Research in my laboratory focuses on the synthesis of complex molecular architectures; in particular naturally occurring substances with novel structural features and interesting biological function. Unpredictable and unique chemical reactivity patterns oftentimes encountered during the assembly of a particular natural product target continues to challenge synthetic chemists. These challenges demand novel insights and methodology development in order to formulate a solution and as such drives discovery and innovation in synthetic chemistry. Taking advantage of the research environment at UT Southwestern, we are increasingly integrating molecular pharmacology and biochemical aspects into our research program. Current targets of interest are the Vacuolar V-ATPase inhibitors salicylihalamide, apicularen, and palmerolide, the microtubule-stabilizing agent peloruside A, and the potent cytotoxic marine metabolite psymberin. Salicylihalamide A is a unique metabolite isolated from an unidentified species of the marine sponge Haliclona and was reported to exhibit a unique differential cytotoxicity profile in the NCI 60-cell line human tumor assay. Apicularen A was isolated from a myxobacteria based on its extremely potent cytostatic activity against human cancer cell lines including a multi-drug resistant cervix carcinoma cell line. Unfortunately, further studies were precluded due to a lack of natural product. Therefore, a chemical approach remains as the only option to offer insight into the molecular mechanism(s) underlying the highly differential response of human tumor cells to salicylihalamide A. Our group initiated a synthetic program that culminated in the first total synthesis of apicularen A and salicylihalamide A, as well as a revision of the absolute configuration of salicylihalamides. We have also prepared a variety of modified compounds to study their function at the cell biological and biochemical level. In parallel with the National Cancer Institute, we have shown that these intriguing marine metabolites are very potent and mammalian selective inhibitors of the Vacuolar (H+)-ATPase, of importance to the treatment of cancer and osteoporosis. This finding is of extreme importance inasmuch that previously known inhibitors are non-selective and difficult to develop as drug candidates. We recently have also accomplished a total synthesis of the Antarctic marine metabolite palmerolide A and have confirmed that it also has potent inhibitory activity against the mammalian Vacuolar ATPase. We have also accomplished a total synthesis of peloruside A, a complex marine-derived natural product with potent antitumor activity. Peloruside affects microtubule dynamics in a manner similar to paclitaxel, but has better in vivo antitumor activity. This compound is currently being evaluated in preclinical studies for the treatment of solid tumors. During our efforts towards the total synthesis of the macrocyclic bis-lactone natural product SCH 351448, we encountered a major obstacle related to a key acylation with a 2-hydroxy-6-substituted benzoic acid derivative. Current methodology, including acylation with active-esters and nucleophilic displacement reactions under Mitsunobu-type conditions, was ineffective in performing the desired transformation. To solve this problem, we have developed a photochemical method for esterification of notoriously difficult ortho-substituted salicylic acid derivatives. In essence, irradiation (300 nm) of 2-phenyl or 2,2-diphenyl substituted benzodioxinones generates in situ oxo-ketenes that are trapped in the presence of nucleophiles. We have examined the scope, limitations and mechanism of this reaction which permits esterifications of a variety of substituted salicylic acid derivatives with even the most hindered alcohols, phenols, anilines, and amines under virtually neutral conditions. We are now applying this methodology to the synthesis of SCH 351448 and other natural products containing a salicylate moiety.
RESEARCH INTERESTS
Synthesis of complex, naturally occurring, molecular architectures
Integration of molecular pharmacology and biochemistry
RECENT PUBLICATIONS
Pan, Y.; De Brabander, J. K., "Synthesis of Spirastrellolide A Fragments for Structure Elucidation" Synlett, 853-856, 2006
Jiang, X.; Garcia-Fortanet, J.; De Brabander, J. K., "Synthesis and Complete Stereochemical Assignment of Psymberin / Irciniastatin A. Journal of the American Chemical Society 127, 11254-11255" J. Am. Chem. Soc., 127:11254-11255, 2005
Liu, B. and De Brabander, J.K., "Metal-Catalyzed Regioselective Oxy-Functionalization of Internal Alkynes: An Entry into Ketones, Acetals, and Spiroketals." Org. Lett., 8:4907-4010, 2006
Jiang, X.; Liu, B.; Lebreton, S.; De Brabander, J. K., "Total Synthesis and Structural Revision of the Antarctic Marine Metabolite (-)-Palmerolide A." J. Am. Chem. Soc., 129:6386-6387, 2007
Jiang, X; Williams, N.; De Brabander, J. K., "Synthesis of Psymberin Analogs: Probing a Functional Correlation with the Pederin/Mycalamide Family of Natural Products." Org. Lett., 9:227-230, 2007
SIGNIFICANT PUBLICATIONS
Lin Li, Ranny Mathew Thomas, Hidetaka Suzuki, Jef K. De Brabander, Xiaodong Wang, Patrick G. Harran, "A Small Molecule Smac Mimic Potentiates TRAIL- and TNFa-Mediated Cell Death." Science, 305:1471-1474, September 2004
Wu, Y., Esser, L., De Brabander, J.K., "Revision of the Absolute Configuration of Salicylihalamide A through Asymmetric Total Synthesis." Angew. Chem. Int. Ed. Engl., 39:4308-4310, 2000
? Xie X-S, Padron-Perez D, Liao X, Wang J, Roth MG, De Brabander JK, "Salicylihalamide A inhibits the V0 sector of the V-ATPase through a mechanism distinct from bafilomycin A1." J. Biol. Chem., 279:19755-19763, 2004
Wu Y, Liao X, Wang R, Xie X-S, De Brabander JK, "Total Synthesis and Initial StructureFunction Analysis of the potent V-ATPase Inhibitors Salicylihalamide A and Related Compounds" J. Am. Chem. Soc., 124:3245-3253, 2002
Liao X, Wu Y, De Brabander JK, "Total Synthesis and Absolute Configuration of the Novel Microtubule Stabilizing Agent Peloruside A" Angew. Chem. Int. Ed., 42:1648-1652, 2003
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