Isolation, structure elucidation, and total synthesis of bioactive natural products

• Main Author: Forestieri, Roberto
• Language: English
• Published: University of British Columbia 2013
• Online Access: http://hdl.handle.net/2429/45668

Marine organisms are a potential source of lead compounds for drug discovery. Complex and unique chemical structures isolated from marine invertebrates and their associated microorganisms can interact with specific cellular targets and selectively modulate biological pathways that play an important role in the pathogenesis of various diseases such as diabetes and tuberculosis (TB). The isolation, structure elucidation, and total synthesis of bioactive marine natural products are described herein. Alotaketals A (2.1), B (2.3), D (2.4), and E (2.5) are a new class of sesterterpenoids isolated from the marine sponge Hamigera sp. that activate the cAMP cell signaling pathway. Here, the chemical structures of alotaketals and their unprecedented "alotane" skeleton are described. The ability of alotaketal A (2.1) to activate cAMP signaling (EC50 = 18 nM) can be attributed to direct activation of adenylyl cylcase. Alotaketal A (2.1) is a chemical tool that can be useful for the study of cAMP signaling function in diabetes and other diseases. Clionamines A (5.1), B (5.2), C (5.3), and D (5.4) are a new class of aminosteroids isolated from the marine sponge Cliona celata that strongly stimulate autophagy in MCF-7 human breast cancer cells. Clionamine A (5.1) was tested for its ability to clear Mycobacterium tuberculosis (Mtb) from infected THP-1 cells and it gave a clear dose response with complete clearance at 5 μM and an IC50 of ≈ 3 μM. The anti-TB activity of clionamines confirms the role of autophagy in the response of human macrophages against Mtb infection. Clionamine B (5.2) was synthesized starting from the steroidal sapogenin tigogenin (5.30) in 12 steps with ≈ 2% overall yield. Synthetic clionamine B (5.2) strongly stimulates autophagy at 30 μg/mL and inhibits Mtb proliferation in humane macrophages via autophagy activation. The clionamine pharmacophore was identified by structure-activity analysis of unnatural clionamines analogues that were synthesized starting from the steroidal sapogenin sarsasapogenin (5.5). Among these synthetic analogues, N-benzyl-3,5-epi-clionamine B (5.24) was found to be a potent inhibitor (MIC = 5 μg/mL) of Mtb proliferation in THP-1 human monocytic cells, indentifying N-benzyl-aminosteroids as a new class of potent antimicrobial compounds that are able to kill Mtb. === Science, Faculty of === Chemistry, Department of === Graduate