Title

Axial Chirality to increase selectivity of AIMs as anti tumor agents

Presentation Type

Presentation

Abstract

The focus of this project is to improve the efficacy of Anthracenyl isoxazolyl amides (AIMs) by adding axial chirality via strategic halogenation. AIMs are a new class of antitumor agents specially synthesized to bind and interact with G-quadruplex (G4) DNA; binding G4 DNA has been shown to repress the replication of oncogenes in cancerous tumors. By using asymmetric halogenation to introduce axial chirality into the AIMs, our goal is to create a molecule that is divided by a bond, or axis, that cannot freely rotate due to steric hindrance. Many biologically active molecules are chiral and the stereoisomers often display a significant difference in activity due to interactions with chiral targets, such as DNA. Our efforts are currently centered on over halogenating the anthracene followed by selective cleavage. Over halogenation of unsubstituted anthracenes in synthetically significant yields has been published by Cakmak. However, with the added complexity of the substituted anthracene used as a starting material in the production of the AIMs, the addition of halogens has become quite a challenge. We have successfully isolated a 2,3,4,5,10-pentabromo-anthracenyl-nitrile oxide. The original methods by which we synthesized this compound proved to be inefficient and require optimization. The methods that we are investigating require consideration of the mechanism of the reactions, and catalysts can change the course of the respective reactions, in which ionic and radical intermediates are expected to predominate. The future focus will then shift to optimization of the cycloaddition and methods of selective cleavage. The benefit of stereospecific activity is that a patient may be able to take less of the chemotherapeutic agent and achieve equally beneficial results with fewer side effects. Our progress will be described.

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Apr 12th, 3:40 PM Apr 12th, 4:00 PM

Axial Chirality to increase selectivity of AIMs as anti tumor agents

UC 331

The focus of this project is to improve the efficacy of Anthracenyl isoxazolyl amides (AIMs) by adding axial chirality via strategic halogenation. AIMs are a new class of antitumor agents specially synthesized to bind and interact with G-quadruplex (G4) DNA; binding G4 DNA has been shown to repress the replication of oncogenes in cancerous tumors. By using asymmetric halogenation to introduce axial chirality into the AIMs, our goal is to create a molecule that is divided by a bond, or axis, that cannot freely rotate due to steric hindrance. Many biologically active molecules are chiral and the stereoisomers often display a significant difference in activity due to interactions with chiral targets, such as DNA. Our efforts are currently centered on over halogenating the anthracene followed by selective cleavage. Over halogenation of unsubstituted anthracenes in synthetically significant yields has been published by Cakmak. However, with the added complexity of the substituted anthracene used as a starting material in the production of the AIMs, the addition of halogens has become quite a challenge. We have successfully isolated a 2,3,4,5,10-pentabromo-anthracenyl-nitrile oxide. The original methods by which we synthesized this compound proved to be inefficient and require optimization. The methods that we are investigating require consideration of the mechanism of the reactions, and catalysts can change the course of the respective reactions, in which ionic and radical intermediates are expected to predominate. The future focus will then shift to optimization of the cycloaddition and methods of selective cleavage. The benefit of stereospecific activity is that a patient may be able to take less of the chemotherapeutic agent and achieve equally beneficial results with fewer side effects. Our progress will be described.