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Electrophiles02:28

Electrophiles

11.2K
This lesson explains the definition, classification, and characteristic features of an electrophile that are key features of nucleophilic substitution reactions. An analysis of their charge and orbital picture helps understand their reactivity for seeking electrons. Electrophiles can be classified into positive and neutral species. Other classes include free radicals and polar functional groups.
While a positive electrophile, like a proton, reacts due to its vacant, low-energy 1s orbital, the...
11.2K
Regioselectivity of Electrophilic Additions-Peroxide Effect02:35

Regioselectivity of Electrophilic Additions-Peroxide Effect

8.9K
In the presence of organic peroxides, the addition of hydrogen bromide to an alkene yields the isomer that is not predicted by Markovnikov’s rule. For example, the addition of hydrogen bromide to 2-methylpropene in the presence of peroxides gives 1-bromo-2-methylpropane. This addition reaction proceeds via a free radical mechanism, which reverses the regioselectivity. The free radical reaction mechanism involves three stages: initiation, propagation, and termination.
8.9K
Diels–Alder Reaction: Characteristics of Dienophiles01:24

Diels–Alder Reaction: Characteristics of Dienophiles

6.5K
In a Diels–Alder reaction, the diene is usually an electron-rich system and acts as a nucleophile, whereas the dienophile is electron-deficient and functions as an electrophile. Much like the diene, the nature of the dienophile significantly impacts the outcome of the reaction. 
Characteristics of Dienophiles
Generally, the best dienophiles are alkenes containing electron-withdrawing substituents such as carbonyl, nitrile, and nitro groups. The feasibility of a Diels–Alder reaction depends...
6.5K
Drug-Receptor Bonds01:25

Drug-Receptor Bonds

3.3K
Drug-receptor bonds are formed through various chemical forces when drugs interact with target cells. Covalent bonds, strong and irreversible, are exemplified by DNA-alkylating anticancer agents that inhibit cell division. However, such irreversible drug binding lacks selectivity and can modify the DNA of the surrounding healthy cells. Covalent binding often contributes to tissue toxicity, as seen with chloroform and paracetamol metabolites binding to the liver, causing hepatotoxicity.
In...
3.3K
Properties of Organometallic Compounds01:23

Properties of Organometallic Compounds

1.1K
Organometallic compounds are compounds that contain a carbon–metal bond. Carbon belongs to an organyl group like alkyl, aryl, allyl, or benzyl groups. The metal can be from Group I or Group II of the periodic table, a transition metal, or a semimetal.
1.1K
VSEPR Theory and the Basic Shapes02:52

VSEPR Theory and the Basic Shapes

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Overview of VSEPR Theory
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Updated: Sep 22, 2025

Covalent Fragment Screening Using the Quantitative Irreversible Tethering Assay
06:17

Covalent Fragment Screening Using the Quantitative Irreversible Tethering Assay

Published on: February 28, 2025

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Improved Electrophile Design for Exquisite Covalent Molecule Selectivity.

José L Montaño1, Brian J Wang1, Regan F Volk1

  • 1Department of Pharmaceutical Chemistry and Cardiovascular Research Institute, University of California, San Francisco, California 94158, United States.

ACS Chemical Biology
|May 19, 2022
PubMed
Summary
This summary is machine-generated.

Chemists developed a new strategy to improve covalent inhibitor selectivity by increasing steric bulk, reducing off-target effects. This approach enhances specificity for targeted proteins like Bruton

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Area of Science:

  • Medicinal Chemistry
  • Chemical Biology
  • Pharmacology

Background:

  • Covalent inhibitors are effective therapeutics but face challenges due to off-target reactivity.
  • Strategies to improve selectivity often involve modifying the reactivity of electrophilic warheads.

Purpose of the Study:

  • To develop a novel, warhead-independent method for enhancing covalent inhibitor selectivity.
  • To investigate if increasing steric bulk on electrophilic warheads can improve selectivity without compromising on-target reactivity.

Main Methods:

  • Utilized the Bruton's tyrosine kinase (BTK) inhibitor Ibrutinib scaffold for proof-of-concept.
  • Synthesized and tested a tert-butyl (t-Bu) fumarate ester analogue.
  • Employed chemical proteomic techniques to assess protein targets and reactivity.
  • Compared the selectivity and downstream effects of the t-Bu analogue against Ibrutinib.

Main Results:

  • The t-Bu fumarate analogue significantly reduced time-dependent and abolished time-independent off-target reactivity.
  • A t-Bu fumarate probe analogue identified only 7 protein targets, compared to 247 for an alkyne analogue.
  • The t-Bu inhibitor demonstrated 70% greater selectivity for BTK, with fewer downregulated proteins (8 vs. 107).

Conclusions:

  • Increasing steric bulk of electrophilic warheads is a viable strategy to enhance covalent inhibitor selectivity.
  • This approach offers a complementary method to existing strategies for optimizing covalent therapeutics.
  • Electrophilic structure optimization can lead to more selective covalent inhibitors with improved therapeutic profiles.