Design and synthesis of novel quinones targeting the redox function of Ape1/Ref-1

Rodney Louis Nyland, Purdue University

Abstract

The bifunctional protein apurinic endonuclease 1/redox-enhancing factor 1 (Ape1/Ref-1) has two functions in the cell: repair of apurinic sites in DNA and regulation of transcription factors through redox events. All X-ray structures currently available for Ape1 depict the base excision repair (BER) site, and little structural information is known about the redox site. Cysteine 65 is the critical residue for redox function, unfortunately it is not solvent accessible in any structure. A novel quinone, E3330 (1, (E)-3-(4,5-dimethoxy-2-methyl-3,6-dioxocyclohexa-1,4-dienyl)-2-nonylpropenoic acid), has previously been identified to inhibit the redox function of Ape1 without affecting BER. The goal of this project was to design and synthesize analogs of E3330 in an effort to increase activity and druggability of the parent benzoquinone. Analog development began by examining the redox-inhibitory effects of modifying various aspects of the E3330 structure, including the nonyl substituent on the double bond, the methyl ring substituent, the benzene core, the E character of the double bond, and the carboxylic acid group. Using E3330 as a starting point, analogs with higher affinity and druggability were designed and synthesized, resulting in drugs with submicromolar redox IC50 values. Studies are presently directed toward synthesizing biotin conjugates of the most potent analogs to collect binding data.

Degree

Ph.D.

Advisors

Borch, Purdue University.

Subject Area

Organic chemistry

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