Coumarinic derivatives as mechanism-based inhibitors of α-chymotrypsin and human leukocyte elastase

Abstract

AbstractÐNovel coumarinic derivatives were synthesized and tested for their inhibitory potency toward a-CT and HLE. Cycloalkyl esters and amides were found to be essentially inactive on both enzymes. On the opposite, aromatic esters strongly inactivated a-CT whereas HLE was less e ciently inhibited with dichlorophenyl ester derivatives (k inact /K I =4000 M À1 s À1 for 36). Representative examples of amide, ester, thioester and ketone derivatives were prepared in order to evaluate the in¯uence of the link between the coumarinic ring and the phenyl side chain. The irreversible inactivation of a-CT by 6-chloromethyl derivatives should be due to alkylation of a histidine residue as suggested by the amino acid analysis of the modi®ed chymotrypsin. Conversely the inhibition of HLE was transient. Intrinsic reactivity of coumarins has been calculated using a model of a nucleophilic reaction between the ligand and the couple methanol±water. From this calculation, it appears that di erences in the inhibitory potency expressed by these molecules cannot only be explained by di erences in the reactivity of the lactonic carbonyl group toward the nucleophilic attack. #

6-Substituted 2-oxo-2H-1-benzopyran-3-carboxylic acid derivatives in a new approach of the treatment of cancer cell invasion and metastasis

“…2), can be superimposed to the preferential conformation adopted, in the solid state and probably in solution, by aryl esters of coumarin-3-carboxylic acid derivatives (9'; Fig. 2) in accordance to recent published crystallographic and molecular modelling studies [21,22]. In contrast to aryl esters of 6-substituted coumarin-3-carboxylic acids, the corresponding aryl amides 10 ( Fig.…”

“…Compound 12 obtained from 11 by acetylation was converted into the corresponding acid chloride 13 as previously described [21,23]. The acyl chloride intermediate 13 then reacted with appropriate thiophenols and anilines to provide the thioesters 14, the secondary amides 15 and the tertiary amides 16 (Scheme 1).…”

“…and 3-iodophenyl 6-chloromethyl-2-oxo-2H-1-benzopyran-3-carboxylate (25e) were obtained according to previously described procedures [21,23].…”

“…In contrast to aryl esters of 6-substituted coumarin-3-carboxylic acids, the corresponding aryl amides 10 ( Fig. 2) are not able to adopt such conformation because a strong intra-molecular hydrogen bound is established between the hydrogen atom of the exocyclic NH group and the lactonic carbonyl group [21].…”

3-Bromophenyl 6-acetoxymethyl-2-oxo-2H-1-benzopyran-3-carboxylate inhibits cancer cell invasion in vitro and tumour growth in vivo

“…In previous works, we have investigated a series of original coumarin derivatives (6-substituted 2-oxo-2H-1-benzopyran-3-carboxylic acid analogues). Some of them were potent inhibitors of serine proteases such as a-chymotrypsin (a-CT), human leucocyte elastase (HLE) and thrombin (THR) (Pochet et al, 1996(Pochet et al, , 2000Doucet et al, 1999). Based on the invasive assay, among eight coumarin derivatives evaluated, we have selected two compounds, 3-chlorophenyl 6-acetoxymethyl-2-oxo-2H-1-benzopyran-3-carboxylate (compound 4) and 3-bromophenyl 6-acetoxymethyl-2-oxo-2H-1-benzopyran-3-carboxylate (compound 7) (Figure 1), which were further examined for their ability to affect the tumorigenicity in vivo of human fibrosarcoma and human breast adenocarcinoma cells.…”