The research interests of our group include the total synthesis of biologically active natural products, the development of new synthetic methods, heterocyclic chemistry, bioorganic and medicinal chemistry, combinatorial chemistry, the study of DNA-agent interactions, and the chemistry of antitumor antibiotics. We place a special emphasis on investigations to define the structure-function relationships of natural or designed agents in efforts to understand the origin of their biological properties.
As the exploration of the properties of complex natural products becomes increasingly more sophisticated with the technological advances being made in their screening and evaluation and as structural details of their interaction with biological targets becomes more accessible, the importance and opportunities for providing unique solutions to complex biological problems has grown. A powerful complement to the examination of the naturally-derived agents themselves is the preparation and subsequent examination of key partial structures, agents containing deep-seated structural modifications, and the corresponding unnatural enantiomers of the natural products. Well conceived deep-seated structural modifications may be used to address the structural basis of the natural products interactions with biological targets and to define fundamental relationships between structure, functional reactivity, and properties. In these studies we address the challenging problem of understanding the beautiful solutions and subtle design elements that nature has provided in the form of a natural product and work to extend the solution through rational design elements to provide more selective, more efficacious, or more potent agents designed specifically for the problem or target under investigation.
Central to such studies is the development of dependable synthetic strategies and the advent of new synthetic methodology to permit the preparation of the natural products, key partial structures, and analogs incorporating deep-seated structural changes. The resulting efforts have reduced many difficult or intractable synthetic challenges to manageable problems providing an approach not only to the natural product but one capable of simple extrapolation to a series of structural analogs as well. In our own efforts this has provided the opportunity to fully explore the origin of the natural products properties and to devise agents with improved selectivity and efficacy.
Our ongoing investigations emphasize the development and application of hetero Diels-Alder reactions, the thermal reactions of cyclopropenone ketals, inter- and intramolecular acyl radical-alkene addition reactions, medium and large ring cyclization procedures, and the benzannulation reaction of arylchromium carbene complexes. In each instance, the methodology development represents the investigation of chemistry projected as a key step in the total synthesis of a natural or nonnatural product.
Natural Products Total Synthesis
Problems currently being addressed include (+)-CC-1065 and functional analogs (antitumor antibiotic possessing sequence selective DNA alkylation properties), duocarmycins (antitumor antibiotics possessing sequence selective DNA alkylation properties), tropoloalkaloids including colchicine, deoxybouvardin/bouvardin, K-13, OF4949-I - OF4949-IV (immunopotentiating agents with confirmed antitumor activity), piperazinomycin, luzopeptins, and sandramycin (DNA- binding peptides with antitumor and antiviral properties), bleomycin A2 (clinically employed antitumor antibiotic), quinolinequinone antitumor antibiotics including streptonigrone, streptonigrin, and lavendamycin (antiviral agents), isochrysohermidin, fredericamycin A and CI-920 (antitumor agents with topoisomerase I and II inhibitory activity), rhizoxin (antitumor antibiotic and potent mitotic inhibitor), combretastatins, azinomycins (antitumor antibiotics with potential DNA cross-linking capabilities), fostriecin (CI-920), sultriecin, cytostatin, trikentrin A, vancomycin, teicoplanin, ristocetin, chloropeptins, ramoplanin, HUN-7293, RP-66453, thiocoraline, BE-22179, storniamides, ningalins, rebeccamycin, phomazarin, nothapodytine, prodigiosin, roseophilin, mappicine, camptothecin, rubrolone, vindoline, vincristine and vinblastine.
Natural Products Total Synthesis References
Chemical & Engineering News article on Ramoplanin (May 13, 2002)
Science Editorial: (Volume 311, pg 321)
Article from Nature (Volume 439, pg 766)
Article from Chemical and Engineering News (Volume 84, Number 7, pg 15)
Article from Nature Reviews: Drug Discovery (Volume 5, pg 281)
Article from Microbe Magazine (Volume 1, pg 219)
Considerable efforts have been devoted to exploring and defining the structural basis for the sequence-selective recognition of duplex DNA by a series of naturally occurring antitumor antibiotics including CC-1065 and the duocarmycins, bleomycin A2, sandramycin and the luzopeptins, and isochrysohermidin. In each instance, deep-seated structural changes in the natural product are enlisted to probe the basis for the recognition or ensuing chemical reaction with duplex DNA.
Story in Modern Drug Discovery (September 2001)
Oleamide: An Endogenous Sleep-inducing Lipid
Since the collaborative (with R. Lerner, S. Hendriksen, B. F. Cravatt) discovery of oleamide, a fatty acid primary amide with natural, physiological sleep-inducing properties, the continued study of this prototypical member of a new class of endogenous chemical messengers has led to the identification of an enzyme responsible for its degradation and regulation (Fatty Acid Amide Hydrolase, FAAH), the characterization of an endogenous inhibitor of FAAH (2-octyl-g-bromoacetoacetate), and the discovery of potential sites of action including inhibition of gap junction cell-cell communication (with N. B. Gilula) or potentiation of serotonin receptor activation. Effective inhibitors of FAAH which also degrade anandamide, an endogenous cannabinoid receptor (CB1) agonist with analgesic and cannabinoid properties, have been designed, prepared and characterized and should continue to aid in the examination of the effects of oleamide.
San Diego Union-Tribune Article on Oleamide Research at Scripps
Article from Discovery Channel Canada
Article from Nature:Medicine
Receptor activation by homodimerization, heterodimerization, and higher order homo- and hetero-oligomerization has emerged as a general mechanism of initiating intracellular signal transduction. Studies have been initiated to investigate the fundamental principles and structural features that are embodied in such receptor activation events with the erythropoietin receptor (EPOr).
Solution-phase Combinatorial Chemistry
Complementary to the emerging techniques of solid-phase combinatorial chemistry for advancing drug discovery, we have been engaged in efforts to develop solution-phase approaches to the multi-step preparation of combinatorial libraries that, for the proper applications, offer substantial advantages. For example, the direct dimerization linkage of combinatorial libraries of iminodiacetic acid diamides, which is precluded by solid-phase techniques, provides a unique approach to the discovery of agonists for the receptor dimerization and activation events detailed above.
GAR and AICAR Transformylase Inhibitors
Employing X-ray crystallographic structures (I. A. Wilson, Scripps) of the apo enzymes and complexes of the enzymes with substrates (GAR, AICAR), folate cofactors, and in-house inhibitors, the novo design and examination of potential potent enzyme inhibitors as antineoplastic agents are being pursued.
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