoplastic Agents; D016861:Cyclooxygenase Inhibitors; D011758:Pyrroles; C088092:licofelone