title: Design, synthesis and biological evaluation of novel steroidal spiro-oxindoles as potent antiproliferative agents.
abstract: Two series of novel steroidal spiro-pyrrolidinyl oxindoles 3a-t and 6a-c were designed and synthesized from dehydroepiandrosterone using the 1,3-dipolar cycloaddition as the key step and further evaluated for their antiproliferative activities for four human cancer cell lines (MGC-803, EC109, SMMC-7721 and MCF-7). This protocol achieved the formation of two CC bonds, one CN bond and the creation of one new five-membered pyrrolidine ring and three contiguous stereocenters in a single operation. Biological evaluation showed that these synthesized steroidal spiro-pyrrolidinyl oxindoles possessed moderate to good antiproliferative activities against the tested cell lines and some of them were more potent than 5-Fu. Particularly, compound 3g showed good antiproliferative activity against SMMC-7721 (IC50=0.71μM). Steroid dimer 6b showed improved antiproliferative activities against SMMC-7721 and MCF-7 with the IC50 values of 4.30 and 2.06μM, respectively. Flow cytometry analysis demonstrated that compound 3n caused the cellular early apoptosis and cell cycle arrest at G2/M phase in a concentration- and time-dependent manner. [Corrected]
authors: School of Pharmaceutical Sciences and New Drug Research & Development Center, Zhengzhou University, Zhengzhou 450001, PR China. Electronic address: zzuyubin@hotmail.com.
authors: Bin
authors: B
authors: Yu
authors: School of Pharmaceutical Sciences and New Drug Research & Development Center, Zhengzhou University, Zhengzhou 450001, PR China.
authors: Xiao-Jing
authors: XJ
authors: Shi
authors: School of Pharmaceutical Sciences and New Drug Research & Development Center, Zhengzhou University, Zhengzhou 450001, PR China.
authors: Ping-Ping
authors: PP
authors: Qi
authors: School of Pharmaceutical Sciences and New Drug Research & Development Center, Zhengzhou University, Zhengzhou 450001, PR China. Electronic address: dqyu@imm.ac.cn.
authors: De-Quan
authors: DQ
authors: Yu
authors: School of Pharmaceutical Sciences and New Drug Research & Development Center, Zhengzhou University, Zhengzhou 450001, PR China. Electronic address: liuhm@zzu.edu.cn.
authors: Hong-Min
authors: HM
authors: Liu
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D061565:Cycloaddition Reaction; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000494:pharmacology; D007664:Ketosteroids / Q000138:chemical synthesis / Q000494:pharmacology*; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000494:pharmacology*; D013141:Spiro Compounds / Q000138:chemical synthesis / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D007664:Ketosteroids; D011759:Pyrrolidines; D013141:Spiro Compounds
keywords: 1,3-Dipolar cycloaddition; Antiproliferative activity; Apoptosis; Cell cycle arrest; Dehydroepiandrosterone; Spiro-oxindoles