College of Pharmacy at ULM

, accounting for one of every four deaths. In 2008, a total of 1,437,180 new cancer cases and 565,650 deaths from cancer are projected to occur in the United States. This includes 184,450 new breast cancer cases and 40,930 deaths. Projected new prostate cancer cases are 186,320 and 28,660 men are expected to die in 2008. The high incidence and death rate of breast and prostate cancer types emphasize the need for new strategies to combat this pandemic disease.Cancer treatment includes surgery, radiation, chemotherapy, hormones, and immunotherapy. Current anticancer drugs are associated with severe side effects and frequent resistance, emphasizing an urge to find novel, effective, and non-toxic anticancer lead compounds. Hence, developing new anticancer agents would be important medically and economically.

Natural products as a unique drug resource

Nature has been and still is the single most important source of drugs or drug precursors. Approximately half of all modern pharmaceutical agents are derived from or are modeled on natural products. Unwittingly, the use of extracts and whole plants as remedies amounted to the administration of several chemical entities at once, whose constitution and synergism was wholly unknown. It was not until the 19^th century when techniques for partitioning some of these extracts into individual components did single entity drugs become available. The growing interest in natural products including higher plant secondary metabolites, particularly in the area of anticancer is attributed to the urgent therapeutic need in this areas, the diverse structure and biological activity ranges as well as the adequacy of natural secondary metabolites as biochemical and molecular probes. The development of techniques to accurately detect, isolate, characterize, and solve the demand for supply further encouraged the interest in bioactive natural products. Historically, the majority of the natural product-based drugs including cyclosporin, paclitaxel, and camptothecin derivatives were first discovered by traditional cell-based in vitro assays before their real molecular biological targets were identified. These cellular biological responses of natural products are likely to be associated with the inherent properties of secondary metabolites for the defense of their producing organisms.

Marine natural products

Seas cover over 70% of the earth. Total global biodiversity is 3-500 x 10⁶ species of prokaryote and eukaryote organisms. Of these, marine macrofauna comprise an estimated range of 0.5-30 x 10⁶ species which represents a broader range of taxonomic diversity than that found in the traditional source of natural products, the terrestrial environment. Only a few thousand compounds have been reported from marine origin and hence oceans are enormous potential providers of new bioactive metabolites. Marine natural products display an extraordinary chemical and pharmacological scope. This could be attributed to the ability of marine organisms to release secondary metabolites as their own chemical defense tools to survive in extreme temperature, salinity, and pressure and to resist their own predators. Although comprehensive marine natural products chemistry science is recent compared to terrestrial natural products chemistry, several marine-derived or marine-related drugs are currently in preclinical or clinical evaluation as anti-inflammatory agents, e.g., manoalide, debromohymenialdisine, and pseudopterosins and as anticancer agents, e.g., ecteinascidin 743, bryostatin 1, discodermolide, dehydrodidemnin B, didemnin B, Kahahalide F, and isohomohalichondrin B. Only the analgesic w-conotoxin made its way to the market as the first marine-derived drug in clinical use.

Biocatalysis

The use of microorganisms as effective biocatalysts is as old as human history. Ancient civilizations used the microbes to make vinegar, wine, and cheese. Modern civilizations extended the friendly relationship with microbes through using them as unique resources to produce indispensable antibiotics, essential hormones, and to produce many important chemicals and pharmaceuticals. Biocatalysis is the use of growing microbial cultures, enzymes, or immobilized cells to enhance the bioactivity of a starting material through induction of stereospecific reactions. The use of biocatalysis to generate new chiral derivatives, and increase the efficacy of drugs by metabolic activation is well documented. Biocatalysis offers several advantages, including mild reaction conditions, highly stereo-, regio-, and chemoselective, unique and diverse chemistry, and environmental safety. Other advantages of using biocatalysis for generating organic libraries include the natural diversity of enzymatic reactions, the compatibility of reaction conditions and high-throughput screening techniques, ease of automation, and the ability to retrace synthetic pathways leading to active products. It is also well known that gastrointestinal bacterial flora plays an important role in drug metabolism. The use of marine microorganism for bioremediation and biodegradation of environmentally hazardous compounds is well known.

Marine natural products research program

The ultimate goal of our program is to discover and optimize prototype anticancer small molecule leads of natural origin. Targeted anticancer activity includes inhibition of tumor cell invasion, metastasis, migration, angiogenesis, proliferation, HIF-1, and MDR P-glycoprotein. Our research is focused on four different classes of readily available marine natural products. These compounds occur in the Red Sea sponges and soft corals. We have access to these animals through collaborative agreement with Egyptian collaborators. We use biocatalytic and /or computer-assisted design/molecular modeling approaches to design novel semisynthetic analogs of readily available marine and plant scaffolds with enhanced binding affinity toward certain molecular targets. Examples of molecular targets of interest: EGF, VEGFR, caspase-3, actin, tubulins, topoisomerases, and Pgp.