title: Simultaneous presence of unsaturation and long alkyl chain at P'1 of Ilomastat confers selectivity for gelatinase A (MMP-2) over gelatinase B (MMP-9) inhibition as shown by molecular modelling studies.
abstract: Structural analogues of Ilomastat (Galardin), containing unsaturation(s) and chain extension carrying bulky phenyl group or alkyl moieties at P'1 were synthesized and purified by centrifugal partition chromatography. They were analyzed for their inhibitory capacity towards MMP-1, MMP-2, MMP-3, MMP-9 and MMP-14, main endopeptidases involved in tumour progression. Presence of unsaturation(s) decreased the inhibitory potency of compounds but, in turn increased their selectivity for gelatinases. 2b and 2d derivatives with a phenyl group inhibited preferentially MMP-9 with IC50 equal to 45 and 38 nM, respectively, but also display activity against MMP-2 (IC50 equal to 280 and 120 nM, respectively). Molecular docking computations confirmed affinity of these substances for both gelatinases. With aims to obtain a specific gelatinase A (MMP-2) inhibitor, P'1 of Ilomastat was modified to carry one unsaturation coupled to an alkyl chain with pentylidene group. Docking studies indicated that MMP-2, but not MMP-9, could accommodate such substitution; indeed 2a proved to inhibit MMP-2 (IC50=123 nM), while displaying no inhibitory capacity towards MMP-9.
authors.affiliation: Laboratoire de Spectroscopies et Structures Biomoléculaires (LSSBM), Faculté des Sciences, IFR53 Biomolécules, Université de Reims-Champagne-Ardenne, BP 1039, 51687 Reims Cedex 2, France.
authors.forename: Gautier
authors.initials: G
authors.lastname: Moroy
authors.forename: Clément
authors.initials: C
authors.lastname: Denhez
authors.forename: Haquima
authors.initials: H
authors.lastname: El Mourabit
authors.forename: Alix
authors.initials: A
authors.lastname: Toribio
authors.forename: Alexandra
authors.initials: A
authors.lastname: Dassonville
authors.forename: Martine
authors.initials: M
authors.lastname: Decarme
authors.forename: Jean-Hugues
authors.initials: JH
authors.lastname: Renault
authors.forename: Catherine
authors.initials: C
authors.lastname: Mirand
authors.forename: Georges
authors.initials: G
authors.lastname: Bellon
authors.forename: Janos
authors.initials: J
authors.lastname: Sapi
authors.forename: Alain J P
authors.initials: AJ
authors.lastname: Alix
authors.forename: William
authors.initials: W
authors.lastname: Hornebeck
authors.forename: Erika
authors.initials: E
authors.lastname: Bourguet
mesh_terms: D000478:Alkylation; D002942:Circular Dichroism; D003198:Computer Simulation; D006860:Hydrogen Bonding; D006877:Hydroxamic Acids / Q000737:chemistry / Q000494:pharmacology; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*; D020778:Matrix Metalloproteinase 2 / Q000737:chemistry / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000737:chemistry / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D008958:Models, Molecular; D015394:Molecular Structure; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*; D011485:Protein Binding; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D006877:Hydroxamic Acids; D007211:Indoles; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; C119203:ilomastat