Selective non-zinc binding MMP-2 inhibitors: Novel benzamide Ilomastat analogs with anti-tumor metastasis

Jiao Song; Peng Peng; Jun Chang; Ming-Ming Liu; Jian-Ming Yu; Lu Zhou; Xun Sun

doi:10.1016/j.bmcl.2016.03.064

Selective non-zinc binding MMP-2 inhibitors: Novel benzamide Ilomastat analogs with anti-tumor metastasis

Bioorg Med Chem Lett. 2016 May 1;26(9):2174-8. doi: 10.1016/j.bmcl.2016.03.064. Epub 2016 Mar 16.

Authors

Jiao Song¹, Peng Peng¹, Jun Chang¹, Ming-Ming Liu², Jian-Ming Yu¹, Lu Zhou³, Xun Sun⁴

Affiliations

¹ Department of Natural Products Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China.
² Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China.
³ Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China. Electronic address: zhoulu@fudan.edu.cn.
⁴ Department of Natural Products Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China; Shanghai Key Lab of Clinical Geriatric Medicine, 221 West Yanan Road, Shanghai 200040, China. Electronic address: sunxunf@shmu.edu.cn.

PMID: 27038494
DOI: 10.1016/j.bmcl.2016.03.064

Abstract

Novel Ilomastat analogs with substituted benzamide groups, instead of hydroxamic acid groups, were designed, synthesized and evaluated against MMP-2 and MMP-9. Among these analogs, the most potent compound 10a exhibited potent inhibitory activity against MMP-2 with IC50 value of 0.19 nM, which is 5 times more potent than that of Ilomastat (IC50=0.94 nM). Importantly, 10a exhibited more than 8300 fold selectivity for MMP-2 versus MMP-9 (IC50=1.58 μM). Molecular docking studies showed that 10a bond to the catalytic active pocket of MMP-2 by a non-zinc-chelating mechanism which was different from that of Ilomastat. Furthermore, the invasion assay showed that 10a was effective in reducing HEY cells invasion at 84.6% in 50 μM concentration. For 10a, the pharmacokinetic properties had been improved and especially the more desirable t1/2z was achieved compared with these of the lead compound Ilomastat.

Keywords: Benzamide groups; Enzyme inhibition; HEY cell invasion; Ilomastat analogs; MMP-2 and MMP-9; Non-zinc binding.

Publication types

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

MeSH terms

Anilides / chemical synthesis
Anilides / pharmacokinetics
Anilides / pharmacology*
Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / pharmacokinetics
Antineoplastic Agents / pharmacology*
Binding Sites
Cell Line, Tumor
Drug Screening Assays, Antitumor
Humans
Hydrogen Bonding
Hydroxamic Acids / chemical synthesis
Hydroxamic Acids / pharmacokinetics
Hydroxamic Acids / pharmacology*
Indoles / chemical synthesis
Indoles / pharmacokinetics
Indoles / pharmacology*
Matrix Metalloproteinase 2 / metabolism*
Matrix Metalloproteinase 9 / metabolism
Matrix Metalloproteinase Inhibitors / chemical synthesis
Matrix Metalloproteinase Inhibitors / pharmacokinetics
Matrix Metalloproteinase Inhibitors / pharmacology*
Molecular Docking Simulation
Neoplasm Invasiveness / pathology*
Neoplasm Metastasis
Rats
Rats, Sprague-Dawley

Substances

Anilides
Antineoplastic Agents
Hydroxamic Acids
Indoles
Matrix Metalloproteinase Inhibitors
N-(3-(1H-indol-3-yl)-1-(methylamino)-1-oxopropan-2-yl)-N-(2-aminophenyl)-2-isobutylsuccinamide
Matrix Metalloproteinase 2
Matrix Metalloproteinase 9
ilomastat