Synthesis of a cooperative DNA alkylating agent

ORGN 193

Jifeng Dai, jdai@mail1.vcu.edu, Chemistry, Virginia Commonwealth University, 1001 West Main St, Richmond, VA 23284 and Qibing Zhou, qzhou@vcu.edu, Department of Chemistry, Virginia Commonwealth University, 1001 West Main St, Richmond, VA 23284.

Natural chemotherapeutic drugs have been extensively studied for its impact on gene regulations including DNA repair, transcription and translation in the past decade.  However, the cytotoxicity of these drugs has become a major concern due to the low sequence specificity and/or the high nonselective reactivity.  Our goal of research is to develop a high affinity DNA-alkylating agent in which DNA modification interacts cooperatively with sequence recognition.  This target-promoted activation is achieved through a reversible quinone methide intermediate, driven thermodynamically in the DNA complex.  To demonstrate this strategy, model compounds conjugated with acridine intercalator were designed and synthesized.  The reversible QM moiety was achieved through a Mutsunobu coupling of a fluorenone and a L-serine derivative, and then coupled with the acridine derivative via an activated ester.