title: Selective non-zinc binding MMP-2 inhibitors: Novel benzamide Ilomastat analogs with anti-tumor metastasis.
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.
authors.affiliation: Department of Natural Products Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China.
authors.forename: Jiao
authors.initials: J
authors.lastname: Song
authors.affiliation: Department of Natural Products Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Peng
authors.affiliation: Department of Natural Products Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Chang
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China.
authors.forename: Ming-Ming
authors.initials: MM
authors.lastname: Liu
authors.affiliation: Department of Natural Products Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China.
authors.forename: Jian-Ming
authors.initials: JM
authors.lastname: Yu
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China. Electronic address: zhoulu@fudan.edu.cn.
authors.forename: Lu
authors.initials: L
authors.lastname: Zhou
authors.affiliation: 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.
authors.forename: Xun
authors.initials: X
authors.lastname: Sun
mesh_terms: D000813:Anilides / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D001665:Binding Sites; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D006860:Hydrogen Bonding; D006877:Hydroxamic Acids / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D007211:Indoles / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D062105:Molecular Docking Simulation; D009361:Neoplasm Invasiveness / Q000473:pathology*; D009362:Neoplasm Metastasis; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000813:Anilides; D000970:Antineoplastic Agents; D006877:Hydroxamic Acids; D007211:Indoles; D061965:Matrix Metalloproteinase Inhibitors; C000621251:N-(3-(1H-indol-3-yl)-1-(methylamino)-1-oxopropan-2-yl)-N-(2-aminophenyl)-2-isobutylsuccinamide; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; C119203:ilomastat
keywords: Benzamide groups; Enzyme inhibition; HEY cell invasion; Ilomastat analogs; MMP-2 and MMP-9; Non-zinc binding