Our group's research in marine natural products explores several facets of organic and biological chemistry. All discoveries in our group have been initiated by field collection. Group members collect organisms using SCUBA from tropical areas to the California coastline to maximize species diversity within our collection. The organisms are described and cataloged in the field, then brought back to the lab for biological testing and chemical isolation.
1. Isolation and Structure Elucidation:
With the emergence of newly resistant strains of disease-causing bacteria and fungi, there is always a pressing need for novel antibiotics and antifungal compounds with better activity. For example, more effective drugs are needed to treat opportunistic infections in advanced HIV patients and others with deficient immune systems. This project focuses on the isolation and structural elucidation of novel antifungal marine natural products from marine sponges, ascidians, mollusks, and other marine organisms. Compounds are tested against a panel of fungi which are pathogenic (Candida albicans and related species, Cryptococcus neoformans). Novel compounds are isolated by a combination of common chromatographic techniques and sometimes not so common methods (eg. centrifugal counter current chromatography). The structures of pure compounds are determined by spectroscopic techniques including mass spectrometry, infrared spectroscopy, nuclear magnetic resonance spectroscopy (NMR), in particular 2D NMR methods such as COSY, NOESY, ROESY, HMQC and HMBC. NMR experiments are carried out in the chemistry department and at the UC Davis NMR facility. We have been successful in finding several potent antifungal leads (eg. see bengazole A), some of which have promising mechanisms of action.
The chemistry skills acquired by our group members include: Isolation and analytical chemistry of small quantities of biologically active molecules; Implementation and interpretation of sophisticated multidimensional NMR experiments; Determination of stereochemistry using chemical synthesis and micro-chemical, multi-step correlation with compounds of known configuration; Chiroptical spectroscopy (eg. circular dichroism, CD).
2. Isolation and Structure Elucidation:
A recent expansion of the isolation/structural elucidation program involves the search for compounds with antitumor properties, in particular those that induce apoptosis or 'programmed cell death'. Apoptosis is a natural end point to the lifespan of a normal cell, however some cancer cells have aberrant cell-signaling which prevents cell death allowing them to become immortal and proliferate. The discovery of compounds that induce apoptosis is an exciting new area that may find application in anti-cancer chemotherapy. Recent results in the antitumor program include the isolation and structural elucidation of the potent antitumor macrolides, phorboxazole A. The structure of phorboxazole A was elucidated by extensive analysis of 2D NMR spectra (1H COSY from the upfield region of Phorboxazole A). The complete stereochemistry (absolute) was determined by interpretation of NOESY experiments, modified Mosher's ester method, oxidative degradation and correlation to a chiral standard with coupling constant comparisons to synthetic model compounds.
3. Isolation and Structure Elucidation:
Calcium Channel Modulators
Regulation of intracellular and extracellular Ca2+ concentrations are essential to the proper functioning of living cells. The release of Ca2+ ions initiates a myriad of cellular processes and signaling events modulated through one of several families of calcium ion channels. Ca2+ ion channels are macromolecular structures embedded in the plasma membrane of the sarcoplasmic reticulum (SR) and the endoplasmic reticulum (ER) in virtually every cell. In collaboration with Dr. Isaac Pessah (UC Davis, Division of Molecular Biosciences) we have discovered several compounds from extracts of marine sponges that stimulate the opening (gating) of the SR calcium channel or blocking of the SR/ER (eg. bastadin 5 and its analogs from Ianthella basta). These exciting discoveries provide valuable tools useful in probing the relationship between structure and function of Ca2+ ion gating, possibly finding promise as leads to the treatment of heart disease and other afflictions involving Ca2+ channels. Our ongoing work in this area includes synthesis of novel calcium modulators and preparation of labeled derivatives for probing the structure of the proteins that constitute the SR Ca2+ channel.
4. Synthesis of Biologically Active Marine Natural Products
Total synthesis of marine natural products is carried out in our lab on several target molecules that are of particular interest because of their biological activity. Our synthetic research is focused on those compounds discovered in our structure elucidation program with exceptional biological activity. Each synthesis is designed to secure useful quantities of natural product and/or analogs for ongoing investigation into their biological chemistry. A particularly exciting aspect of this synthetic program is the discovery of novel synthetic methodology with applications to related areas of organic synthesis (eg. a novel SeO2 promoted oxidative rearrangement of 2-oxazolines to dihydrooxazinones that is useful for the synthesis of beta-branched alpha-amino acids). Two of our current targets are bastadin 5 and bengazole A.
5. Chemical Deterrence and Marine Natural Products
Some marine natural products are potent fish feeding deterrents or toxic to potential predators (eg. crustaceans), thereby conferring a form of chemical defense to the host invertebrate. Undertaking of the isolation and chemical structure elucidation of potent chemical deterrents from marine sponges is carried out in our lab. Discovery of each compounds role in predator-prey dynamics of coral reef habitats is the ultimate goal of each study. This work is carried out in collaboration with Dr. Joe Pawlik, University of North Carolina, Wilmington.