title: Lasiokaurin derivatives: synthesis, antimicrobial and antitumor biological evaluation, and apoptosis-inducing effects.
abstract: Herein, a series of lasiokaurin derivatives were designed and synthesized. All the derivatives together with lasiokaurin and oridonin were tested for their antimicrobial and antiproliferative activity. Compound 16 showed the most promising antimicrobial activity with MICs of 2.0 and 1.0 μg/mL against Gram-Positive bacteria S. aureus and B. subtilis, respectively. All the synthetic lasiokaurin derivatives showed better antiproliferative activity than parent compound lasiokaurin 1. Compound 10 exhibited the strongest cytotoxicity with IC50values of 0.47 and 0.20 μM against MGC-803 and CaEs-17 cells, accordingly. Moreover, it was shown to have potent antitumor activity in vivo in a murine model of MGC-803 gastric cancer. Preliminary SARs were also concluded based on obtained data. The apoptosis-inducing effects of 10 were further investigated using CaEs-17 cells. The results showed that lasiokaurin derivative 10 could induce apoptosis via mitochondria related pathway and arrest CaEs-17 cell cycle at S phase. Compound 10 could also affect apoptosis-related proteins that was up-regulation of CDK2 and down-regulation of ATM and cyclin A1.
authors.affiliation: Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical College, Xuzhou, 221004, China.|Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, and School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, 110016, China.
authors.forename: Da-Hong
authors.initials: DH
authors.lastname: Li
authors.affiliation: Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, and School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, 110016, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Hu
authors.affiliation: Department of Medicinal Chemistry and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China.
authors.forename: Sheng-Tao
authors.initials: ST
authors.lastname: Xu
authors.affiliation: Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, and School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, 110016, China.
authors.forename: Chun-Yan
authors.initials: CY
authors.lastname: Fang
authors.affiliation: Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, and School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, 110016, China.
authors.forename: Shuang
authors.initials: S
authors.lastname: Tang
authors.affiliation: Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, and School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, 110016, China.
authors.forename: Xin-Yu
authors.initials: XY
authors.lastname: Wang
authors.affiliation: Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, and School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, 110016, China.
authors.forename: Xing-Yan
authors.initials: XY
authors.lastname: Sun
authors.affiliation: Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, and School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, 110016, China.
authors.forename: He
authors.initials: H
authors.lastname: Li
authors.affiliation: Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, and School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, 110016, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical College, Xuzhou, 221004, China. gu_xk@163.com.
authors.forename: Xiao-Ke
authors.initials: XK
authors.lastname: Gu
authors.affiliation: Department of Medicinal Chemistry and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China. jinyixu@china.com.
authors.forename: Jin-Yi
authors.initials: JY
authors.lastname: Xu
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D004224:Diterpenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045786:Diterpenes, Kaurane / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D059807:S Phase Cell Cycle Checkpoints / Q000187:drug effects; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000473:pathology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000890:Anti-Infective Agents; D000970:Antineoplastic Agents; D004224:Diterpenes; D045786:Diterpenes, Kaurane; C011959:oridonin; C011893:lasiokaurin
keywords: Antimicrobial; Antitumor; Apoptosis; Diterpenoid; Lasiokaurin