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Rivas Lab: Research

Research in the Rivas Laboratory focuses on the field of natural product synthesis with an emphasis on the development of catalytic asymmetric methods that facilitate the construction of complex molecules of promising pediatric therapeutic value. Lead discovery for the treatment of pediatric malignancies, particularly glucocorticoid resistant acute lymphoblastic leukemia (ALL) are amongst our priorities. We narrow on strategic bond disconnections promoted enzymatically in nature, which remain inaccessible enantioselectively using modern synthetic methodologies. Current areas of research in the Rivas laboratory include total synthesis of sesquiterpenoids, alkaloids, and the development of catalytic systems for enantioselective electrophilic halogenation. In parallel, our laboratory has an ongoing research program in the area of bioactive-guided terrestrial natural product isolation and chemical structure elucidation. Our research integrates the critical areas of synthetic method development, total synthesis and medicinal chemistry.

Synthetic Studies of Acorane Sesquiterpenoids

Terrestrial plants are capable of producing an overwhelming variety of secondary metabolites among others sesquiterpenoids, both in terms of complexity and quantity. Sesquiterpenoids allow plants to cope with various types of stress, and often have important biological activities in humans. Many of these compounds show anti-cancer activities, or serve as specific enzyme modulators. The Rivas laboratory is working on developing strategies towards construction of spiro-quaternary carbon centers found in acorane sesquiterpenoids. Synthesis of quaternary centers in a stereochemical and asymmetric controlled manner remain a challenge in the field of organic chemistry. New asymmetric methodologies are needed to facilitate the large scale synthesis of these compounds to derivatize and evaluate their biological properties. Colletoic Acid is a novel acorane sesquiterpenoid isolated from the fungus colletrotrichum gleosporioides. It was reported by Takatsu, T. to exert remarkable selective inhibition against 11-▀ Hydroxysteroid dehydrogenase 1 (11-▀HSD1) with an IC50 of 13nM. This biological profile renders colletoic acid a potential molecular probe to elucidate important biological mechanisms mediated by 11-▀ Hydroxysteroid dehydrogenase type 1 action in cancer metabolism. In a campaign to develop asymmetric synthetic strategies to this family of natural products, we have developed an efficient synthetic route to afford multigram quantities of the core of this novel scaffold that will allow us to develop analogs and establish their structure-activity relationships (SAR).

A Rich Family of Alkaloids

Erythrina alkaloids are found in flowering plants of the Fabaceae family. The family contains about 130 species, which are distributed throughout the American continent in subtropical regions particularly Central America. Erythrina plants contain a broad range of secondary metabolites, especially a diverse pool of Erythrina alkaloids, which have been used in Native American medicine for decades to treat bacterial infections, anxiety, and control convulsions. In laboratory settings, the crude extracts have shown to exert important properties from antibiotics, anticancer to sedative effects due to their pharmacophore, a spiro-isoquinoline core decorated with methoxy or glycosylated at the aromatic ring. These compounds display good drug-like properties and in model animal systems have shown to readily enter the central nervous system. The synthesis and refinement of these novel templates will be directed towards lead discovery and optimization in our search of new drugs to treat pediatric brain tumors and CNS disorders.

Natural Product Isolation, and Structure Elucidation

The Rivas laboratory has recently initiated a multi-site collaboration to screen terrestrial natural products from South America against various cancer cell lines available at St. Jude. Our goal is to identify new leads for the treatment of these pediatric cancers capitalizing on the abundance and broad diversity of terrestrial natural products. Natural products have been used as medicines throughout human history. Currently, 60% of new cancer drugs and 75% of infectious disease therapeutics come from natural products and more than 70% of all approved antitumor drugs have been natural products or the corresponding derivatives with modified pharmacophores, or spatial mimics of the parent structures. Natural products are the outcome of eons of natureĺs experimentation and can be exploited to design new therapeutics with less toxicity and/or greater specificity for untreatable or resistant pediatric cancers. While natural products have been researched by both academia and industry, solid and rare pediatric cancers remain to be tested with a large number of potential natural products. Our Chemical Biology and Therapeutics Department has developed an efficient high throughput natural product purification/fractionation, which will strongly support our natural product program.

Fatima Rivas, PhD - Faculty Biography