Jogyamycin is an aminocyclopentitol natural product and belongs to the same family of molecules that includes pactamycin and cranomycin as well as other members. The biological activity of jogyamycin has been briefly studied, showing that it has exceptional activity against drug-resistant malaria and the parasite responsible for African sleeping sickness. Pactamycin and other molecules in this family have also shown anti-protozoal, anti-bacterial and anti-cancer activity. One issue with these molecules is that they also exhibit potent cytotoxic effects that have limited their therapeutic development. Exploring the mode of action of these molecules may yield a strategy for alleviating this cytotoxicity. This family of molecules prevents protein synthesis from occurring by binding to a region of the ribosome that is highly conserved across all domains of life. Despite these similar binding pockets, small changes to the core structure of these molecules can have dramatic influence on their biological activity. How these small structural changes play a role in determining the biological activity is currently poorly understood, but would be of great value in creating less cytotoxic analogs. The objective of this research is to develop a predictive binding model that indicates which structural features are important for binding to the eukaryotic and prokaryotic ribosomes. Developing this model will be enabled through an enantioselective synthesis of jogyamycin which can be altered to access different analogues. Jogyamycin is a challenging molecule where every carbon of the cyclopentane scaffold contains a heteroatom substituent. Furthermore, there are three contiguous carbons bearing different aminated functional groups as well as three contiguous fully substituted carbons. Current syntheses to access related compounds are unamendable to synthesizing jogyamycin and its analogs, requiring a new synthesis. This proposed 14 step enantioselective synthesis of jogyamycin will utilize a few key reactions, including an asymmetric reductive aldol reaction, a metal-mediated nitrene C-H insertion and a ring closing metathesis. To develop a predictive binding model, energies will be calculated for the binding of jogyamycin and other related molecules to both the prokaryotic and eukaryotic ribosomes. Furthermore, binding energies of several analogues will be calculated to evaluate how these systematic changes affect the binding energies. The analogues will then be synthesized by using the previously developed synthesis of jogyamycin as a template. These analogues will then be tested using biological assays for bacteria, malaria and cancer. The relative biological activity will then be compared to the calculated binding energy to validate or refine our predictive model. This would further expand our understanding of the relative importance of each structural feature to binding. This fundamental knowledge gained through both computational and experimental techniques would be useful for developing future generations of jogyamycin analogs that exhibit limited cytotoxicity while also maintaining potent activity against a variety of diseases.
Jogyamycin and other aminocyclopentitol natural products have exhibited the ability to target a wide range of diseases, including various kinds of cancer and drug-resistant malaria, but their potent cytotoxicity limits their use. By synthesizing jogyamycin and other similar molecules, we will be able to explore the reasons for why they are toxic to human cells, malaria and bacterial diseases. Through this study it is hoped that knowledge we gain will eventually lead to the design of new therapeutic agents.
