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FRISC: The Faculty Research Interests Science Comparator |
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Assistant Professor of Biochemistry
Biological Chemistry
Office: (214) 648-7808
FAX: (214) 648-6455
Email: jdebra@biochem.swmed.edu
During the past decades,
products of secondary metabolic pathways have fueled the pharmaceutical research
enterprise and for example, have provided valuable lead compounds for the
treatment of various human diseases. Furthermore, small molecule ligands that
elicit specific and unique biological responses in mammalian cells also
constitute extremely valuable research tools in discovery biology efforts. In
this context, a unique opportunity is provided by the discovery of a variety of
unusual macrocyclic salicylate natural products that were isolated from both
terrestrial and marine sources based on their ability to induce a particular
phenotype in mammalian cells. 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 osteoporosis. This finding is of extreme
importance inasmuch that previously known inhibitors are non-selective and
difficult to develop as drug candidates.
We have also initiated a
synthetic program towards peloruside A, a complex marine-derived natural product
with potent cytotoxic activity against a variety of cultured tumor cell lines,
including a human neuroblastoma cell line. An efficient synthesis of peloruside
A (only 3 mg of peloruside A was isolated) which is amenable to modifications
for the development of analogs and probe reagents is essential in order to
identify and study the molecular target(s) of peloruside and its relation to
cancer, thereby helping in a substantive way to validate their potential use in
chemotherapy.
Selected Publications:
Wu Y, Esser
L, De Brabander JK (2000) Revision of the Absolute Configuration of
Salicylihalamide A through Asymmetric Total Synthesis. Angew.
Chem. Int. Ed. Engl. 39, 4308-4310.
Bhattacharjee
A, De Brabander JK (2000) Synthesis of Side Chain Truncated Apicularen A. Tetrahedron
Lett. 41, 8069-8073.
Wu Y, Seguil
OR, De Brabander JK (2000) Synthesis and Initial Structure-Activity
Relationships of Modified Salicylihalamides. Organic
Letters 2, 4241-4244.
Bhattacharjee A, Seguil OR, De Brabander JK (2001) Total synthesis and
biological evaluation of apicularen A and synthetic analogs. Tetrahedron
Lett. 41, 1217-1220.
Wender PA, De Brabander J, Harran PG, Jimenez JM, Koehler MFT, Lippa B,
Park CM (1998) Synthesis of the First Members of a New Class of Biologically
Active Bryostatin Analogs. J. Am. Chem.
Soc. 120, 4534-4535.
Wender PA, De Brabander J, Harran PG, Jimenez JM, Koehler MFT, Lippa B, Park CM,
Siedenbiedel C, Pettit GR (1998) The Design, Computational Analysis, Solution
Structure and Biological Evaluation of the First Totally Synthetic Analogs of
Bryostatin. Proc. Natl. Acad. Sci. USA 95, 6624-6629.
Page maintained by Stephanie
Robertson
Last updated: 26 Sep 2001
Extraction Method: Expand using Medical Synonyms-
Eliminated words list: MedlinePlus List
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Similarity Method: Weighted keyword count
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Database: Medline abstracts (1967 - Present)
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Publication Type: All
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Score Calculation Method: Cosine Similarity Method
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Results computed on: 6/9/2006