RESEARCH IN CHEMICAL BIOLOGY
Three main research areas involving natural products, medicinal/synthetic organic chemistry, and macromolecules constitute the major efforts.
1. Organic Synthesis/Medicinal Chemistry
In medicinal chemistry, we have been focusing on various aspects of “lamellarins”, a group of marine natural products which exhibited a wide array of interesting biological activities—anticancer, anti-HIV, and immunomodulatory properties. Three efficient synthetic routes have been devised to produce natural and unnatural lamellarins. Comprehensive structure-activity relationship (SAR) has been performed against 11 cancer cell lines. In addition, general toxicity was evaluated against normal cells. Recently, drug-likeness of lamellarins has been assessed, and our current efforts have been put toward streamlining the structural requirements for good anticancer activity while minimizing the general toxicity. Moreover, incorporation of pharmacologically desirable groups, such as those enhancing aqueous solubility, has been designed. Studies directed toward understanding molecular mechanism have also been initiated as collaborative research with faculties from other programs, as well as the experts from other national and international institutions.
The use of microwave has enabled a number of organic reactions to occur more efficiently as microwave has served as an alternative to provide energy to the reaction. Some reactions, which remained inert when conventional heating was employed, furnished the desired products in excellent yields. In addition, use of microwave has resulted in shortening the reaction time. Microwave irradiation has been utilized for metal-mediated cross coupling reactions, such as Suzuki as well as the Ullmann-type reactions. More importantly, microwave irradiation has been employed in conjunction with water as solvent since water, at higher temperature and pressure, possesses an organic-like property. Thus, the use of microwave and water as solvent conforms well to the “Green Chemistry” concepts.
2. Natural Products Chemistry
In natural products chemistry, we have intensively investigated bioactive compounds from plants, marine invertebrates, and microorganisms. Various plants and marine invertebrates are collected, and their crude extracts are screened for biological activities, including cytotoxic, antimalarial, and cancer chemopreventive activities. The organisms exhibiting biological activities are chemically explored, and chemical structures of bioactive principles are elucidated by analysis of spectroscopic data. In addition, for pure compounds, we also evaluate for their antimycobacterial, antibacterial, antifungal, and α-glucosidase inhibitory activities. In some cases, the isolated compounds with interesting biological activity are chemically modified in order to improve their activity.
We are interested in secondary metabolites from microorganisms, including marine-derived and endophytic fungi, and actinomycetes. These microorganisms are isolated from unique habitats (cells of plants and marine invertebrates), and they produce several classes of bioactive compounds with diverse chemical structures and biological activities. We also investigate biosynthetic genes in fungi for the production of particular bioactive compounds. Moreover, biotransformations of compounds with pharmaceutical interests using these microorganisms are carried out in our laboratory.
3. Chemistry and Biology of Biomolecules
Cyclic peptides (CPs) increase metabolic stability, provide better receptor selectivity, control bioavailability and increase activity profiles. Additionally, CPs are metabolized more slowly due to their higher resistance to chemical degradation. On the other hand, due to their hydrophobicity, they are excreted more readily than their corresponding linear counterparts. Recently, CPs have been found in plants, fungi, and bacteria. They are useful in the studies of receptor-ligand interactions due to their restricted conformation and decreased flexibility; therefore there is continued interest in finding better synthetic routes and experimenting with modifications including, but not limited to, ring size, side chains, and amino acid substitutions. More importantly, the modification of proteins by labeling with receptor molecules is a very powerful research tool in immunology. Some CP-derived toxins are synthesized for the preparation of protein conjugates to develop immunological assays.