Syntheses and reactions of the diethyl α-alkynylmalonates involving the generation of conjugated allenyl esters as the latent active species: A new approach to the development of cysteine proteinase inhibitors

Nagao, Yoshimitsu; Kim, Kweon; Sano, Shigeki; Kakegawa, Hisao; Lee, Woo Song; Shimizu, Hisashi; Shiro, Motoo; Katunuma, Nobuhiko

doi:10.1016/0040-4039(95)02284-8

Cited by 31 publications

(10 citation statements)

References 19 publications

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“…1). This lack of in vivo inhibition was ascribed to depletion of the inhibitor through competing reactions with endogenous low molecular weight thiol compounds such as cysteine and reduced glutathione 7. As a result of our efforts to develop allene compounds which would be stable and active in vivo, we found that α-methyl-γ,γ-diphenylallenecarboxylic acid ethyl ester 3 could inhibit the catalytic activities of cathepsin B8 (IC 50 = 2.32 × 10 −4 M) and urease9 (IC 50 = 1.1 × 10 −6 M) 10.…”

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confidence: 99%

Possible involvement of radical intermediates in the inhibition of cysteine proteases by allenyl esters and amides

Takéuchi

Fujiwara

Shimone

et al. 2008

Bioorganic & Medicinal Chemistry Letters

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In order to investigate crystallographically the mechanism of inhibition of cysteine protease by α-methyl-γ,γ-diphenylallenecarboxylic acid ethyl ester 3, a cysteine protease inhibitor having in vivo stability, we synthesized N- (α-methyl-γ,γ-diphenylallenecarbonyl)-L-phenylalanine ethyl ester 4. Reaction of 4 with thiophenol, the SH group of which has similar pKa value to that of cysteine protease, produced oxygen-mediated radical adducts 6 and 7 in ambient air but did not proceed under oxygen-free conditions. Catalytic activities of two thiol enzymes including cathepsin B were also lowered in the absence of oxygen. These results suggest that cysteine protease can act through an oxygen-dependent radical mechanism. KeywordsAllene; Cysteine protease; Cysteine protease inhibitor; Oxygen; Radical Cysteine proteases are an important class of peptide-processing enzymes and, as the name implies, are characterized by having a cysteine residue within the active site. 1 These proteases are also ubiquitous enzymes that play important roles in many biochemical processes. 1,2 The presence of cysteine proteases in pathogenic microorganisms and roles in facilitating metastases of tumors are examples of many factors that make selective cysteine protease inhibitors important targets for drug design. 1 As a consequence of the wide therapeutic potential of these compounds, many cysteine protease inhibitors have been developed. 3 In much of the design of these inhibitors, it has been assumed that the catalytic mechanism of *Corresponding author. Tel.: +81 76 434 7555; e-mail: takeuchi@pha.u-toyama.ac.jp. † Deceased, 6 July 2001. ‡ Dedicated to the memory of Professor Toshio Satoh of Tokushima Bunri University who made many lasting contributions to the field of medicinal chemistry.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. cysteine proteases is similar to that of serine proteases. Thus, the cysteinyl and histidinyl residues present in the active site form a thiolate/imidazolium ion pair that promotes the formation of an S-acyl-enzyme intermediate that is necessary for cleavage of the peptide bond. 4 However, despite the similarities of the proposed catalytic mechanism of cysteine and serine proteases, important differences have been revealed. Thus, the replacement of the active site serine with cysteine in two serine proteases (trypsin and subtilisin) abolished activity. 5 This result implies that cysteine proteases have another reaction mechanism, for example, a radical reaction mechanism that has been found in several enzymatic systems. 6 NIH Public AccessAllenyl esters 2 deri...

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Possible involvement of radical intermediates in the inhibition of cysteine proteases by allenyl esters and amides

Takéuchi

Fujiwara

Shimone

et al. 2008

Bioorganic & Medicinal Chemistry Letters

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“…Interestingly, compound lb did not inhibit the enzymatic hydrolysis of Suc-Leu-Leu-Val-Tyr-MCA with a serine protease, human pancreatic chymotrypsin as we anticipated on the basis of the chemical reactions (Scheme 3). 5 In general, decarboxylation of the malonic half-esters in the enolization mode ("E" mode in Figure 1) seems to be difficult under mild basic conditions. However, decarboxylation of the a-alkynyl-malonic half-esters toward the conjugated allenyl ester formation ("A" mode in Figure 1) may be facilitated by satisfying a stereoelectronic requirement due to the…”

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confidence: 99%

“…5 Subsequently, we investigated several chemical and enzymatic reactions of DAM la-d in order to rationalize our new idea depicted in Scheme 1. All results are summarized in Scheme 3.…”

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Cyclization, Ring-Expansion, and Several Cascade Reactions Utilizing Allenylic Molecular Structure Characteristics

Nagao

Sano

2003

J. Syn. Org. Chem., Jpn.

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“…30) Specifically, the compounds 2, 5, and 6 must be expected to be cysteine protease inhibitors. 27) Finally, an enzymatic hydrolysis of diethyl a-alkynyl-aacetylaminomalonate 5a using porcine liver esterase (PLE) was tentatively investigated by using reaction conditions similar to those used for the enzymatic hydrolysis of prochiral s-symmetrical esters with PLE, [45][46][47][48][49] as shown in Chart 8. Namely, 5a was treated with PLE (Sigma Type I, 100 units) in a solution of 0.1 M phosphate buffer (pH 7.5)-acetone (10 : 1) at 35-45°C for 5 d. After methylation of the resulting carboxylic acid with CH 2 N 2 , trisubstituted oxazole methyl ester 15 was obtained in 83%.…”

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“…[1][2][3][4][5][6][7][8][9][20][21][22][23][24][25][26] Previously, we communicated a characteristic synthetic method for conjugated allenyl esters and trisubstituted oxazoles via alkaline hydrolysis of diethyl a-alkynyla-methoxy(or acetylamino)malonates followed by decarboxylation of the corresponding resultant monocarboxylates in a cascade reaction manner. 27) We now describe, in detail, expeditious syntheses of conjugated allenyl esters and trisubstituted oxazoles and the related reactions based on the following concept and background. 28) Cysteine proteases of the papain family have been implicated in the pathogenesis of a various of serious diseases.…”

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Expeditious Syntheses of Conjugated Allenyl Esters and Oxazoles through a Cascade Reaction of .ALPHA.-Alkynyl Malonates under Alkaline Conditions

Sano

Shimizu

Kim

et al. 2006

CHEMICAL & PHARMACEUTICAL BULLETIN

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Since the development of various synthetic methods for the achiral and chiral allenes, extensive studies on the structure and reactivity of the characteristic allenes have been performed. [1][2][3][4][5][6][7][8][9] Allenylic compounds have been efficiently utilized as a key intermediate to synthesize biologically active natural products. [10][11][12] The specific reactivities of allenylic compounds have been widely applied to carbon-carbon and carbon-hetero atom cyclizations, aldol reactions, DielsAlder reactions, [2ϩ2] and [4ϩ2] cycloadditions, etc. [13][14][15][16][17][18][19] Because of this usefulness of allenes, there have been many reports on methods for constructing the allenylic moieties. [1][2][3][4][5][6][7][8][9][20][21][22][23][24][25][26] Previously, we communicated a characteristic synthetic method for conjugated allenyl esters and trisubstituted oxazoles via alkaline hydrolysis of diethyl a-alkynyla-methoxy(or acetylamino)malonates followed by decarboxylation of the corresponding resultant monocarboxylates in a cascade reaction manner. 27)We now describe, in detail, expeditious syntheses of conjugated allenyl esters and trisubstituted oxazoles and the related reactions based on the following concept and background.28) Cysteine proteases of the papain family have been implicated in the pathogenesis of a various of serious diseases. Hence, the development of cysteine protease inhibitors has been extensively studied worldwide. 29) We thus designed diethyl a -alkynyl-a -methoxy(or acetylamino)malonates (DAM, A) as new lead compounds for developing cysteine protease inhibitors, as shown in Chart 1.27) Chart 1 illustrates our idea of the enzyme inhibition and latent function of DAM (A), readily obtained from the reaction of diethyl keto(or acetylimino)malonate with alkynyl anionic species, against cysteine proteases. Namely, enzymatic and/or nonenzymatic hydrolysis of an ethoxycarbonyl group (a "trigger" moiety leading compounds A to the conjugated allenyl ester) of the DAM (A) followed by enzymatic and/or non-enzymatic decarboxylation of the corresponding resultant monocarboxylic acids B may generate the conjugated allenyl esters C. The conjugated allenyl esters C must be capable of trapping an active-site nucleophile (SH group of the cysteine residue) 30) of the target enzyme, which may cause inhibition of the SH enzymes. In the molecule of DAM (A), the R group would be designed as the specific enzyme-recognition moiety bearing a di-or tripeptide substituent.Diethyl a-alkynyl-a-methoxymalonates 2a-e, employed for syntheses of conjugated allenyl esters (vide infra), were readily prepared from diethyl ketomalonate by its treatment with various ethynyl lithiums derived from 1a-e, as shown Sho-machi, Tokushima 770-8505, Japan: and b Rigaku Corporation; 3-9-12 Matsubara-cho, Akishima, Tokyo 196-8666, Japan. Received September 3, 2005; accepted November 4, 2005; published online November 11, 2005 Diethyl a a-alkynyl-a a-methoxymalonates (2a-e) were smoothly hydrolyzed and then decarboxylated under a...

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Syntheses and reactions of the diethyl α-alkynylmalonates involving the generation of conjugated allenyl esters as the latent active species: A new approach to the development of cysteine proteinase inhibitors

Cited by 31 publications

References 19 publications

Possible involvement of radical intermediates in the inhibition of cysteine proteases by allenyl esters and amides

Possible involvement of radical intermediates in the inhibition of cysteine proteases by allenyl esters and amides

Cyclization, Ring-Expansion, and Several Cascade Reactions Utilizing Allenylic Molecular Structure Characteristics

Expeditious Syntheses of Conjugated Allenyl Esters and Oxazoles through a Cascade Reaction of .ALPHA.-Alkynyl Malonates under Alkaline Conditions

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