Abstract
Recently there has been a growing interest in covalent protease inhibitors in both industry and academia, caused by their longer residence times, their higher potency and their high ligand efficiency. Covalently reactive moieties which interact with activated amino acid residues such as serine or cysteine in enzymes like proteases or esterases mostly act through nucleophilic addition, substitution or ring opening. In contrast, nucleophilic aromatic substitution (SNAr) is rarely employed. In our previous work, we prepared and investigated electrophilic “warheads”, which contain aromatic, heteroaromatic or quinoid fragments. Some of them show potent inhibition constants for cathepsin L, cathepsin B, rhodesain or dengue-protease, and depending on the exact nature of the electrophile they exhibit reversible covalent or irreversible inhibition modes. In the present work, we demonstrate the synthesis of fluorescent “warhead” candidates based on 2,1,3-benzoxadiazoles and the investigation of their physicochemical and photophysical properties. These molecules shall serve as probes for the detailed analysis of association/dissociation mechanism and of the kinetic parameters of the bond forming event.
Highlights
Alkyl halides, Michael acceptors, alkyl boronates, nitriles, sulfonyl fluorides, epoxides or aziridines have been used as reactive groups for the design of covalent inhibitors of proteases or esterases [1,2]
We have synthesized a series of different aromatic, heteroaromatic or quinoid electrophilic compounds, which exhibited a strong inhibitory activity on some proteases [4]. While the latter electrophilic moieties did not show a significant fluorescence, we became interested in the design and synthesis of fluorescent SNAr reactive groups to investigate the association and the bond-forming event with the target enzyme in detail
The synthesis of electrophilic protease inhibitors was carried out according to Scheme 1
Summary
Michael acceptors, alkyl boronates, nitriles, sulfonyl fluorides, epoxides or aziridines have been used as reactive groups for the design of covalent inhibitors of proteases or esterases [1,2]. The general feasibility of SNAr-based covalent protein ligands has recently been demonstrated [3] For this reason, we have synthesized a series of different aromatic, heteroaromatic or quinoid electrophilic compounds, which exhibited a strong inhibitory activity on some proteases [4]. We have synthesized a series of different aromatic, heteroaromatic or quinoid electrophilic compounds, which exhibited a strong inhibitory activity on some proteases [4] While the latter electrophilic moieties did not show a significant fluorescence, we became interested in the design and synthesis of fluorescent SNAr reactive groups to investigate the association and the bond-forming event with the target enzyme in detail. In our previous work, we showed the possibility of introducing fragments of 2,1,3benzoxadiazoles into nucleosides and oligonucleotides [5,6] They are used for the synthesis of fluorescent amino acids, glucosides or protein binders [7,8,9]
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