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I am primarily interested in applying synthesis to the construction of naturally occurring molecules important in a broad pharmaceutical/biochemical context. The design and fabrication of probes and analogs of bioactive molecules that advance our understanding of novel molecular targets is desirable. As additional tools, I am interested in using computational techniques to understand protein-drug interactions and structure-activity relationships (QSAR). I am recently intrigued by the role of advanced glycation endpoint processes (AGE) as they relate to metabolic disorder (hypertension, obesity, diabetes, heart and cardiovascular diseases). In the pursuit of these goals I have engaged over 40 postdoctoral associates and graduated about 30 PhD/MS students. I enjoy interacting with students in the classroom as well as in the lab. Some examples of projects I have undertaken follow: 1.Development of Synthetic Methodology for the Total Synthesis of the Antimalarial Agent (+)-Artemisinin. Our earliest contributions to science were the development of a concise, elegant approach to the stereocontrolled total synthesis of Artemisinin, a potent antimalarial natural product reported in ancient Chinese medical texts. Its reported structure came just as resistance of malaria to conventional antimalarials had reached an alarming level. Artemisinin is a highly complex structure with a stable peroxide and seven stereocenters, but at the time no chemistry was available for its construction. 2. Structure-Activity Relationship studies of Artemisinin. The total synthesis developed by our group allowed us to modify specific positions about the molecule and to thence utilize computational methods to study SAR in 3D. This information was important to the worldwide effort to improve upon the artemisinin lead structure. 3. Molecular Probes of Artemisinin Mechanism of Action. Much about the action of artemisinin was gleaned from modification of various positions about the ring system and a predictive QSAR was evolved. However, these studies ultimately did not shed light on how the drugs worked and while very potent analogs were developed (25Xartemisinin), they were complex and expensive. We explored the ring-system itself by synthesizing analogs devoid of bonds or entire rings, including replacing the supposedly irreplaceable trioxane oxygen by carbon and obtained potent analogs. With the advent of pfATP6 as a potential protein target for artemisinin, we also set out to explore introduction of peroxides into pseudoquaianolide inhibitors of pfATP6. Most recently, work in publication is involved in identifying sites within an homology model of pfATP6 wherein artemisinin and Fe(II) bind in exact orientations adjacent to cysteine residues in order to enable capture of the C3/C4 scissioned, C4 radical intermediate responsible for the putative MOA of artemisinin. Finally, artemisinin analogs substituted adjacent to the insipient C4 radical intermediate were synthesized and studied upon exposure to Fe(II). The results are also in the process of being published. 4. The Discovery of Dual Antidiabetic-Antihypertensive Agents and Drugs for Topical Psoriasis. While working on computational modeling of the peroxisome proliferator activating receptor PPARg, a signaling protein in the insulin resistance cascade, we developed sub-picomolar inhibitors with hydrophobic properties for use in treating type-II diabetes and specifically, topical psoriasis. I discovered during this modeling work that the known antihypertensive drug Telmesartan also bound with high potency to the PPARg receptor. This finding opened an area of research for single drug therapy for metabolic syndrome. The publication resulting from this work has been cited over 1300 times. 5. Total Synthesis of Pseudolaric Acid B. We found that the Chinese traditional medicine Tu Jin Pi was a potent antifungal agent with PPAR inhibition occurring via an allosteric mechanism. The unexpected activity against PPARg is expected to result in antidiabetic agents devoid of the side-effects and black-box warnings of the glitazones. 8. Total Synthesis of the Anti-cancer Drug Epothilone A and B. We were one of the first to publish an efficient total synthesis of the new tubulin binding natural product Epothilones, distinctively less complicated than taxols but active against taxol-resistant cancers. We garnered a WO patent from this work. 7. Other Completed Total Syntheses of Biologically Relevant Molecules. Boromycin is a novel macrolide ionophore antibiotic natural product containing a core boron atom and is of considerable interest against drug resistant bacteria. Nodularin and microcystin are algal bloom toxins whose cytotoxicity has potential use against cancers. The caspace-1 inhibitor Berkeleyamide was discovered in a bacteria growing in an extreme environment and has potential for cancer chemotherapy whereas Laurenditerpenol has potent HIF-1 activity.
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Bioorganic & medicinal chemistry lettersno. 24 (2019): 126741-126741
CHEMISTRY & BIODIVERSITYno. 8 (2017)
Reference Module in Chemistry, Molecular Sciences and Chemical Engineering (2016)
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作者统计
#Papers: 343
#Citation: 9860
H-Index: 51
G-Index: 84
Sociability: 6
Diversity: 3
Activity: 3
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