TOWARDS THE SYNTHESIS OF DRAGONAMIDE E AND ANALOGS THEREOF

Leishmaniasis is a disease caused by a parasite spread through the female sand fly. It is categorized as a Neglected Tropical Disease and can cause very severe symptoms, even death, if left untreated. Symptoms include skin lesions that can cause permanent scarring, and mucosal membrane infections that can cause facial deformities. More aggressive forms of leishmaniasis can lead to infections of internal organs like the liver and/or spleen and can lead to death. Drug resistance of these parasites has rendered treatment limited and the side effects of which can be harmful as well. Scientists looking towards new treatments for tropical diseases have experimented with bioactive compounds from certain marine life. One of the results of which are compounds from the organism Lyngbya majuscula, a cyanobacteria that grows all over the world, but for this research, was isolated off the coast of Panama. After testing against a variety of tropical diseases, there was notable activity against leishmaniasis. Subsequent isolation and testing were done to single out dragonamide E as the main contributor to the antileishmanial activity. Previous work in our lab found many struggles in the full synthesis of the compound due to the methylation on the amide nitrogens in the peptide backbone of the compound. One such route to circumventing this issue is the use of peptoids rather than methylating the peptide. Peptoids have been seen to have incredibly useful properties in terms of biocompatibility. The hope is that by using a peptoid version of dragonamide E, we can mimic the methylation of the amide nitrogen while maintaining the R groups functionality. Unfortunately, leishmaniasis being a neglected disease, it is unclear the mechanism for antileishmanial properties of dragonamide E, so towards that end, alanine substitution mutations were introduced into the peptoids. This was done to reduce the chemical reactivity and interactions of the molecule under the logic that if the R group was necessary for binding, removing it would decrease its effectiveness, thus screening for the most important structures that give dragonamide its antileishmanial function. The investigation into dragonamide E also led to an interest in other natural products that can be used to treat tropical diseases in the form of almiramides and the other dragon amide structures. This led to more peptoid synthesis by making progress towards almiramides A, B, and C peptoid analog, and dragonamides B, C, and D peptoid analogs as well.