A new class of proteinase inhibitor. Cyclopropenone-containing inhibitor of papain

Ando, Ryoichi; Morinaka, Yasuhiro; Tokuyama, Hidetoshi; Isaka, Masahiko; Nakamura, Eiichi

doi:10.1021/ja00056a067

Cited by 40 publications

(30 citation statements)

References 4 publications

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“…The reactant had a strong interaction between all bonds. This is exemplified by the fact that E (2) for the interactions between donor (sigma C1-C2 bond) and acceptor (sigma* C3-O bond) is 85.85 kcal mol -1 .…”

Section: Resultsmentioning

confidence: 99%

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Theoretical investigation of the photochemical reaction mechanism of cyclopropenone decarbonylation

2011

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The gas-phase decomposition mechanism of the photochemical and thermal reaction of cyclopropenone leading to carbon monoxide and acetylene has been investigated theoretically. We employed the B3LYP, MP2, and CASSCF methods with the 6-311 þ G** basis set to determine the pathways and the potential energy surface (PES) of this reaction. PES minima were characterized by the absence of any imaginary frequencies and compared with the transition states that contained single imaginary frequencies. The intrinsic reaction coordinate (IRC) method was used to find the minimum energy paths in which reactants and products were connected to the transition states. Activation barrier, thermodynamic, and IRC analyses were performed using the above three methods. Our computations indicated that the decomposition of cyclopropenone proceeds through a stepwise mechanism containing two transition states (TS1 and TS2) and an intermediate. The results show that TS1, the critical transition state, determines the rate of the cyclopropenone decomposition reaction. Therefore, we employed natural bond order (NBO) calculations to probe the structure of the intermediate. The calculations showed that the intermediate has resonance structures containing a carbene and a zwitterion. Our results are in good agreement with previous theoretical and experimental studies.

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Section: Resultsmentioning

confidence: 99%

“…The cyclopropenone framework is present in the natural antibiotic penitricin [1] and functions as an active protease inhibitor [2]. Since they were first prepared in 1959 [3], cyclopropenones have attracted considerable attention because they are good electrophiles and may be classified as aromatic compounds [4].…”

Section: Introductionmentioning

confidence: 99%

Theoretical investigation of the photochemical reaction mechanism of cyclopropenone decarbonylation

2011

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“…Mitsubishi Kasei made the interesting discovery that peptidyl cyclopropenone alcohols (29, IC 50 = 350 nM) are fairly potent inhibitors of cysteine proteases, including calpain [67,135]. The inhibitory mechanism of this class of compounds has not yet been elucidated.…”

Section: Peptide Ketonesmentioning

confidence: 99%

Calpain inhibitors as potential treatment for stroke and other neurodegenerative diseases: recent trends and developments

Wells¹,

Bihovsky²

1998

Expert Opinion on Therapeutic Patents

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Calpain, a calcium-activated cysteine protease present in most mammalian tissues, including the brain, has been implicated in neurodegenerative processes resulting from its overactivation following cerebral ischaemia or traumatic injury to the head or spinal cord. Through significant effort, particularly over the past ten to fifteen years, the complex biochemistry and physiological roles of this important regulatory enzyme have been partially clarified. Despite remarkable advances in understanding calpain's normal functions, as well as its involvement in neuropathological conditions, a full appreciation of its role in neuronal cells remains elusive. A wide array of peptidic, peptide mimetic and non-peptide inhibitors have recently emerged, some of which display potency both in vitro and in vivo in various cell lines and animal models of focal and global ischaemia. A drug candidate has yet to be identified for advancement to clinical testing.

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“…The main structural feature of this molecule, a cyclopropenone containing inhibitor (CCI), consists of a penitricin-like reactive site and a dipeptide-like binding site connected by a C-C bond (ref. 19). 17 18 19 20 15:…”

Section: Cyclopropenonesmentioning

confidence: 99%

“…Thus, 2-phenylcyclopropenone acetal 17 was lithiated and added to (S)-N-(tert-butoxycarbony1)-valinal to obtain the alcohol 18 and its 1'R-epimer as a 2:1 diastereomeric mixture, which was carried through to the final stage without separation. Removal of the acetal and the Boc group gave the amino alcohol hydrochloride (19). Condensation of 19 with the mixed anhydride obtained by the reaction of (S) -N-(cyclohexylmethoxycarbonyl)leucine 20 with isobutyl chloroformate then gave the target CCI 15 and its 1'R epimer 16 as a ca.…”

Section: Cyclopropenonesmentioning

confidence: 99%

Synthetic Chemistry of Cyclopropenone Acetals. Penitricin and Buckminsterfullerene.

Nakamura

1994

J. Syn. Org. Chem., Jpn.

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A variety of substituted cyclopropenone acetals have been prepared and studied for the purpose of gaining further insights into their organometallic and thermal chemistry. Acidic hydrolysis of the acetals gave the corresponding cyclopropenones, among these are a naturally occurring cyclopropenone antibiotic, penitricin. A new class of cysteine protease inhibitor can be realized if the penitricin moiety is contrived as a dipeptide-like binding site. Thermolysisbf substituted cyclopropenone acetals generates vinyl carbene species that undergo [1 + 2] and [3 + 2] cycloadditions to electrondeficient olefins. The cyclopropenone acetal also serves as a precursor to a dipolar trimethylenemethane. The vinyl carbene and the trimethylenemethane species undergo cycloaddition to give buckminsterfullerenes, with which the various organic derivatives of fullerenes generated have been shown to exhibit photo-induced cytotoxicity, DNA cutting activity and enzyme inhibition.

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A new class of proteinase inhibitor. Cyclopropenone-containing inhibitor of papain

Cited by 40 publications

References 4 publications

Theoretical investigation of the photochemical reaction mechanism of cyclopropenone decarbonylation

Theoretical investigation of the photochemical reaction mechanism of cyclopropenone decarbonylation

Calpain inhibitors as potential treatment for stroke and other neurodegenerative diseases: recent trends and developments

Synthetic Chemistry of Cyclopropenone Acetals. Penitricin and Buckminsterfullerene.

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