We aim to synthesize marine metabolites with potential clinical applications. The focus of this research is the synthesis of biologically significant and synthetically challenging natural pyrrole-imidazole alkaloids, in particular, massadine, a newly discovered geranylgeranyltransferase type I (GGTase I) inhibitor. Massadine is a valuable synthetic target because selective GGTase I inhibitors are potential treatments for cancer, cardiovascular disease as well as fugal and viral infection. Toward this end, we have devised a radical cascade cyclization and an oxidative rearrangement reaction to construct the key skeleton of massadine. We will explore the scope and generality of the two approaches. We will utilize these approaches to synthesize massadine and prepare a variety of massadine analogs to facilitate its biological study and clinical evaluation. We believe this research will provide a solution not only to the massadine synthesis, but the synthesis of other oroidin dimers, such as palau'amine, axinellamine, ageliferin and nagelamide. This project serves as our first step toward the construction of both natural and unnatural oroidin dimers with all stereochemical possibilities. We wish to create a focused oroidin dimer library and fill nature's gap in stereochemical diversity. Combining with future collaborative biological studies at UT Southwestern, we wish to help advance oroidin dimer-based drug development. This research program involves development of new chemical methods, which will find applications in pharmaceutical industry. The ultimate goal is to discover new therapeutics using the lessons learned from natural substances.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Synthetic and Biological Chemistry B Study Section (SBCB)
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Schwab, John M
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University of Texas Sw Medical Center Dallas
Schools of Medicine
United States
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You, Lin; Chen, Chuo (2018) Rapid access to the core skeleton of the [3 + 2]-type dimeric pyrrole-imidazole alkaloids by triplet ketone-mediated C-H functionalization. Tetrahedron 74:769-772
Ma, Zhiqiang; Chen, Chuo (2018) Natural products as inspiration for the development of new synthetic methods. J Chin Chem Soc 65:43-59
Han, Lei; Xia, Jibao; You, Lin et al. (2017) Ketone-catalyzed photochemical C(sp3)-H chlorination. Tetrahedron 73:3696-3701
Ma, Zhiqiang; You, Lin; Chen, Chuo (2017) Stereocontrolled Formation of a [4.4]Heterospiro Ring System with Unexpected Inversion of Configuration at the Spirocenter. J Org Chem 82:731-736
Chen, Chuo (2016) The past, present, and future of the Yang reaction. Org Biomol Chem 14:8641-7
Ma, Zhiqiang; Wang, Xiao; Ma, Yuyong et al. (2016) Asymmetric Synthesis of Axinellamines A and B. Angew Chem Int Ed Engl 55:4763-6
Zhang, Chengwei; You, Lin; Chen, Chuo (2016) Palladium-Catalyzed C-H Arylation of 1,2,3-Triazoles. Molecules 21:
Shi, Heping; De, Saptarshi; Wang, Qiaoling et al. (2015) Construction of the 5,6,7-tricyclic skeleton of lancifodilactone F. Tetrahedron Lett 56:3225-3227
Wang, Xiaolei; Chen, Chuo (2015) An approach for the synthesis of nakamuric acid. Tetrahedron 71:3690-3693
Ma, Yuyong; De, Saptarshi; Chen, Chuo (2015) Syntheses of Cyclic Guanidine-Containing Natural Products. Tetrahedron 71:1145-1173

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