title: Synthesis of chiral ND-322, ND-364 and ND-364 derivatives as selective inhibitors of human gelatinase.
abstract: Compounds 10 (ND-322) and 15 (ND-364) are potent selective inhibitors for gelatinases, matrix metalloproteinase 2 (MMP2) and matrix metalloproteinase 9 (MMP9). However, both of them are racemates. Herein we report facile synthesis of optically active (R)- and (S)-enantiomers of compounds 10 and 15. And the sulfonyl of 15 was transformed to sulfinyl to obtain four epimeric mixtures. All synthesized thiirane-based compounds were evaluated in MMP2 and MMP9 inhibitory assays. Our results indicated that the configuration of thiirane moiety had little effects on gelatinase inhibition, but the substitution of sulfinyl for sulfonyl was detrimental to gelatinase inhibition. Besides, all target compounds exhibited no inhibition against other two Zn(2+) dependant metalloproteases, aminopeptidase N (APN) and histone deacetylases (HDACs), which confirmed the unique Zn(2+) chelation mechanism of thiirane moiety against gelatinases.
authors.affiliation: Institute of Medicinal Chemistry, School of Pharmacy, Shandong University, Ji'nan 250012, PR China.
authors.forename: Yugang
authors.initials: Y
authors.lastname: Yan
authors.affiliation: The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health, Shandong University, Qilu Hospital, No. 107, Wen Hua Xi Road, Ji'nan 250012, PR China.
authors.forename: Xueying
authors.initials: X
authors.lastname: Chen
authors.affiliation: Institute of Pharmaceutical Analysis, School of Pharmacy, Shandong University, Ji'nan 250012, PR China.
authors.forename: Xinying
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Medical Chemistry, School of Pharmacy, Weifang Medical University, 7166, West Baotong Road, Weifang, Shandong 261042, PR China.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Institute of Medicinal Chemistry, School of Pharmacy, Shandong University, Ji'nan 250012, PR China. Electronic address: wenfxu@gmail.com.
authors.forename: Wenfang
authors.initials: W
authors.lastname: Xu
authors.affiliation: Institute of Medicinal Chemistry, School of Pharmacy, Shandong University, Ji'nan 250012, PR China. Electronic address: zhangyingjie@sdu.edu.cn.
authors.forename: Yingjie
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D001120:Arginine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D018093:Gelatinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D010647:Phenyl Ethers / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D061965:Matrix Metalloproteinase Inhibitors; C568509:ND 322; C000606944:ND-364; D010647:Phenyl Ethers; D013450:Sulfones; D001120:Arginine; D018093:Gelatinases; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9
keywords: CD; Chiral; MMP2; MMP9; N-364; ND-322; Sulfoxide