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Functionalized Spirocyclic Heterocycle Synthesis and Cytotoxicity Assay
Published on: February 9, 2021
Cytotoxic thiol alkylators.
Hari N Pati1, Umashankar Das, Rajendra K Sharma
1College of Pharmacy and Nutrition, University of Saskatchewan, 110 Science Place, Saskatoon, Saskatchewan S7N 5C9, Canada.
Mini Reviews in Medicinal Chemistry
|February 20, 2007
Summary
This study details cytotoxic compounds that alkylate cellular thiols, like unsaturated ketones and lactones. Modulating thiol concentrations can enhance drug potency and reverse multidrug resistance.
Area of Science:
- Biochemistry
- Pharmacology
- Medicinal Chemistry
Background:
- Cellular thiols play a crucial role in various biological processes.
- Cytotoxic compounds that target thiols are of significant interest in drug development.
- Understanding the mechanisms of thiol alkylation is key to designing effective therapeutics.
Purpose of the Study:
- To describe various classes of cytotoxic compounds that alkylate cellular thiols.
- To elucidate the mechanisms of action for these thiol-alkylating agents.
- To explore the influence of thiol concentration modulation on drug cytotoxicity and multidrug resistance.
Main Methods:
- Review and description of diverse chemical classes including alpha,beta-unsaturated ketones, alpha-methylene-gamma-lactones, azines of Mannich bases, imexon, isothiocyanates, and benzoacronycine.
- Presentation of proposed mechanisms of action, including the generation of reactive oxygen species.
- Investigation into the effects of thiol activation and modulation on drug potency and multidrug resistance reversal.
Main Results:
- Identification of multiple classes of cytotoxic compounds that function by alkylating cellular thiols.
- Demonstration that thiol activation can significantly increase the potency of certain drugs.
- Evidence for the ability of specific thiol reagents to overcome multidrug resistance.
- Observation of reactive oxygen species formation as a mechanism for some compounds.
Conclusions:
- Cytotoxic compounds targeting cellular thiols represent a promising area for therapeutic development.
- Modulation of cellular thiol levels offers a viable strategy to enhance drug efficacy and combat resistance.
- Thiol alkylators possess diverse mechanisms and applications, including potential in reversing multidrug resistance.
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