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.
Exotic Natural Products
Targeted synthesis in the group focuses on naturally occurring molecules we find special, both in terms of what they ask us to create structurally and their potential pharmacology. Current interests include palau’amine type bis guanidine-containing immunosuppressives, an unusual trithiocane isolated as an antimicrobial by Rezanka, complex prodigiosins potentially useful as BH3 helix mimetics, fusicoccin fungal toxins that bind 14-3-3 proteins, and various other intriguing substances. In experiments of this kind, we devise plans that position us to discover new reactivity and methods. Longer term, synthetic forms of such bioactive materials become valuable probes of their effects on living systems at a molecular level – wherein biochemistry, biophysics and cell biology become important aspects of the work.
Molding Form and Character with Synthesis
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. Intracellular communications are a web of protein-protein interactions. Arguably there is no group of ‘small’ molecules better suited to probe and perturb these networks than pieces of protein (namely, peptides). The problem is those pieces 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 negatives while retaining the positives – and do so systematically? This is a unique chemistry question. Methods in medicinal and combinatorial synthesis, or perhaps diversity-oriented synthesis, may be useful – but the task itself is not one of building molecules per se, but rather molding the properties of existing ones. Nature creates small molecules via schemes related to those that form proteins and nucleic acids. The majority are oligomers, except those polymers are small and often modified during and/or post assembly. We are trying to emulate this processive nature of small molecule biosynthesis – beginning with common peptides and related oligomers that can be made by machine.
An overview of the project is shown in Figure 1. Polymers of α amino acids are flexible chains of nucleophilic functionality dispersed along a polyamide backbone. If one engages those polymers with a modular organic electrophile (E) – first bimolecularly, and then multiple times intramolecularly, initiating reactions orthogonally from within insert E at each stage – a stepwise, sequence-dependent amalgamation is possible. The intent is a hybrid of posttranslational peptide modification and secondary metabolism – a means to transform abundant biopolymers into complex alkaloids. As a complement to small heterocycles found in most drug-screening collections, such structures will be complex and potentially able to bind avidly to protein interaction domains and allosteric sites.
Our concept is simple, but finding the right chemistry is challenging. In the amalgamation with E, the goal from each polymer is not one product, but rather a collection of molecules. These should have structures that vary according to polymeric input (essentially unlimited – Fig. 1A) yet possess characteristics making them valuable in biological research. As mentioned, this includes an ability to traverse lipid membranes, resist degradation and to interact specifically with receptors. Stereochemical richness and a potential for molecular recognition is inherent to the biopolymer. Value-added properties derive from E – and thus the nature of these reagents defines the program.
Opportunities in Medicinal Chemistry
We interface our chemistry with biological research in numerous ways. The collections of complex molecules generated above are being screened for diverse functions, including potentiation of cytokine signaling, stem cell differentiation, cell death regulation, and hormone mimicry. In addition to empirical screening, we also pursue projects in defined systems where the biology suggests an opportunity for chemistry. Current efforts include second-generation Smac mimetics (in collaboration with Xiaodong Wang), targeted inhibitors of the ghrelin acyl transferase (in collaboration with Michael Brown and Joe Goldstein) and small molecules useful in various aspects of neurobiology research (in collaboration with Stanley Prusiner).