Radhika Venkataraman

Design, synthesis, and in vitro inhibitory activity toward human leukocyte elastase, cathepsin G, and proteinase 3 of saccharin-derived sulfones and congeners

The inhibitory activity toward human leukocyte elastase (HLE), cathepsin G (Cat G), and proteinase 3 (PR 3) of a series of saccharin derivatives having a sulfinate leaving group was investigated. The results of this study revealed that (a) inhibitory activity is dependent on the nature and pKa of the leaving group, and (b) the synthesized saccharin derivatives exhibit selective inhibition toward HLE and PR 3, with low or no activity toward cathepsin G. The results of exploratory biochemical, HPLC and high-field 13C NMR studies are also described.

Use of the 1,2,5-thiadiazolidin-3-one 1,1 dioxide and isothiazolidin-3-one 1,1 dioxide scaffolds in the design of potent inhibitors of serine proteinases

The attachment of a phosphate leaving group to the 1,2,5-thiadiazolidin-3-one 1,1 dioxide and isothiazolidin-3-one 1,1 dioxide scaffolds was found to yield highly potent, time-dependent inhibitors of human leukocyte elastase (HLE).

Isoxazoline derivatives as potential inhibitors of the proteolytic enzymes human leukocyte elastase, cathepsin G and proteinase 3: a structure-activity relationship study.

Abstract A series of isoxazoline derivatives were synthesized and investigated for their in vitro inhibitory activity towards human leukocyte elastase, cathepsin G and proteinase 3.

Design, synthesis and biological evaluation of succinimide derivatives as potential mechanism-based inhibitors of human leukocyte elastase, cathepsin G and proteinase 3

Structure-activity relationship study and in vitro biochemical studies with human leukocyte elastase, cathepsin G and proteinase 3 were conducted using a series of succinimide derivatives.

Dual-action inhibitors of proteolytic enzymes: potential therapeutic agents for cystic fibrosis and related ailments

Abstract The design, synthesis and in vitro inhibitory activity toward human leukocyte elastase of a series of dual action saccharin derivatives are described.

Potential mechanism-based inhibitors of proteolytic enzymes

Abstract The design, synthesis, and inhibitory activity toward human neutropil elastase, of a series of potential mechanims-based inhibitors is described. The design, synthesis, and inhibitory activity toward human neutrophile elastase, of a series of potential mechanism-based inhibitors (I-III) is described.

Mechanism-based inhibition of human leukocyte elastase and cathepsin G by susbtituted dihydrouracils

A series of dihydrouracil derivatives has been synthesized and investigated for their in vitro inhibitory activity toward human leukocyte elastase (HLE) and cathepsin G (Cath G). Alkyl [sulfonyl(oxy)] uracils 1-2 were found to be efficient, time-dependent inhibitors of elastase (kobs/[I] M-1 s-1 values ranged between 480 and 8110). These compounds formed acyl enzymes that exhibited variable hydrolytic stability which appeared to be dependent on the nature of the R1 group (believed to be accommodated at the primary specificity site, S1). The acyl enzymes formed with cathepsin G deacylated rapidly, leading to a significant regain of enzymatic activity. In sharp contrast, the corresponding phosphorus compounds 3-4 were found to be potent, time-dependent irreversible inhibitors of HLE. Furthermore, the results of the structure-activity relationship studies suggest that the binding modes of compounds 1-2 and 3-4 may be different.

3-(Alkylthio)-N-hydroxysuccinimide derivatives: potent inhibitors of human leukocyte elastase

A series of 3-(alkylthio)-N-hydroxysuccinimide derivatives was synthesized and their inhibitory activity towards human leukocyte elastase (HLE) was investigated. The interaction of the compounds having a 3-alkylthioether side chain (compounds 1 and 2) with HLE was found to involve rapid acylation of the enzyme, followed by total regain of enzymatic activity within 3 h. Interestingly, compounds 3-8, having an oxidized thioether side chain, were found to be highly effective, time-dependent, irreversible inhibitors of the enzyme. The k(obs)/I values for compounds 3-8 ranged between 890 and 24,000 M-1 s-1. These findings demonstrate that, unlike the physiological inhibitor of HLE (alpha-1-proteinase inhibitor), which is inactivated upon oxidation, low-molecular-weight compounds retain and/or show enhanced inhibitory activity towards HLE upon oxidation of the thioether side chain and lay the groundwork for the development of compounds that embody proteinase inhibitory and antioxidant activity.

Enantioselective inhibition of human leukocyte elastase

(RS)-Diethyl-2-benzyl-succinate was resolved using alpha-chymotrypsin. The two enantiomers were then elaborated to yield (S)-(+) and (R)-(-)-3-benzyl-N-[(methyl-sulfonyl)oxy]succinimide and the inhibitory activity of the two enantiomers toward human leukocyte elastase was subsequently determined. The k2/KI values for the R and S isomers were found to be 330 and 1500 M-1 s-1, respectively.

The Gabriel-Colman rearrangement in biological systems: design, synthesis and biological evaluation of phthalimide and saccharin derivatives as potential mechanism-based inhibitors of human leukocyte elastase, cathepsin G and proteinase 3

The results of a structure-activity relationship study focusing on the interaction of a series of phthalimide and saccharin derivatives with leukocyte elastase, cathepsin G and proteinase 3 are described. The phthalimide derivatives were found to be inactive while some of the saccharin derivatives were found to be fair inhibitors of these enzymes.