Tuberculosis is a devastating disease that kills over 1 million people each year. Despite the fact that over 20% of tuberculosis cases are untreatable with standard antibiotics, no new TB- specific drugs have been introduced into clinical practice in over 40 years. Recently, two structurally related natural products were isolated from the stem wood of the plant Cinnamomum kotoense that were capable of inhibiting the growth of M. tuberculosis at low micromolar concentrations. Importantly, while these molecules are structurally similar to one another, they have no structural similarities to any tuberculosis drugs on the market today. Herein, we propose the development of simple and scalable synthetic routes to these anti- tubercular small molecules and preliminary structure-activity relationship studies that will illuminate the importance of specific structural features common between the two targets. To achieve this goal, we will carry out the following specific aims: (1) The first toal synthesis of the natural product lincomolide B will be completed, and the development of a complementary Cram-chelate Baylis-Hillman reaction will be developed to improve upon the efficiency of the process;(2) The first total synthesis of the natural product kotolactone A will e carried out. To achieve this in an efficient manner, a novel ?-hydroxybutenolide/aldehyde cascade process will be developed that will set all of the necessary stereocenters of the molecule in a single step;(3) Structural analogs of the natural products will be accessed through the syntheses developed, and these molecules will be tested against a M. tuberculosis cell line. The analogs will focus on understanding the common lipophilic side chains of the molecules, the stereochemistry, and the importance of the electrophilic ?,?-unsaturated lactone that both targets share. The long-term goal of the proposed research is to develop new therapeutics for TB treatment. Synthetic studies on the natural products will enable far-reaching biological studies toward this goal, and preliminary biological experiments will uncover important information that can be exploited in the design of more in-depth drug development pursuits. Moreover, these syntheses will also lead to the development of molecular probes that will help elucidate the mechanism of action of the natural products, which is not currently known. Information resulting from these studies could uncover new paradigms for tuberculosis treatment.
Tuberculosis (TB) is a devastating disease that kills over 1 million people worldwide each year. Despite this fact, no new TB-specific drugs have been introduced into clinical practice in over 40 years. The proposed research could lead to the development of new treatment options for TB, and thus is of interest to public health.
|Zhao, Haiyan; Lin, Zihan; Lynn, Anna Y et al. (2015) Two distinct modes of metal ion binding in the nuclease active site of a viral DNA-packaging terminase: insight into the two-metal-ion catalytic mechanism. Nucleic Acids Res 43:11003-16|
|Hirsch, Danielle R; Cox, Georgina; D'Erasmo, Michael P et al. (2014) Inhibition of the ANT(2")-Ia resistance enzyme and rescue of aminoglycoside antibiotic activity by synthetic Î±-hydroxytropolones. Bioorg Med Chem Lett 24:4943-7|
|Meck, Christine; D'Erasmo, Michael P; Hirsch, Danielle R et al. (2014) The biology and synthesis of Î±-hydroxytropolones. Medchemcomm 5:842-852|
|D'Erasmo, Michael P; Smith, William B; Munoz, Alberto et al. (2014) 7,9-Diaryl-1,6,8-trioxaspiro[4.5]dec-3-en-2-ones: readily accessible and highly potent anticancer compounds. Bioorg Med Chem Lett 24:4035-8|
|Williams, Yvonne D; Meck, Christine; Mohd, Noushad et al. (2013) Triflic acid-mediated rearrangements of 3-methoxy-8-oxabicyclo[3.2.1]octa-3,6-dien-2-ones: synthesis of methoxytropolones and furans. J Org Chem 78:11707-13|
|Munoz, Alberto; Murelli, Ryan P (2012) Acid-mediated coupling of Ã½Ã½-hydroxybutenolides and aldehydes: Synthesis of a new class of spirocyclic ketal-lactones. Tetrahedron Lett 53:6779-6781|
|Meck, Christine; Mohd, Noushad; Murelli, Ryan P (2012) An oxidopyrylium cyclization/ring-opening route to polysubstituted Ã½Ã½-hydroxytropolones. Org Lett 14:5988-91|