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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Lees, Robert G
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University of Texas Sw Medical Center Dallas
Schools of Medicine
United States
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Ma, Zhiqiang; Wang, Xiao; Ma, Yuyong et al. (2016) Asymmetric Synthesis of Axinellamines A and B. Angew Chem Int Ed Engl 55:4763-6
Chen, Chuo (2016) The past, present, and future of the Yang reaction. Org Biomol Chem 14:8641-7
Zhang, Chengwei; You, Lin; Chen, Chuo (2016) Palladium-Catalyzed C-H Arylation of 1,2,3-Triazoles. Molecules 21:
Shi, Heping; Wu, Jiaxi; Chen, Zhijian J et al. (2015) Molecular basis for the specific recognition of the metazoan cyclic GMP-AMP by the innate immune adaptor protein STING. Proc Natl Acad Sci U S A 112:8947-52
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
Wang, Xiaolei; Gao, Yang; Ma, Zhiqiang et al. (2015) Syntheses of Sceptrins and Nakamuric Acid and Insights into the Biosyntheses of Pyrrole-Imidazole Dimers. Org Chem Front 2:978-984
Ma, Zhiqiang; Wang, Xiaolei; Wang, Xiao et al. (2015) ORGANIC SYNTHESIS. Response to Comment on ""Asymmetric syntheses of sceptrin and massadine and evidence for biosynthetic enantiodivergence"". Science 349:149
Ma, Yuyong; De, Saptarshi; Chen, Chuo (2015) Syntheses of Cyclic Guanidine-Containing Natural Products. Tetrahedron 71:1145-1173
Ma, Zhiqiang; Wang, Xiaolei; Wang, Xiao et al. (2014) Asymmetric syntheses of sceptrin and massadine and evidence for biosynthetic enantiodivergence. Science 346:219-24

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