scholarly journals The synthesis of lysylfluoromethanes and their properties as inhibitors of trypsin, plasmin and cathepsin B

1987 ◽  
Vol 241 (3) ◽  
pp. 871-875 ◽  
Author(s):  
H Angliker ◽  
P Wikstrom ◽  
P Rauber ◽  
E Shaw
Keyword(s):  
Proximity Effect ◽  
Cathepsin B ◽  
Chemical Reactivity ◽  
Bond Formation ◽  
Synthesis Method ◽  
Covalent Bond ◽  
Active Centre ◽  
Fluoro Derivative ◽  
Order Of Magnitude ◽  
Covalent Bond Formation

The synthesis of two lysylfluoromethanes is described by an extension of the synthesis method of Rauber, Angliker, Walker & Shaw [(1986) Biochem. J. 239, 633-640]. Ala-Phe-Lys-CH2F was found to be an active-centre-directed inhibitor of plasmin and trypsin, as is the corresponding chloromethane. However, the rate of covalent-bond formation is about an order of magnitude lower at 25 degrees C for the fluoro derivative. It was, in addition, an extremely effective inactivator of cathepsin B at pH 5.4 and 6.4. The chemical reactivity of fluoromethanes was compared with that of chloromethanes as alkylators of GSH. At pH 7.4 and 37 degrees C, a fluoromethane has 1/500th the reactivity of a chloromethane. A comparison of the rates of reaction of the fluoromethane with cathepsin B and with GSH at pH 6.4 revealed an enhancement of 10(8)-fold for the alkylation of the enzyme, ascribable largely to a proximity effect.

scholarly journals The synthesis of peptidylfluoromethanes and their properties as inhibitors of serine proteinases and cysteine proteinases

1986 ◽  
Vol 239 (3) ◽  
pp. 633-640 ◽  
Author(s):  
P Rauber ◽  
H Angliker ◽  
B Walker ◽  
E Shaw
Keyword(s):  
Cathepsin B ◽  
Cysteine Proteinase ◽  
Bond Formation ◽  
Serine Proteinase ◽  
Covalent Bond ◽  
Serine Proteinases ◽  
Cysteine Proteinases ◽  
Active Centre ◽  
Covalent Bond Formation ◽  
The Difference

A synthesis of peptidylfluoromethanes is described that utilizes the conversion of phthaloyl amino acids into their fluoromethane derivatives. These can be deblocked and elongated. The inactivation of chymotrypsin by Cbz-Phe-CH2F (benzyloxycarbonylphenylalanylfluoromethane) was found to be considerably slower than that of the analogous chloromethane. The fluoromethane analogue inactivates chymotrypsin with an overall rate constant that is 2% of that observed for the inactivation of the enzyme with the chloromethane. However, the result is the same. The reagent complexes in a substrate-like manner, with Ki = 1.4 × 10(-4) M, and alkylates the active-centre histidine residue. Cbz-Phe-Phe-CH2F and Cbz-Phe-Ala-CH2F were investigated as inactivators of the cysteine proteinase cathepsin B. The difference in reactivity between fluoromethyl ketones and chloromethyl ketones is less pronounced in the case of the cysteine proteinase than for the serine proteinase. Covalent bond formation takes place in this case also, as demonstrated by the use of a radiolabelled reagent.

scholarly journals Chemical Investigations Into the Biosynthesis of the Gymnastatin and Dankastatin Alkaloids

2021 ◽  
Author(s):  
Bingqi Tong ◽  
Bridget Belcher ◽  
Daniel Nomura ◽  
Thomas Maimone
Keyword(s):  
Natural Products ◽  
Protein Function ◽  
Bond Formation ◽  
Covalent Bond ◽  
Fungal Strain ◽  
Fertile Ground ◽  
Covalent Bond Formation

Electrophilic natural products have provided fertile ground for understanding how nature inhibits protein function using covalent bond formation. The fungal strain Gymnascella dankaliensis has provided an especially interesting collection of...

Material Adhesion through Direct Covalent Bond Formation Assisted by Noncovalent Interactions

2021 ◽  
Author(s):  
Motofumi Osaki ◽  
Tomoko Sekine ◽  
Hiroyasu Yamaguchi ◽  
Yoshinori Takashima ◽  
Akira Harada
Keyword(s):  
Noncovalent Interactions ◽  
Bond Formation ◽  
Covalent Bond ◽  
Covalent Bond Formation

scholarly journals Mechanism of Covalent Binding of Ibrutinib to Bruton’s Tyrosine Kinase revealed by QM/MM Calculations

2020 ◽  
Author(s):  
Angus Voice ◽  
Gary Tresadern ◽  
Rebecca Twidale ◽  
Herman Van Vlijmen ◽  
Adrian Mulholland
Keyword(s):  
Tyrosine Kinase ◽  
Covalent Binding ◽  
Bond Formation ◽  
Covalent Bond ◽  
Covalent Modification ◽  
Mechanistic Study ◽  
Bruton’S Tyrosine Kinase ◽  
Bruton's Tyrosine Kinase ◽  
Covalent Inhibitors ◽  
Covalent Bond Formation

<p>Ibrutinib is the first covalent inhibitor of Bruton’s tyrosine kinase (BTK) to be used in the treatment of B-cell cancers. Understanding the mechanism of covalent inhibition is crucial for the design of safer and more selective covalent inhibitors that target BTK. There are questions surrounding the precise mechanism of covalent bond formation in BTK as there is no appropriate active site residue that can act as a base to deprotonate the cysteine thiol prior to covalent bond formation. To address this, we have investigated several mechanistic pathways of covalent modification of C481 in BTK by ibrutinib using QM/MM reaction simulations. The lowest energy pathway we identified involves a direct proton transfer from C481 to the acrylamide warhead in ibrutinib, followed by covalent bond formation to form an enol intermediate. There is a subsequent rate-limiting keto-enol tautomerisation step (DG<sup>‡</sup>=10.5 kcal mol<sup>-1</sup>) to reach the inactivated BTK/ibrutinib complex. Our results represent the first mechanistic study of BTK inactivation by ibrutinib to consider multiple mechanistic pathways. These findings should aid in the design of covalent drugs that target BTK and related proteins. </p>

Supramolecular Assembly-Enabled Homochiral Polymerization of Short (dA)n Oligonucleotides

2021 ◽  
Author(s):  
Sreejith Mangalath ◽  
Suneesh C Karunakaran ◽  
Gary Newnam ◽  
Gary Schuster ◽  
Nicholas Hud
Keyword(s):  
Supramolecular Chemistry ◽  
Bond Formation ◽  
Supramolecular Assembly ◽  
Covalent Bond ◽  
Complex Mixtures ◽  
Covalent Bond Formation

A goal of supramolecular chemistry is to create covalent polymers of precise composition and stereochemistry from complex mixtures by the reversible assembly of specific monomers prior to covalent bond formation....

scholarly journals Light‐Controlled Orthogonal Covalent Bond Formation at Two Different Wavelengths

2019 ◽  
Vol 58 (22) ◽  
pp. 7470-7474 ◽  
Author(s):  
Jan P. Menzel ◽  
Florian Feist ◽  
Bryan Tuten ◽  
Tanja Weil ◽  
James P. Blinco ◽  
...  
Keyword(s):  
Bond Formation ◽  
Covalent Bond ◽  
Covalent Bond Formation

Photoinduced Intramolecular Covalent Bond Formation in Structurally Rigid -Bpa-(spacer)-Met Hexapeptides

2009 ◽  
pp. 449-450
Author(s):  
Alessandro Moretto ◽  
Simona Oancea ◽  
Fernando Formaggio ◽  
Claudio Toniolo ◽  
Laurence A. Huck ◽  
...  
Keyword(s):  
Bond Formation ◽  
Covalent Bond ◽  
Covalent Bond Formation
Sign in / Sign up

Export Citation Format

Share Document