Studies directed at the chemistry and biology of bioactive compounds

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Research activities in my group at UdeM will focus on four main areas at the interface of chemical synthesis and biology. In this context, our research program will continue to be biology-inspired and chemically driven. Our choice of natural products for synthetic studies is primarily driven by the potential to improve and extend biological activity, to provide sufficient material for testing in the case of meager-yielding sources, and to expand our knowledge toward a better understanding of their mode of action at the molecular level. The very nature of the science of synthesis provides an excellent training ground for young collaborators, teaching them the rigors of research, perseverance and the resolve to reach the intended goal. My role is to teach them how to apply chemical knowledge to solve challenging problems in research. Information gleaned from the co-crystal structures of synthetic molecules with macromolecules such as proteins (enzymes in particular), DNA, and RNA, have allowed us to develop excellent drug prototypes. Our privileged collaborations with other academics and with the pharma industry, where testing and X-ray work are done, will continue to provide further insights into these interactions which will allow us to improve biological activities, especially against resistant bacteria and protozoa. Constrained amino acids such as the 4,5 methanoprolines, first synthesized in our group, have gained wide prominence and are constituents of marketed antidiabetics. The consequence of flattening the proline ring holds great promise in the field of peptidomimetics, and this property will be studied to understand the nature of the amide bonds in peptides as well as their susceptibility to enzymatic cleavage by the enzyme prolidase vis-à-vis proline. Constrained polyprolines will be studied in relation to their tertiary structure. Forming bonds to carbon atoms towards the practical synthesis of enantiomerically pure target molecules is the very backbone of organic chemistry. These methods must address reaction types that do not have universal solutions as yet, such as the formation of quaternary carbons centers, reagent and catalyst controlled asymmetric reactions, activation of otherwise inert C-H atoms, and the chemistry of highly functionalized azacyclic compounds of medicinal interest. The advent of flow chemistry will facilitate the development of such methods. Our research has contributed to many facets of the drug discovery process through basic synthetic work delineating the relationship between structure, property, and function. In the process, excellent training was provided to young men and women who have gone on to chart their own paths in the pharma, biotech and other industries as well as in academia. We hope to continue this tradition of excellence of coworker training through the next granting period by addressing the areas highlighted in this summary.