I. Design, Synthesis, and Biological Characterization of Subglutinol A Analogs II. Synthetic Efforts Towards the Total Synthesis of RhodojaponinB
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Natural products have a significant influence on the development of chemical treatments for diseases as well as the exploration of biological pathways and are still a major pipeline for novel drug discovery. However, their use has diminished in past decades, because of technical barriers to secure compounds. Recently, the development of new techniques, such as combinatorial chemistry and high-throughput screening, revitalizes the value of natural products. In this regard, the synthetic studies of natural products and their analogs for biological evaluations are still important for utilizing them.
Subglutinols A and B were reported as natural immunosuppressive products. Our group reported the first total synthesis of subglutinols A and B and also revealed that subglutinol A effectively blocks T-cell proliferation and survival in vitro and in vivo. However, subglutinols cannot be easily obtained from natural sources and synthesis of these molecules is challenging because of their structural complexity. Therefore, our aim has been to develop structurally simple and readily synthesized subglutinol-derived chemical probes for the investigation of autoimmune mechanisms. In attempts to develop a more efficient biological probe as well as a potential therapeutic, we designed and synthesized subglutinol A analogs, and then evaluated their biological activities. Our efforts have resulted in the identification of simple analog 2.170, based on several in vitro experiments, which led to the evaluation of in vivo efficacy in EAE mouse model. Although the analog 2.170 treated mice were worse than the DMSO control group, we were able to find the reason by immune profiling. We hope this study could be a good starting point to develop new immunosuppressants.
Grayanoids are isolated from the plants of Ericaceae and exhibit a wide variety of biological activities. Recently, the potent antinociceptive activities of rhodojaponins, which belong to the diterpenoids of grayanoids, were reported. Although over 290 natural grayanoids have been identified, only one total synthesis was reported in 1994. Rhodojaponins possess a 5/7/6/5 membered fused ring system, which is the featuring structure of grayanane diterpenoids. Therefore, a unique structural feature and remarkable biological activities determine these molecules as a great target for the total synthesis. Our synthetic efforts focused on the conjugate addition to establish the quaternary carbon center and the Conia-ene reaction to obtain the 6/5 bicyclic system. These synthetic strategies will contribute to the completion of the total synthesis of rhodojaponins in the future.
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