Publication list via PubMed

Organic synthesis plays a pivotal role in drug discovery and also provides many of the tools for probing the molecular mechanisms of biochemical pathways. Most chemotherapeutic agents in current use against cancer are semisynthetic (e.g. taxol) or are completely synthetic (e.g. 5-fluorouracil). Even when the initial lead compound is a natural product, as it is in the case of taxol, the optimal drug often requires one or more chemical modifications. Organic synthesis is always required to determine the structural features of a drug molecule that are essential for activity, and is often necessary to elucidate the mechanism of action.

Organic synthesis has marked impressive advances during the past few decades. Synthesis of complex natural products on large scale still represents a challenge. For example, if the problem is to produce gram quantities of a complex natural product of molecular weight ca. 1000, there are two approaches that can be followed. The first is to treat this as a logistical problem, and to organize the efforts of a large team; the second approach is to redefine the way one thinks about problem solving in organic synthesis and to devise an approach that can be implemented by a small team.

In our research we have attempted to follow this second approach. We have worked in two areas: total synthesis and the development of new synthetic methods. We have recently completed syntheses of madindolines A and B, two naturally occurring IL-6 inhibitors, and of terpestacin, an anti-angiogenic terpenoid that was originally isolated from several species of phytopathogenic fungi. These total syntheses are brief and efficient in large part because they make use of an exceptionally effective method that has been developed in my group, the allene ether version of the Nazarov cyclization. For example, our terpestacin synthesis is accomplished in 15 steps and in 6.4% overall yield. The terpestacin synthesis is noteworthy for its brevity but also for offering a flexible approach to access analogs of the natural product. This, in turn, has made it possible to explore the molecular mechanism of action in a collaborative effort with Dr. Patricia Lorenzo. An observation of unusual chemical reactivity in one part of the chemical structure led to our hypothesis for the mechanism of action. A systematic synthesis of approximately 10 terpestacin analogs is currently underway. An understanding of the mechanism of action will enable the rational design and synthesis of compounds with improved activity, and may lead to a clinical candidate.

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Active Grants

M.A. Tius, Principal Investigator
"Cyclopentannelation In Total Synthesis"
R01
April 1, 2007-March 31, 2011

"Cannabinergic Ligands and Drugs"
R01  (A. Makriyannis at Northeastern University is P.I.)
April 1, 2008-March 31, 2013

"Endocannabinoid Active Sites as Therapeutic Target"
P01 (A. Makriyannis at Northeastern University is P.I.)
Apri 1, 2008-March 31, 2013