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Jef De Brabander

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Synthesis of natural products.

Architecturally unique natural products instil chemical challenges that demand novel insights to formulate a synthetic solution, thus laying the foundation for chemical discoveries. Also, getting intimately acquainted with chemical reactivity and compatibility issues related to the particular class of natural products under study is essential for the development of probe reagents and structural variants for mode-of-action studies and eventually control of function. The De Brabander group's primary interest has been polyketide natural products that display selective toxicity towards human cancer cells. We have completed the first total syntheses of salicylihalamide A, apicularen A, peloruside A, gustastatin, psymberin (irciniastatin A), and palmerolide A. These studies lead to structural reassignments in the case of salicylihalamide A and palmerolide A and demonstrated that psymberin and irciniastatin are the same compound. Additionally, the De Brabander group has reported elegant total syntheses of SCH-351448, berkelic acid, and saliniketal B. All these syntheses are characterized by the recognition and exploitation of elements of local symmetry, the minimal use of protecting groups, and the convergent assembly of fragments, and have instilled the development of novel synthetic methodology (vide infra). Accordingly, although several other groups' syntheses have followed the ones from the De Brabander group, rarely have the subsequent syntheses represented significant improvements.

Selected completed targets.

Berkelic Acid
Berkelic Acid
Saliniketal B
Saliniketal B
Palmerolide A
Palmerolide A
Psymberin
Psymberin
Apicularen
Apicularen
Peloruside A
Peloruside A
SCH-351448
SCH-351448
Salicylihalamide A
Salicylihalamide A

Medicinal chemistry and mechanism of action of natural products.

Our group targets natural products that display activity against various cancer cell lines. As an outgrowth of our synthetic efforts, we prepare and evaluate analogs to address issues of potency, selectivity, metabolic liability, etc. We also develop structure-function studies to explore the mode-of-action of the natural products under study. For example, in collaboration with Xiao-Song Xie at UT Southwestern, we identified the V0 segment of V-ATPase as the target of salicylihalamide. Furthermore, we demonstrated that the natural product forms a covalent adduct with its target. Similarly, in connection with our synthesis of psymberin, we have collaborated with Michael Roth (Department of Biochemistry) to perform a C. elegans mutant screen which identified a dominant drug resistant mutant worm for which the mutation was mapped to a ribosomal protein (single point mutation). We have also demonstrated that this psymberin-resistant worm is not cross-resistant to mycalamide, a structurally related natural product.

Additionally, we have prepared and evaluated analogs of psymberin, apicularen and salicylihalamide. The latter compounds are undergoing pre-clinical development for oncology indications at Reata Pharmaceuticals, a company for which Jef was a founding member. Additionally, the De Brabander group has collaborated with the Harran and Wang groups at UT Southwestern to prepare and evaluate mimetics of the protein Smac to promote apoptosis in TRAIL-activated cells. These compounds are undergoing preclinical development at Joyant Pharmaceuticals for oncology indications.

The development of small molecule orexin-receptor agonists for the treatment of narcolepsy.

Narcolepsy is a debilitating disorder characterized by an inability to properly maintain wakefulness, sleep attacks, a sudden loss of muscle function, and sleep paralysis. Narcolepsy is a non-progressive, life-long condition, which is estimated to affect approximately 1/1,000 - 1/2,000 individuals (200,000 Americans) and is often under-diagnosed or mistaken for depression, epilepsy or medication side effects. Current available treatments for narcolepsy are palliative, symptom-oriented pharmacotherapies. Thus, not only are they ineffective for correcting the underlying neurochemical deficits, but they also exhibit various undesirable side-effects.

Accumulating evidence indicates that the hypothalamic neuropeptides, termed orexins (also hypocretins), play an important role in sleep/wake control and that narcolepsy is an orexin-deficiency syndrome. Transgenic mouse strains that have been engineered to closely mimic the neurochemical situation in human narcoleptics, i.e. with a postnatal loss of orexin neurons, exhibit all symptoms of narcolepsy/cataplexy and can be cured by providing exogenous orexin. However, orexins are peptides, thus orally inactive and blood-brain barrier impermeable and cannot be used as a therapeutic agent. Using high throughput screening, we have identified the first orexin receptor-specific small molecule agonists. We have initiated a medicinal chemistry program to improve their potency and pharmacokinetic properties to provide brain penetrable pre-clinical candidates for use in proof-of-concept studies in a transgenic animal model of human narcolepsy. A unique multidisciplinary team with biological, chemical and pharmacological expertise has been assembled to tackle this problem via a multi-pronged approach. Synthetic chemistry will be deployed for the iterative synthesis and optimization of small molecule orexin agonists, studies which will be guided by a comprehensive in vitro evaluation of potency and selectivity, and pharmacological assessment for drug-like properties. Finally, selected candidates will be evaluated in in vivo animal models of human narcolepsy. Our team is ideally suited to achieve the above stated overall goal. The discovery of orexins, and their role in sleep/wake cycles and narcolepsy, emanated from the laboratory of our collaborator Dr. Yanagisawa, who also developed the transgenic animal models that fully recapitulate the human disease. Combining these strengths in orexin biology with synthetic chemistry and pharmacological expertise, there is a high likelihood that this team will provide the first small molecule preclinical candidates for orexin replacement therapy.

Synthetic methodology.

In the course of their synthetic studies, the De Brabander group has developed novel synthetic methodology to construct challenging functionality. For example, when traditional approaches to forming salicylate esters failed, the group invented a photochemical acylation based on the intermediacy of a quino-ketene.

Our laboratory developed a catalytic hydroalkoxylation of alkynes as a strategy to ketal/spiroketal substructures present in many natural products. This approach takes advantage of the alkyne functionality as a nucleus for metal-catalyzed reorganization of linear precursors into valuable heterocycles. In an extension of these studies, we investigated the reactivity of ω-hydroxy propargylic esters and uncovered two distinct modes of reactivity depending on the nature of the metal catalyst that initiates electrophilic activation of the triple bond. We envisioned that a metal with dual alkynophilic/ allenophilic properties would be poised to catalyze a tandem 1,3-acyloxy migration/ cycloisomerization of ω-hydroxy propargylic esters to heterocyclic enolesters. We found that AuCl led exclusively to the expected stereodefined oxacyclic enol acetates, whereas square planar platinum(II)chloride catalyzed the formation of propargylic substitution products. A mechanistic rationale reconciling this divergent behavior in the context of metal coordination chemistry was developed and we will continue to test this model experimentally.

Propargylic substitutions

We have extended this methodology to include the formation of various substituted dioxanes, morpholines, oxazoles, and other nitrogen-containing heterocycles. For example, we have demonstrated that propargylamides derived from amino acids undergo Au(III)-catalyzed cyclization, and the corresponding exo-methylene intermediates can be trapped in situ with Br2 to deliver substituted bromomethyl-oxazoles. These compounds can be alkylated with various chiral amino alcohols without epimerization to yield depeptide mimetics in three operations from commercially available starting. Furthermore, we have applied our cycloisomerization methodology for the synthesis of oxygen-containing heterocycles and spiroketals to the synthesis of the natural products berkelic acid and saliniketal B. This synthesis takes advantage of a Ag(I)-catalyzed cascade dearomatization-cycloisomeization-cycloaddition sequence to couple two natural product inspired fragments to yield berkelic acid in 10 steps and ~20% overall yield.

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