We study architectural aspects of building molecules. This is expressed through exercises in total synthesis, the development of reactions and processes, and in attempts to generally emulate small-molecule biosynthetic schemes. We seek to create new structures in new ways, and for those molecules to have valuable biological functions.
Evolution provides chemists much inspiration and opportunity. We explore the synthesis of small molecule natural products, in particular those having special structures and potentially valuable pharmacology. Current interests include unusual antimicrobial trithiocanes isolated from a marine tunicate, complex prodigiosins that can bind microRNA, spirocyclic imines that initiate apoptosis selectively and various other exotic bioactive substances.
The chemistry and biology of natural products is prominent in the group. We’re also involved in new tactics to create non-natural molecules – particularly those able to fuel discovery in areas of biochemistry where drug-like heterocycles and/or toxins can be limited. Specific and potent agonists/antagonists of intracellular protein-protein interactions are of particular interest.
We interface our chemistry with biological research in numerous ways. We screen complex molecule collections in silico and experimentally, searching for new functions in cytokine signaling, stem cell differentiation, cell death regulation, and hormone mimicry. We also study the biology of specific compounds.
Evolution provides chemists much inspiration and opportunity. We explore the synthesis of small molecule natural products, in particular those having special structures and potentially valuable pharmacology. Current interests include unusual antimicrobial trithiocanes isolated from a marine tunicate, complex prodigiosins that can bind microRNA, spirocyclic imines that initiate apoptosis selectively and various other exotic bioactive substances. In our experiments, we devise plans that position us to discover new reactions and methods. Longer term, our target molecules become probes of their effects on living systems at a molecular level – wherein biochemistry, biophysics and cell biology become important aspects of the work. Recent achievements in these areas are highlighted below, along with structures that are currently being studied.
The chemistry and biology of natural products is prominent in the group. We
also study methods to create non-natural molecules – particularly those useful in biological
research. Cellular signaling pathways are a web of protein-protein interactions. Arguably there
is no group of small molecules better suited to probe and perturb those networks than segments
of protein, i.e. peptides. However, in isolation, small peptides generally have poor properties:
they lose structure – they aggregate – they are degraded readily – and they tend not to move
passively through membranes. How can we offset those liabilities while retaining molecular
recognition – and do so systematically?
Our approach to this challenge uses constrained, hybrid macrocycles. We have designed scaffolding reagents that can be integrated into peptide structure to afford diverse ring systems having embedded heterocyclic motifs. Our experiments run as processes, wherein templates G1-G3 are reacted incrementally with unprotected oligomers to form composite products. These compounds retain molecular recognition elements in the oligomer, yet display that functionality as part of stable polycyclic structures having improved pharmacological properties. The methodology allows systematic alteration of product topology by engaging a range of native peptide functional groups in carbon–heteroatom and carbon–carbon bond-forming reactions. Templates G1–G3 engage aromatic side chains (including but not limited to phenol, indole, and imidazole) in Friedel Crafts alkylations, metal-catalyzed allylic substitutions and N-acyliminium ion-mediated cyclizations. Catalyzed macrocyclization affords C-O or C-N bonded macrocycles, wherein chemoselectivity is switchable via additives. Macrocyclizations under acidic conditions generate C-C bonded products via electrophilic aromatic substitutions. These structures can also incorporate polycyclic motifs via sequential, diastereoselective N-acyliminium ion cyclizations. G3 is able to itself participate in N-acyliminium ion-promoted EAS reactions to yield structures such as 7 and 8. Templates G1 and G2 can generate bridged endopyrroloindolines such as 3 and 5. New methods and templates continue to be developed in the lab.
Based on reactivity patterns observed with G1–G3, a much broader platform seemed possible, wherein we could process α-amino acid derived oligomers and also those derived β2- and β3-amino acid monomers, in multiple diastereoisomeric forms. Side chains on those monomers could harbor diverse, drug-like heterocycles, chosen for their susceptibility to engagements by G1–G3. End products in that case could have marked property advantages relative to conventional cyclopeptides. This thought experiment presented a special challenge— possible outcomes were vast and far outpaced our experimental format. We therefore turned to a computational rendering of our synthesis platform to systematically assess the scope of reaction outcomes. We have written a software package called the Composite Peptide Macrocycle Generator (CPMG). CPMG has generated an in silico library of >2 billion composite macrocycles by anticipating products from encoded multi-step reaction sequences. We have adapted conformational search methods to create Confbuster++, which is able to generate three-dimensional conformations for each macrocycle generated. This positions us to deploy the library in ultra-large scale virtual screens, with the intent of validating our combined computational/experimental platform as a tool for discovering unique ligands for all types of structurally characterized proteins.