P2-proline-derived inhibitors of calpain I

Tripathy, Rabindranath; Gu, Zi-Qiang; Dunn, Derek; Senadhi, Shobha E.; Ator, Mark A.; Chatterjee, Sankar

doi:10.1016/s0960-894x(98)00470-3

Cited by 15 publications

(15 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, recent studies have shown that calpains can accommodate N-arylsulfonyl-D-proline or N-arylsulfonyl-L-thiaproline groups at this position, as found in the P 2 -constrained inhibitors (6a) and (6b), (Fig. (8)), respectively [239][240][241]. The introduction of further conformational restriction with the inclusion of a 1,2-benzothiazine 1,1-dioxide ((7a), Fig.…”

Section: Peptide Aldehydesmentioning

confidence: 94%

“…(8)) results in potent P 2 -P 3 mimetics [242]. Compound (6a) displays excellent (150-fold) selectivity for calpain 1 over cathepsin B [240,241] and is a poor inhibitor of various serine proteases [239,240]. In addition, (6a) and (6b) demonstrate potent anti-proliferate activity against leukemia and solid tumor cell-lines via an induction of a G2-M phase arrest and apoptosis that involves caspase-3 activation.…”

Section: Peptide Aldehydesmentioning

confidence: 99%

See 1 more Smart Citation

Calpains: Attractive Targets for the Development of Synthetic Inhibitors

Pietsch

Chua²,

Abell

2010

CTMC

View full text Add to dashboard Cite

The physiological roles of calpains are discussed, as are the associated pathological disorders that result from their over-activation. We also present practical information for establishing functional inhibition assays and an overview of X-ray crystal structures of calpain-inhibitor complexes to aid inhibitor design. These structures reveal the expected extended beta-strand conformation for the inhibitor backbone, a geometry that has been engineered into inhibitors with the introduction of either an N-terminal heterocycle or a macrocycle that links the P(1) and P(3) residues. The structure and function of all the main classes of inhibitors are reviewed, with most examples being classified according to the nature of the C-terminal reactive warhead group that reacts with the active site cysteine of calpains. These inhibitor classes include epoxysuccinate derivatives, aldehydes, aldehyde prodrugs (hemiacetals) and alpha-keto carbonyl compounds. Inhibitors derived from the endogenous inhibitor calpastatin and examples lacking a warhead, are now known and these are also discussed.

show abstract

Section: Peptide Aldehydesmentioning

confidence: 94%

Section: Peptide Aldehydesmentioning

confidence: 99%

Calpains: Attractive Targets for the Development of Synthetic Inhibitors

Pietsch

Chua²,

Abell

2010

CTMC

View full text Add to dashboard Cite

show abstract

“…Protected 4-aminoproline stereoisomers have been reported frequently during the past 10 years as part of biologically active compounds. These include matrix metalloproteinases inhibitors, spermine analogues to study DNA triplex stability, contrast agents for magnetic resonance imaging, conformationally restricted amino acid analogues for protein−peptide interactions, peptide nucleic acids (PNA), receptor-adhesive modular protein (RAMP), Calpain I inhibitors, building blocks in a potential anti-Tat library, and antifungal cyclic aminohexapeptides . Another recent application is the study of photochemical energy conversion …”

mentioning

confidence: 99%

Short, Highly Efficient Syntheses of Protected 3-Azido- and 4-Azidoproline and Their Precursors

Gómez-Vidal

Silverman

2001

Org. Lett.

View full text Add to dashboard Cite

[structure: see text] An improved synthesis of protected cis- and trans-3-azido-L-proline and cis- and trans-4-azido-L- and -D-proline is reported. These compounds have been synthesized from the corresponding hydroxyproline precursors using diphenylphosphoryl azide under Mitsunobu conditions. Short, highly efficient syntheses of these precursors are described, based on a new lactone-opening reaction and p-nitrobenzoate hydrolysis under very mild conditions.

show abstract

“…However, recent studies from our laboratory 19 and those of others 20,21 have demonstrated that peptidyl aldehydes with D D-amino acids at the P 2 -position are effective inhibitors of calpain. To further study the significance of the geometry of the P 2 residue on the potency and selectivity of peptidyl calpain inhibitors, we replaced the P 2 a-carbon with a nitrogen atom thus changing the geometry of the P 2 -position from chiral and tetrahedral to achiral and trigonal planar to afford compounds 1-12.…”

mentioning

confidence: 91%