Leishmaniasis is a parasitical infection categorized as one of about twenty Neglected Tropical Diseases. Spread by the female sand fly, it can become very severe if left untreated. Symptoms include skin lesions, which may cause scarring, and mucosal membrane infection, which may lead to facial deformity. The most severe form of leishmaniasis can infect organs such as the liver and spleen, possibly leading to death. The current treatments for leishmaniasis are becoming limited due to an increase in drug resistant parasites. Furthermore, the side effects of these treatments can be very problematic.
In the search for new treatments for tropical diseases such as leishmaniasis, researchers have been exploring marine plant compounds for their potential in drug development. In 2001, the first in a series of linear lipopeptides called the “dragonamides” was reported from marine cyanobacteria Lyngbya. The following years brought forth the isolation of additional members to the series, and in 2010, dragonamide E was discovered. This tetrapeptide has caught our interest due to its display of significant activity against Leishmania parasites in vitro. A total synthesis of dragonamide A was reported in 2005 by the Chen group. However, none of the other dragonamides have been reportedly synthesized to date. Smith conducted synthetic studies of dragonamide E, but encountered various obstacles, especially during amino acid coupling.
In this work, we present our progress toward a total synthesis of dragonamide E as well as a series of analogues that can be used to expand our understanding of the molecule’s activity. Herein we follow a retrosynthetic approach to visually break down dragonamide E into two fragments: the hydrophobic alkyne “tail” and the tetrapeptide “head.” We have successfully developed an efficient synthesis of the tail in excellent yield and high diastereomeric purity.
The latter part of this work will discuss our progress in peptide coupling of the amino acid head as well as the final addition of the tail via solid-phase peptide synthesis. The hindered coupling of N-methyl amino acids posed a significant challenge. We also report our synthesis of two non-methylated dragonamide analogues that might be useful as work continues in our lab.
Date of publication
Dr. Sean C. Butler, Dr. Dustin P. Patterson, Dr. Rachel N. Mason
MS in Chemistry
Glaesemann, Sarah E., "Synthetic Studies of Dragonamide E and Its Potential Treatment of Leishmaniasis" (2023). Chemistry Theses. Paper 5.
Available for download on Thursday, July 24, 2025