Synthesis and biological evaluation of novel benzofuroxan-based pyrrolidine hydroxamates as matrix metalloproteinase inhibitors with nitric oxide releasing activity

Hao Zhang; Xuejian Wang; Jing Mao; Yongxue Huang; Wenfang Xu; Yu Duan; Jian Zhang

doi:10.1016/j.bmc.2018.06.023

Synthesis and biological evaluation of novel benzofuroxan-based pyrrolidine hydroxamates as matrix metalloproteinase inhibitors with nitric oxide releasing activity

Bioorg Med Chem. 2018 Aug 15;26(15):4363-4374. doi: 10.1016/j.bmc.2018.06.023. Epub 2018 Jun 18.

Authors

Hao Zhang¹, Xuejian Wang², Jing Mao¹, Yongxue Huang³, Wenfang Xu⁴, Yu Duan⁵, Jian Zhang⁶

Affiliations

¹ Department of Medicinal Chemistry, School of Pharmacy, Weifang Medical University, Weifang, Shandong 261053, PR China.
² Department of Pharmacology, School of Pharmacy, Weifang Medical University, Weifang, Shandong 261053, PR China.
³ Weifang Bochuang International Biological Medicinal Institute, Weifang, Shandong, 261061, PR China.
⁴ Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Shandong University, Ji'nan, Shandong 250012, PR China.
⁵ Department of Medicinal Chemistry, School of Pharmacy, Weifang Medical University, Weifang, Shandong 261053, PR China. Electronic address: [email protected].
⁶ Department of Medicinal Chemistry, School of Pharmacy, Weifang Medical University, Weifang, Shandong 261053, PR China. Electronic address: [email protected].

PMID: 30093347
DOI: 10.1016/j.bmc.2018.06.023

Abstract

On the basis of the strategy of "multifunctional drugs", a series of novel matrix metalloproteinase inhibitors (MMPIs) containing benzofuroxan scaffold as a nitric oxide donor were designed, synthesized and evaluated. All synthesized compounds, especially 16a, exhibited potent MMP-2,9 inhibitory activities, anti-proliferative activities and could produce high levels of NO in Hela cells. They were also evaluated for both of their anti-invasion and anti-angiogenesis effects. Furthermore, compared with LY52, 16a demonstrated competitive antitumor activity in vivo. These hybrid NO-MMPIs might offer suitable scaffolds to develop valuable MMP inhibitors for the further discovery of novel anti-cancer drugs.

Keywords: Benzofuroxan; MMP inhibitor; Multifunctional drugs; Nitric oxide; Synthesis.

Publication types

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

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis*
Antineoplastic Agents / pharmacology
Antineoplastic Agents / therapeutic use
Benzoxazoles / chemistry
Binding Sites
Cell Line, Tumor
Cell Movement / drug effects
Cell Proliferation / drug effects
Drug Screening Assays, Antitumor
Humans
Hydroxamic Acids / chemistry*
Matrix Metalloproteinase 2 / chemistry
Matrix Metalloproteinase 2 / metabolism
Matrix Metalloproteinase 9 / chemistry
Matrix Metalloproteinase 9 / metabolism
Matrix Metalloproteinase Inhibitors / chemical synthesis*
Matrix Metalloproteinase Inhibitors / pharmacology
Matrix Metalloproteinase Inhibitors / therapeutic use
Mice
Molecular Docking Simulation
Neoplasms / drug therapy
Neoplasms / parasitology
Neovascularization, Physiologic / drug effects
Nitric Oxide / metabolism*
Pyrrolidines / chemistry
Structure-Activity Relationship

Substances

Antineoplastic Agents
Benzoxazoles
Hydroxamic Acids
Matrix Metalloproteinase Inhibitors
Pyrrolidines
Nitric Oxide
benzofuroxan
Matrix Metalloproteinase 2
Matrix Metalloproteinase 9
pyrrolidine