title: Efficient synthesis of novel antiproliferative steroidal spirooxindoles via the [3+2] cycloaddition reactions of azomethine ylides.
abstract: A series of novel steroidal spirooxindoles 3a-h were synthesized from pregnenolone in a high regioselective manner using the 1,3-dipolar cycloaddition as the key step. This protocol resulted in the formation of two C-C bonds, one C-N bond and the creation of one pyrrolidine ring and three contiguous stereocenters in a single operation. Biological evaluation showed that these synthesized steroidal spirooxindoles exhibited moderate to good antiproliferative activity against the tested cell lines and some of them were more potent than 5-FU. Among them, compounds 3e and 3f displayed the best antiproliferative activity against MCF-7 cells with the IC50 values of 4.0 and 3.9μM, respectively. Flow cytometry analysis demonstrated that compound 3d caused the cellular apoptosis and cell cycle arrest at G2/M phase in a concentration-dependent manner. Docking results indicated that compound 3d fitted well into the MDM2 active site 1RV1 by interacting with Lys94 and Thr101 residues.
authors.affiliation: School of Pharmaceutical Sciences and New Drug Research & Development Center, Zhengzhou University, Zhengzhou 450001, PR China. Electronic address: zzuyubin@hotmail.com.
authors.forename: Bin
authors.initials: B
authors.lastname: Yu
authors.affiliation: The Affiliated Hospital of Huanghe Sanmenxia of Henan University of Science and Technology, Sanmenxia 472000, PR China.
authors.forename: Xiao-Nan
authors.initials: XN
authors.lastname: Sun
authors.affiliation: School of Pharmaceutical Sciences and New Drug Research & Development Center, Zhengzhou University, Zhengzhou 450001, PR China.
authors.forename: Xiao-Jing
authors.initials: XJ
authors.lastname: Shi
authors.affiliation: School of Pharmaceutical Sciences and New Drug Research & Development Center, Zhengzhou University, Zhengzhou 450001, PR China.
authors.forename: Ping-Ping
authors.initials: PP
authors.lastname: Qi
authors.affiliation: School of Pharmaceutical Sciences and New Drug Research & Development Center, Zhengzhou University, Zhengzhou 450001, PR China.
authors.forename: Yi-Chao
authors.initials: YC
authors.lastname: Zheng
authors.affiliation: School of Pharmaceutical Sciences and New Drug Research & Development Center, Zhengzhou University, Zhengzhou 450001, PR China. Electronic address: dqyu@imm.ac.cn.
authors.forename: De-Quan
authors.initials: DQ
authors.lastname: Yu
authors.affiliation: School of Pharmaceutical Sciences and New Drug Research & Development Center, Zhengzhou University, Zhengzhou 450001, PR China. Electronic address: liuhm@zzu.edu.cn.
authors.forename: Hong-Min
authors.initials: HM
authors.lastname: Liu
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001391:Azo Compounds / Q000737:chemistry*; D020134:Catalytic Domain; D002455:Cell Division / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005260:Female; D016195:G2 Phase / Q000187:drug effects*; D006801:Humans; D061986:MCF-7 Cells; D062105:Molecular Docking Simulation; D011284:Pregnenolone / Q000737:chemistry*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D013882:Thiosemicarbazones / Q000737:chemistry*
chemical_list: D000970:Antineoplastic Agents; D001391:Azo Compounds; D013882:Thiosemicarbazones; C512188:azomethine; D011284:Pregnenolone; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2
keywords: Antiproliferative activity; Apoptosis; Cell cycle arrest; Docking studies; Pregnenolone; Spirooxindoles