The continued need for biologically active compounds that serve as treatment for some of the most notorious diseases, such as cancer and HIV/AIDS among others, remains a concern throughout the scientific community. A number of natural products, which have been isolated from vegetation, marine life, and various other sources, have been found to exhibit varying potencies against a range of diseases and ailments. However, many times the amount of material that can be obtained from these natural sources is minimal. Thereby, chemical synthesis has arisen as an irreplaceable field that allows access to larger quantities of these compounds to be used for more in depth biological studies and human clinical trials if warranted. Furthermore, the development of synthetic routes to these compounds allows for advanced intermediates to be studied for biological activity and for various analogues of these compounds to be prepared in an effort to generate a more potent drug in accordance with the NIH's mission. While great strides have been made toward the isolation and synthesis of a number of these biologically active natural products, there still is te need for compounds that can be used to treat multidrug-resistant variants of these diseases. Ineleganolide is a polycyclic norcembranoid diterpene that was isolated from the marine sponge Sinularia inelegans along with a variety of structurally related, biologically active norcembranoid diterpenes. Isolated initially using bioassay-guided fractionation, ineleganolide was proven to have cytotoxic effects against the murine leukemia P-388 cell line (ED50=3.82?g/mL). The bioactivity profile of this natural product has yet to be explored further despite the known cross-sensitivity of a variety of cancer cell lines, including those related to leukemia and lung cancer, because of the severely limited quantities available from the natural source. While some members of the norcembranoid diterpene family have shown excellent biological activity, many of the remaining members of this class have not been investigated. Ineleganolide contains a highly oxygenated, pentacyclic framework that makes it a challenging synthetic target. Construction of the central seven-membered ring and diastereoselective formation of the nine stereocenters contained within the natural product will require the careful consideration and employment of novel asymmetric reaction methodology and intramolecular reactions and rearrangements. The construction of a variety of additional norcembranoid diterpene natural products will also be accomplished employing an anionic retrocyclization-cyclization pathway, inspired by their biosynthesis, from a synthetic precursor to ineleganolide. Efficient and scalable access to these natural products will enable structure-activity relationship, mechanism of action, and protein affinity studies through iterative activity-guided derivatization in collaboration with the City of Hope National Cancer Institute-designated Comprehensive Cancer Center.
This proposal outlines a research plan in synthetic organic chemistry designed to provide the natural product ineleganolide, known to exhibit anticancer activity, and additional members of the same natural product family from readily available starting materials. The proposed research will allow access to ineleganolide, the related natural products, and analogous structures in an efficient manner, affording the quantities necessary to perform a full and thorough screening of their biological activity and establishment of the relationship between their structure and their bioactivity as well as their mechanism of biological action. While many of these natural products and analogs have never been subjected to bioactivity screening, their structural similarity to known anticancer and biologically active compounds suggests they will likely possess favorable characteristics for medicinal and therapeutic utility.