Design and Synthesis of Novel ATF-Based Small Molecules for Potential Antiproliferative Activity
Abstract
Arylazothioformamide (ATF) ligands are established metal chelators capable of forming coordination complexes through the oxidative dissolution of metals such as copper, nickel, palladium, and platinum. However, recent studies have shown ATF ligands themselves exhibit a broad spectrum of bioactivity, most notably is their potency for A549 adenocarcinoma cells (lung cancer cells).1 This discovery opens the door to the design and synthesis of small molecule agents for other antiproliferative properties. Founded in the efficacy of fungicides that target the CYP51 enzyme, we hypothesize that through the synthesis of ATF ligand substituted asymmetric thioformamides, we can create a series of biologically active compounds capable of possessing fungicidal properties. A combinatorial approach was taken in which asymmetric amines were appended with phenyldiazoxanthate esters. The aryl and amine variable sites were modified to enhance activity, ultimately creating a small chemical library that can be tested for antifungal activity against common pathogens. Bioinformatics and molecular modeling were utilized to identify promising lead compounds and help predict the binding affinity of potential therapeutics.
Design and Synthesis of Novel ATF-Based Small Molecules for Potential Antiproliferative Activity
Arylazothioformamide (ATF) ligands are established metal chelators capable of forming coordination complexes through the oxidative dissolution of metals such as copper, nickel, palladium, and platinum. However, recent studies have shown ATF ligands themselves exhibit a broad spectrum of bioactivity, most notably is their potency for A549 adenocarcinoma cells (lung cancer cells).1 This discovery opens the door to the design and synthesis of small molecule agents for other antiproliferative properties. Founded in the efficacy of fungicides that target the CYP51 enzyme, we hypothesize that through the synthesis of ATF ligand substituted asymmetric thioformamides, we can create a series of biologically active compounds capable of possessing fungicidal properties. A combinatorial approach was taken in which asymmetric amines were appended with phenyldiazoxanthate esters. The aryl and amine variable sites were modified to enhance activity, ultimately creating a small chemical library that can be tested for antifungal activity against common pathogens. Bioinformatics and molecular modeling were utilized to identify promising lead compounds and help predict the binding affinity of potential therapeutics.