title: Lathyrol diterpenes as modulators of P-glycoprotein dependent multidrug resistance: structure-activity relationship studies on Euphorbia factor L3 derivatives.
abstract: Five series of 37 new acylate and epoxide derivatives (3-39) of Euphorbia factor L3, a lathyrol diterpene isolated from Euphorbia lathyris, were designed by modifying the hydroxyl moiety of C-3, C-5, or C-15. Chemoreversal effects of the acylates on multidrug resistance (MDR) were evaluated in breast cancer multidrug-resistant MCF-7/ADR cells that overexpress P-glycoprotein (P-gp). Eight derivatives exhibited greater chemoreversal ability than verapamil (VRP) against adriamycin (ADR) resistance. Compounds 19 and 25 exhibited 4.8 and 4.0 times, respectively, more effective reversal ability than VRP against ADR resistance. To determine the key characteristics of Euphorbia factor L3 derivatives that contribute to MDR reversal, we conducted a structure-activity relationship study of these compounds. The simulation studies indicated different possible mechanisms and revealed the important influence of hydrophobic interactions and hydrogen bonds in the flexible cavity of P-gp.
authors: †Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China.
authors: Wei
authors: W
authors: Jiao
authors: †Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China.
authors: Zhongmin
authors: Z
authors: Wan
authors: †Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China.
authors: Shuang
authors: S
authors: Chen
authors: ‡Department of Applied Chemistry, China Agricultural University, Beijing 100194, China.
authors: Runhua
authors: R
authors: Lu
authors: †Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China.
authors: Xiaozhen
authors: X
authors: Chen
authors: †Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China.
authors: Dongmei
authors: D
authors: Fang
authors: †Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China.
authors: Jiufeng
authors: J
authors: Wang
authors: †Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China.
authors: Shengcai
authors: S
authors: Pu
authors: †Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China.
authors: Xin
authors: X
authors: Huang
authors: ‡Department of Applied Chemistry, China Agricultural University, Beijing 100194, China.
authors: Haixiang
authors: H
authors: Gao
authors: †Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China.
authors: Huawu
authors: H
authors: Shao
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004224:Diterpenes / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D028481:Euphorbia / Q000166:cytology*; D061986:MCF-7 Cells; D008958:Models, Molecular; D008968:Molecular Conformation; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C000599947:3,5-dibenzoyloxylathyra-6(17),12-dien-15-ol-14-one; C000599948:5-(1-naphthylacetyloxy)-3-propionyloxylathyra-6(17),12-dien-15-ol-14-one; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D004224:Diterpenes; D004317:Doxorubicin