title: Design, synthesis and biological evaluation of 3'-benzylated analogs of 3'-epi-neoponkoranol as potent α-glucosidase inhibitors.
abstract: A group of 3'-epi-neoponkoranol analogs with different hydrophobic substituents attached at 3'-position of side chain moiety were designed and synthesized in order to further improve the inhibitory activities against α-glucosidases. Biological evaluation of these compounds revealed that sulfonium salts attached with ortho-substituted benzyl groups showed best α-glucosidase inhibitory activities. The most potent compound 10i showed greater inhibitory activities than all natural products. Moreover, docking studies on 10i with ntMGAM presented a new binding mode, indicating that amino residue Asp542 should be the key interacting point for strong inhibitory activity of small molecules against α-glucosidase enzymes. The strongest α-glucosidase inhibitory activity of 10i could be rationalized by van der Waals interactions between the 3'-attached substituent and particularly the ortho-substituted trifluoromethyl on benzyl group with the adjacent hydrophobic amino residues. Cytotoxicity evaluation assay demonstrated a high level of safety profile of the synthesized sulfonium salts against normal cell line. The enzyme kinetic studies showed a fully competitive inhibition of these sulfonium salts on each α-glucosidase.
authors: State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China; Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China.
authors: Dan
authors: D
authors: Liu
authors: State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China; Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China.
authors: Weigang
authors: W
authors: He
authors: State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China; Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China.
authors: Zihao
authors: Z
authors: Wang
authors: State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China; Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China.
authors: Long
authors: L
authors: Liu
authors: State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China; Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China.
authors: Chengqian
authors: C
authors: Wang
authors: State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China; Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China.
authors: Chenxi
authors: C
authors: Zhang
authors: State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China; Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China.
authors: Chengcheng
authors: C
authors: Wang
authors: State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China; Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China.
authors: Yuxuan
authors: Y
authors: Wang
authors: Faculty of Pharmacy, Kinki University, 3-4-1 Kowakae, Higashi-Osaka, Osaka 577-8502, Japan.
authors: Genzoh
authors: G
authors: Tanabe
authors: Faculty of Pharmacy, Kinki University, 3-4-1 Kowakae, Higashi-Osaka, Osaka 577-8502, Japan.
authors: Osamu
authors: O
authors: Muraoka
authors: State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China; Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China.
authors: Xiaoming
authors: X
authors: Wu
authors: State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China; Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China. Electronic address: wul2004@hotmail.com.
authors: Liang
authors: L
authors: Wu
authors: State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China; Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China. Electronic address: weijiaxie@cpu.edu.cn.
authors: Weijia
authors: W
authors: Xie
mesh_terms: D001593:Benzyl Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D015195:Drug Design; D065089:Glycoside Hydrolase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D062105:Molecular Docking Simulation; D013329:Structure-Activity Relationship; D013402:Sugar Alcohols / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013876:Thiophenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000520:alpha-Glucosidases / Q000378:metabolism*
chemical_list: C559081:1,4-dideoxy-1,4-((2,3,4,5,6-pentahydroxyhexyl)episulfoniumylidene)arabinitol; D001593:Benzyl Compounds; D065089:Glycoside Hydrolase Inhibitors; D013402:Sugar Alcohols; D013876:Thiophenes; D000520:alpha-Glucosidases
keywords: Molecular docking; Neoponkoranol; Salacia; Structural modification; α-glucosidase inhibitor