Nature has been and still is the single most important source of drugs and precursors. Over the past two decades, only one FDA-approved drug discovered from high-throughput screening of combinatorial chemistry libraries. Natural products-based drugs (parent compounds, analogues, and mimics) are still major entities source among the FDA-approved drugs (57.7% of all drugs). The cellular responses to natural products are likely associated with their inherent properties for the defense of their producing organisms.
The Mediterranean diet correlates with lower incidences of cancer. Computer-assisted study identified the naturally occurring secoiridoid (-)-oleocanthal, from extra-virgin olive oil, as a potential c-Met inhibitor hit. c-Met enhances cell growth, invasion, angiogenesis, metastasis, reduction of apoptosis, and change cytoskeletal functions of many tumors. Oleocanthal inhibited the phosphorylation of c-Met kinase, proliferation, migration, angiogenesis, and invasion of human breast and prostate cancer cell lines. We currently investigate olive oil phenolics and design related analogs with enhanced anticancer activities.
Our group also investigated and design of novel tocotrienol (rare vitamin E members) analogs with enhanced bioavailability, solubility, metabolic and chemical stability. Three tocotrienol-related patents were submitted so far, in which we designed and semisynthesized novel tocotrienol analogs with documented potent in-vivo activity.
We also discovered and patented the anticancer activity of tobacco cembranoids. We try to optimize these compounds as inhibitors of breast and prostate cancer metastasis.
Oceans cover over 70% of the earth and nearly possess 80% of Earth’s animal life. Ziconotide, Cytarabine, and Vidarabine were sponge-derived drugs approved by the FDA for cancer and viral infections. Several other marine natural products are in different phases of clinical trials.Marine environment is excellent resource for novel anticancer drug discovery. Several marine-derived indole diterepene alkaloids (penitrems) were isolated from a marine-derived Penicillium species. These structurally-diverse fungal secondary metabolites can induce tremorgenicity in mammals, toxicity in insects, and most importantly potent inhibition of the high conductance Ca2+-activated potassium channels (BK or maxi-K channels). BK channels have been implicated in the regulation of cell proliferation in a number of malignant cell lines. They showed novel target and antimigratory activity. We are now optimizing these mycotoxins to maximize their antimigratory and minimize their BK channels binding affinity and hence minimize their toxicity. Several other ongoing marine natural product projects from Red Sea sponges include: the anti-invasive and BRK (protein tyrosine kinase-6) inhibitors and reversals of breast cancer resistance sipholanes, actin disruptor macrolide latrunculins, the phenylmethylene hydantoins as stabilizers for metastatic prostate and breast cancer cell-cell adhesion.
Funding: Ongoing projects are supported by NCI/NIH (1R15CA167475-01), Cultural and Educational Bureaus of Egypt, Saudi Arabia, and Libya. Previous support included: Louisiana Biomedical Research Network, Philip Morris USA, Inspire Pharmaceuticals, Neuroscience Research Program, Universidad Central del Caribe, Puerto Rico, FirstTech International Ltd.
|Khalid A. El Sayed, Ph.D.
Professor of Medicinal and Natural Products Chemistry
Department of Basic Pharmaceutical Sciences
School of Pharmacy
University of Louisiana at Monroe