Stephen Martin

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Research
 
       
   
Synthesis of Natural Products and Bioactive Compounds
 
   

The focus of current research is upon inventing and developing general tactics and strategies to synthesize natural and unnatural products of biological or structural interest. A variety of architecturally complex alkaloids, acetogenins, and terpenes serve as targets of opportunity to discover novel chemistry that will have general utility. A key feature of our work in the area is the design of novel and useful ways of assembling molecular subunits common to natural products and other biologically active compound, and these endeavors invariably involve developing and applying new synthetic processes to fill voids in available methodology. The biological activity and profiles of selected compounds are studied with the goal of identifying novel probes of biological function and pathways associated with cancer, neurological disorders and other diseases.

 
   

Actinophyllic acid

Key Intermediate

Several projects are exemplary of current and future work. For example, we recently completed a total synthesis of the unique alkaloid actinophyllic acid by novel strategy that involved a cascade of reactions that delivered a key intermediate. In order to explore the biological activities of this intermediate, we prepared a number of analogs and discovered that several rapidly induced cell death in a number of cancer cell lines. We are now extending these studies to study their mode of action and to identify more potent molecules that might be used to treat cancer.

 
   

In another project, we have developed a general strategy for the synthesis of collections of small molecules having heterocyclic scaffolds derived from natural products of other biologically active compounds. The key feature of our approach is a versatile multicomponent assembly process (MCAP), which was inspired from previous work in alkaloid synthesis, to generate intermediates that bear orthogonal functionality. These functional groups may then be selectively paired in various ring forming reactions to give functionalized compounds that can be further diversified via cross-coupling and other reactions. This work has led to some exciting selective leads for cancers, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), substance abuse, neuropathic pain, depression, hepatitis C, tuberculosis, African sleeping sickness, and a number of other diseases. We generally collaborate with chemical biologists to help develop the chemistry and biology of active compounds.

 
 

 

 
       
   

Molecular Recognition in Protein-Ligand Interactions

The design and synthesis of small molecules that exhibit high affinities and specificities for selected proteins is a key step in the process of identifying potential enzyme inhibitors and receptor antagonists or agonists. Toward this goal, we have adopted a unique, multidisciplinary approach wherein synthetic organic chemistry, micocalorimetry, protein crystallography, NMR spectroscopy, and computational chemistry are integrated in systemic studies to investigate explicitly how specific variations in ligand structure affect energetics, nonbonded interactions, dynamics, and kinetics in protein-ligand interactions.

 
       
 

 

Grb2 SH2 domain-binding ligands
Upper structure: Flexible control phosphotyrosine-containing tri-peptide ligand.
Lower structure: Cyclopropyl-constrained ligand containing same number of heavy-atoms with same connectivity.
The focus of current studies is upon investigating the detailed effects of introducing conformational constraints and nonpolar substituents into small molecules that bind to SH2 domains, hepatitis C viral protease, and several other proteins of biological or medicinal interest. For example, it is commonly assumed that preoganizing a flexible ligand in the three dimensional shape it adopts when bound to a macromolecular receptor will provide a derivative having an increased binding affinity, primarily because the rigidified molecule is expected to benefit from a lesser entropic penalty.
 
   
We have recently found, however, that preorganizing small molecules in their biologically active conformation does not necessarily result in an entropic benefit, and constrained molecules may have higher affinities for a target because of more favorable binding enthalpies. We have also observed the energetic effects associated with changes in nonpolar surface area of a small molecule are not purely entropicIndeed, we and others, have shown that protein-ligand interactions can be dominated by enthalpy driven hydrophic interactions.
 
         
   
These remarkable findings clearly underscore a lack of fundamental knowledge and understanding of structure and energetics in protein-ligand associations; even less is understood regarding the energetic effects of variations in protein dynamics in related protein-ligand complexes. Accordingly, we are engaged in several collaborative efforts with computational NMR spectroscopy experts to probe structure, enthalpy and entropy, and dynamic relationships in protein-ligand interactions.

Overlay of the Grb2 SH2 domain in complex with flexible control (orange) and cyclopropyl-constrained (magenta) ligands.
 
 

 

 

 
 
     

We thank The Robert A. Welch Foundation, the National Institutes of General Medical Sciences (GM 25439, GM 31077, GM 84965, GM 86192), the National Science Foundation (CHE 750329), and the Norman Hackerman Advanced Research Program for their generous support of our research programs. 
                     
 
   
     
     
 
 
 
   
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