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Matthew S. Sigman

Professor of Chemistry

B.S. Sonoma State University

Ph.D. Washington State University

Research

References

 

Matt Sigman's PubMed Literature Search

Research

Our program is focused on the discovery of new practical catalytic reactions with broad substrate scope, excellent chemoselectivity, and high stereoselectivity to access novel medicinally relevant architectures. We believe the best strategy for developing new classes of catalysts and reactions applicable to organic synthesis is using mechanistic insight to guide the discovery process. This allows us to design new reaction motifs or catalysts in which unique bond constructions can be implemented furthering new approaches to molecule construction. An underlying theme to these methodologies is to convert relatively simple substrates into much more complex compounds allowing for access to known and novel pharmacaphores in a modular manner. This provides us the ability to readily synthesis analogs enabling us to understand the important structural features responsibility for a phenotypic response in a given biological assay. We are currently engaged in several collaborative projects to evaluate our compound collections for various cancer types at the Huntsman Cancer Institute and are engaged in follow-up investigations to identify improved compounds as well as understanding the mechanism of action. Depicted below are selected types of molecular architectures accessible using our catalytic processes.

Diarylmethines as Lead Compounds for Breast Cancer Therapy. Very recently, in collaboration with the Welm Laboratory at the Huntsman Cancer Institute, we identified a cancer selective compound, C-6 (pictured above). This compound was identified using a novel anti-cancer drug discovery screen developed by the Welm Lab that encompasses the cellular and genetic diversity of breast cancer. The unique aspect of this screen is that it uses primary tumor organoids that are molecularly classified similar to the breast cancer subtypes observed in patients. In parallel, the compounds are also screened for their effect on normal biological processes. Importantly, this compound is structurally novel, and as such may kill tumor cells through a unique mode of action. C-6 has selective cytotoxicity against both Basal-like and Luminal cancer organoids isolated from mice and patients, but not organoids isolated from normal primary mouse and human tissue. The selective cytotoxicity of C-6 and its minimal effect on normal biological processes suggest that this compound targets a molecular pathway that is vital for the homeostasis of breast cancer cells. Thus, the current objectives of this project are to establish the optimal pharmacophore structure of C-6, identify its molecular target, and evaluate its biological effects in both tumor and normal cells. Group members engaged in this project will work in a truly interdisciplinary atmosphere learning chemical synthesis, molecular biology, and cancer cell biology.

References