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Organosulfur Natural Products Chemistry:

We have launched a broad program of research focusing on the organosulfur chemistry of natural products isolated from plants with insecticidal, agricultural or medicinal value, and whose organoleptic properties imply the presence of organosulfur derivatives other than ubiquitous sulfur containing compounds such as cysteine and methionine. Major concerns include 1) isolation and characterization of novel potentially useful g-glutamyl cysteines; 2) C-S lyase crystallization and structure determination, in addition to studies of their enzymatic mechanisms; 3) an assessment of the variety of cysteine sulfoxide precursors responsible for organosulfur headspace volatiles observed in selected plants; 4) chemotaxonomic classification of plant species; 5) determination of the lachrymatory principle(s) in plants such as Petiveria alliacea; 6) thiosulfinate chemistry and optical activity; 7) determination of formation pathways of observed organosulfur natural products; and 8) synthesis and characterization of observed novel compounds.

In the course of our work on organosulfur compounds in higher plants, we have determined 1) that C-S lyase mediated ‘allium’ chemistry is quite ubiquitous, occurring in a number of plant families that are unrelated to the genus Allium; 2) that Nectaroscordum species may be appropriately classified as alliums, based on observed chemistry that is analogous to that observed in garlic and onions; 3) that the principle in P. alliacea that has a lachrymatory effect on farm animals is the unique sulfine thiobenzaldehyde S-oxide; 4) that P. alliacea contains not only a C-S lyase, but also an L -F synthase that appears to be analogous to that recently observed in onions, and which is directly responsible for the formation of the lachrymator; 5) that a number of novel cysteine sulfoxide derivatives different from those typically observed in garlic and onion varieties exist in some higher plants, and that these and their C-S lyase mediated decomposition products have antimicrobial and anticancer activity.

Work on organosulfur natural products is ongoing, and current studies include complete structural, kinetic and mechanistic characterization of the C-S lyases and LF synthases, as well as isolation and characterization of g-glutamyl dipeptide derivatives which may have novel biological effects and mechanisms of action. More recently, we have established a collaboration with Dr. Gunter Siegel, Professor of Physiology at the Institut fur Physiologie, Freie Universität Berlin, with whom we are conducting in vivo and in vitro studies on the cardiovascular effects of novel organosulfur natural products.

Development of HIV-1 Nucleocapsid Protein Inhibitors:

Currently, therapeutic management of HIV infection and pathogenesis is generally based upon administration of combination therapy with multiple inhibitors of the HIV type 1 (HIV-1) reverse transcriptase and protease. Although this approach has resulted in significant suppression of viral loads in a substantial number of patients, the long-term treatment outlook is negatively impacted by a variety of issues including a high rate of drug protocol violations, drug toxicity, and the persistence of latent reservoirs of virus in long-lived populations of infected cells. Additionally, the extreme mutability of the virus, and the fact that fairly significant changes in the structures of key viral enzymes do not always translate into gross inefficiencies in their respective functions, renders combination therapy with a particular drug protocol eventually ineffectual in most cases.

These considerations imply that an appropriate target against which to develop anti-HIV, and by extension, other antiretroviral therapies, is a mutationally intolerant protein that plays essential and diverse roles in various phases of the viral replication cycle. A heretofore unexploited target that fits this general profile is the nucleocapsid protein of HIV-1. This small, very basic and highly conserved protein participates in numerous obligate stages of the viral replication cycle, and mutations in its primary structure have been observed to result in the production of non-infectious virions. By studying the structure of the nucleocapsid protein when it is bound to other viral molecular components, we have devised a plan to mimic these components with small organic molecules. These molecules may ultimately serve as lead drug compounds.

To aid in the design of the small molecule nucleocapsid protein inhibitors, we have been using a number of computational methods and molecular modeling programs-with each enabling us to add additional layers of refinement to our lead compound structures. As a consequence, we have made significant progress in the design of small molecule inhibitors, and this has enabled us to advance to the stage where the compounds are being synthesized in the laboratory. Completion of the syntheses will allow us to test our ‘first generation’ inhibitors, whose structures we will further refine as the results of their ability to inhibit nucleocapsid protein functions are acquired.

Bioassay Guided Fractionation, Isolation and Structural Characterization of
Natural Products from Medicinal Plants


In principle, there are two general ways in which plants that may have biological activity can be chosen for study. Plants can be randomly selected and subjected to a series of biological assays to determine their potential biological activity, or they can chosen based upon a history of use against a particular ailment in a society or culture. A disadvantage of the first approach is that selected plants, although demonstrating efficacy in a particular biological assay, may ultimately be found to be highly toxic. This issue is, to a certain extent, circumvented in the second approach, in that the toxicology of the herb is generally know. Put simply, herbs that kill on ingestion are likely not used in traditional medicine, and those that have a long and consistent history of use against a particular ailment have a higher probability of working (otherwise, there would be no continued use).

We have launched a program to study natural products derived from various plants and food crops that have been used to treat disease in some cultures of the world. Thus, plants that have a history of use in traditional medicine are subjected to bioassays to determine the active component, or combination of active components responsible for the manifested therapeutic effects. Plants that we are examining in this way include Croton lechleri which produces a red sap known as known as ‘dragon’s blood’, Uncaria tomentosa (also known as cat’s claw), beta vulgaris (table beets) and vigna unguiculata (cowpea).

Dragons’ blood is a viscous tree sap that is used extensively by the indigenous cultures of the Amazon River basin for its remarkable haling properties. When applied to the skin for abrasions, cuts scratches, blisters, bites and stings, Dragon’s blood forms a long-standing barrier possibly due to its ability to coprecipitate with proteins or other matrix elements. In doing so it is claimed to foster accelerated wound healing and does so with reduced pain, inflammation and scarring. We have found in our work that Dragon’s blood confers benefit by suppressing the activation of sensory afferent nerve mechanisms, which supports its ethnomedical use for disorders characterized by neurogenic inflammation.

Cat’s claw is a vine that grows in the Peruvian Amazon and has been used in traditional medicine to alleviate inflammation. Ethnomedically, the bark and root of cat’s claw are the parts of the plant that are most frequently used, and are prepared as an aqueous extraction in hot water. Several groups have reported a wide range of chemical substituents in cat’s claw, although few studies have demonstrated that administration of these isolated components exerts consistent anti-inflammatory effects. Of the compounds that have been isolated, the most well known are the oxindole alkaloids. Based on in vitro experiments, it has been indicated that oxindole alkaloids promote phagocytosis, leading to the claim that cat’s claw has immunostimulant properties, and also the ability to induce a lymphocyte-proliferation-regulating factor in endothelial cells. However, these actions are difficult to reconcile with the use of cat’s claw to treat chronic inflammation. Hence, we have continued our efforts to evaluate alternatives explanations for the mechanisms of action of cat’s claw. In our own studies, we have found that cat’s claw exhibits potent antioxidant and anti-inflammatory activity that is independent of the oxindole content of the plant sample.

There is anecdotal evidence that components of table beets and cowpea extracts may have anticancer activity. We have initiated a bioassay guided fractionation study to determine if there is scientific support for these reports.

 


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