Associate Director, Barnett Institute
Professor Jones’ research group is dedicated to the application of synthetic organic chemistry to the development of diagnostic and therapeutic agents. Since the mid-90’s the program has produced over 120 original research publications and attracted over $8 million in research funding. In most cases projects represent joint efforts between our NU program (housed in the Bioorganic & Medicinal Chemistry Laboratory) and collaborators at the nearby Harvard Medical School. Current projects include:
Targeted delivery and activation of cytotoxic antitumor agents. The Jones group pioneered a new method for the synthesis of enediyne prodrugs and continues to develop targeted variants. The first FDA approved monoclonal antibody-cytotoxin conjugate (MylotargÒ) was an enediyne derivative and interest in this fascinating class of agents continues to inspire the oncology research community. The cycloaromatization of enediynes results in generation of cytotoxic diradicals, which induce DNA strand scission and can also induce proteolysis. Expanding the versatility of the enediyne family, we recently developed methodology for coupling of photo-activated enediynes to both monoclonal antibodies and gold nanoparticles via PEG linker chemistry. The bioconjugated agents retain their photoactivation profiles and immunocompetence and are under investigation for potential as topically applied antiproliferative agents.
SEM of Au-enediyne nanoparticles
Drug targeting of bulged DNA and RNA microenvironments. A variety of neurodegenerative diseases (Huntington’s disease, Freiderich ataxia, fragile X syndrome) are believed to be related to defects in DNA which result in slipped synthesis. It has been suggested that the slippage process is linked to bulged defects in the DNA, and it has become of interest to design and synthesize molecules, which have the ability to recognize these bulges with high affinity. Using the natural product metabolite NCSi-gb as a lead compound a series of spirocyclic agents were designed, synthesized and then optimized for binding to specific 2 base bulged targets. The current lead compound (derived from a 23 step synthesis) binds to a TG bulged with 80 nM affinity, the most effective synthetic agent yet reported. Related to this program, replication of HIV-1 involves binding of the tat protein to an RNA sequence and subsequent formation of an antitermination complex. The tat binding site constitutes a 3 base bulge, and preliminary data confirms that our synthetic compounds have sub-micromolar affinity for these key targets.
Efficient catalytic methods for synthesis of medicinal agents. Our group has a long-standing tradition of developing original synthetic methods, reagents, and catalysts to solve problems of significance in drug development. Very recently, a method for production of xanthine derivatives related to KW-6002 (istradefylline) was developed. This compound is under clinical investigation for the treatment of Parkinson’s disease in combination with levodopa. The new method allows one pot synthesis of the xanthine core and eliminates the need for external oxidants. The method provides facile and direct access to numerous analogues of this class, which are currently the subject of a pre-clinical investigation.