Synthesis of chiral ND-322, ND-364 and ND-364 derivatives as selective inhibitors of human gelatinase

Yugang Yan; Xueying Chen; Xinying Yang; Jian Zhang; Wenfang Xu; Yingjie Zhang

doi:10.1016/j.bmc.2015.09.013

Synthesis of chiral ND-322, ND-364 and ND-364 derivatives as selective inhibitors of human gelatinase

Bioorg Med Chem. 2015 Oct 15;23(20):6632-40. doi: 10.1016/j.bmc.2015.09.013. Epub 2015 Sep 7.

Authors

Yugang Yan¹, Xueying Chen², Xinying Yang³, Jian Zhang⁴, Wenfang Xu⁵, Yingjie Zhang⁶

Affiliations

¹ Institute of Medicinal Chemistry, School of Pharmacy, Shandong University, Ji'nan 250012, PR China.
² 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.
³ Institute of Pharmaceutical Analysis, School of Pharmacy, Shandong University, Ji'nan 250012, PR China.
⁴ Department of Medical Chemistry, School of Pharmacy, Weifang Medical University, 7166, West Baotong Road, Weifang, Shandong 261042, PR China.
⁵ Institute of Medicinal Chemistry, School of Pharmacy, Shandong University, Ji'nan 250012, PR China. Electronic address: wenfxu@gmail.com.
⁶ Institute of Medicinal Chemistry, School of Pharmacy, Shandong University, Ji'nan 250012, PR China. Electronic address: zhangyingjie@sdu.edu.cn.

PMID: 26386821
DOI: 10.1016/j.bmc.2015.09.013

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.

Keywords: CD; Chiral; MMP2; MMP9; N-364; ND-322; Sulfoxide.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Arginine / analogs & derivatives*
Arginine / chemical synthesis
Arginine / chemistry
Arginine / pharmacology
Dose-Response Relationship, Drug
Gelatinases / antagonists & inhibitors*
Gelatinases / metabolism
Humans
Matrix Metalloproteinase 2 / metabolism
Matrix Metalloproteinase 9 / metabolism
Matrix Metalloproteinase Inhibitors / chemical synthesis
Matrix Metalloproteinase Inhibitors / chemistry
Matrix Metalloproteinase Inhibitors / pharmacology*
Molecular Structure
Phenyl Ethers / chemical synthesis
Phenyl Ethers / chemistry
Phenyl Ethers / pharmacology*
Structure-Activity Relationship
Sulfones / chemical synthesis
Sulfones / chemistry
Sulfones / pharmacology*

Substances

Matrix Metalloproteinase Inhibitors
ND 322
ND-364
Phenyl Ethers
Sulfones
Arginine
Gelatinases
MMP2 protein, human
Matrix Metalloproteinase 2
MMP9 protein, human
Matrix Metalloproteinase 9