Our research focuses on two main areas: 1) the development of novel methods and strategies for the preparation of complex polycyclic ring systems, and 2) application of these methods for the synthesis of biologically important natural products. We have been particularly interested in natural products that contain seven-membered (cycloheptane) rings. Compounds that incorporate seven-membered rings are widespread in nature and frequently of considerable medicinal interest as potential anti-tumor, anti-HIV, antibacterial and anti-inflammatory agents. More recently we have also investigated strategies for the generation of eight-membered ring-containing systems, which are also prevalent in nature but challenging to access by synthetic means.
We have found that a “one-pot” 5-exo cyclization/Claisen rearrangement sequence is a very efficient process that allows the preparation of a number of cycloheptanoid ring systems. The reaction sequence involves an appropriately substituted 4-alkyn-1-ol system which, in the presence of catalytic base and heat, undergoes a unique oxyanionic cyclization reaction to provide an exocyclic tetrahydrofuran derivative. On continued heating, this intermediate rearranges spontaneously via the 3,3-sigmatropic process to afford the final product. Although the early studies were conducted using conventional heating, we found that microwave irradiation (MWI) is particularly well suited for this process.
Using a similar strategy, we have recently demonstrated that a variety of cyclooctenone derivatives may be prepared from appropriately substituted 5-alkyn-1-ol systems via microwave-assisted oxy-anionic 6-exo dig cyclization/Claisen rearrangement reaction sequence in the presence of catalytic base. However, the initial 6-exo cyclization is sluggish and requires activation of the triple bond. We found that cyano-substituted 5-alkyn-1-ols are particularly well suited as starting materials for these reactions.
A partial list of natural product targets currently pursued in our laboratory is shown below. So far we have successfully synthesized (±)-frondosin C, (±)-frondosin A (formal total synthesis) and both enantiomers of frondosin B by applying an asymmetric strategy for the synthesis of the requisite 4-alkyn-1-ol precursor.
The phorbols are representative of the unique tetracyclic 5-7-6-3 tigliane class of natural products. Although phorbol itself is only moderately bioactive, its C12, C13 diesters are extremely potent activators of protein kinase C (PKC), the phosphorylating enzyme, which has been shown to play a major role in cellular signal transduction. Signal transduction is an important regulatory process that mediates cell growth and division including the types of abnormal cell proliferation associated with tumor promotion. Therefore, compounds capable of interacting with PKC are of great interest as they provide unique opportunities for research on tumor development and cancer.
Interestingly, there are some close structural analogues of phorbol that elicit very different biological activity. An example of these is prostratin, initially isolated from the Samoan medicinal plant Homalanthus Nutans which, unlike phorbol, does not appear to activate PKC; on the contrary, it has been shown to inhibit neoplasia and tumor promotion. Moreover, prostratin is currently being investigated as a possible anti-HIV agent. At noncytotoxic concentrations, prostratin was found to prevent reproduction of the HIV-1 virus in lymphocytic and monocytic target cells. The anti-viral properties of Homalanthus Nutans have been known for a very long time. A brew prepared from the stem wood of this plant containing prostratin as the active ingredient has been used for generations by traditional Samoan healers to treat yellow fever, a viral disease.
Structurally related ingenol derivatives have also been shown to exhibit anti-HIV activity as well as tumor-promoting properties similar to those belonging to the phorbol family. The synthesis and investigation of structurally diverse and modified derivatives of the phorbol family of compounds should ultimately permit full assessment of the features necessary for biological activity, and potentially lead to the development of novel therapeutic agents having anti-cancer and anti-viral activity.
Guanacastepene A is a unique, naturally-occurring diterpene initially isolated from Costa Rican endophytic fungi, possesses significant antibacterial activity toward methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium bacteria. Thus, it serves as a potential lead compound for a new class of antibacterial agents. In addition to guanacastepene A, researchers have identified 14 structurally related compounds that together make up the guanacastepene family of natural products.
Five structurally related sesquiterpene hydroquinones, frondosins A-E, were isolated in 1997 from the Micronesian marine sponge dysidea frondosa . All members of the frondosin family (A-E) are antagonists of interleukin-8 (IL-8) and inhibitors of protein kinase C (PKC) in the low micromolar range. In addition to being involved in cellular inflammatory events, IL-8 is now known to also play an important role in tumor progression and metastasis in several human cancers, including lung cancers. It is has also been reported that IL-8, along with growth-regulated oncogene alpha, is involved in chemoattraction, neovascularization and stimulation of HIV-1 replication both in T-lymphocytes and macrophages. Importantly, it was recently demonstrated that compounds, which inhibit the actions of IL-8 also inhibit HIV-1 replication. Overall, inhibitors of IL-8 action hold therapeutic potential as novel anti-inflammatory and antiviral agents, and may prove useful against cancer as inhibitors of tumorigenesis and proangiogenesis.
* Student co-authors indicated by asterisk
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