Dragonamide E, a modified linear lipopeptide from Lyngbya majuscula with antileishmanial activity

Abstract

Tropical parasitic and infectious diseases, such as leishmaniasis, pose enormous global health threats, but are largely neglected in commercial drug discovery programs. However, the Panama International Cooperative Biodiversity Group (ICBG) has been working to identify novel treatments for malaria, Chagas' disease, and leishmaniasis through an investigation of plants and microorganisms from Panama. We have pursued activity-guided isolation from an extract of Lyngbya majuscula that was found to be active against leishmaniasis. A new modified linear peptide from the dragonamide series was isolated, dragonamide E (1), along with two known modified linear peptides, dragonamide A (2) and herbamide B (3). Dragonamides A and E and herbamide B exhibited antileishmanial activity with IC50 values of 6.5, 5.1, and 5.9 microM, respectively. Spectroscopic and stereochemical data for dragonamide E (1) and herbamide B (3; the spectroscopic and stereochemical data for this substance is incomplete in the literature) are presented as well as comparisons of biological activity within the dragonamide compound family. Biosynthetic differences among marine compounds with a terminal free amide are also discussed.

Figure 1

Semi-synthetic strategy utilized to determine stereochemical configuration of herbamide B (3) at C-2.

Figure 2

¹H NMR comparison of chemical shifts for the S-PGME derivative of the herbamide B fragment (A), the S-PGME derivative of the barbamide fragment (B), and the R-PGME derivative of the barbamide fragment (C). The S-PGME derivative of the herbamide B fragment directly overlaps with the S-PGME derivative of the barbamide fragment and has distinctive shift differences from the R-PGME derivative of the barbamide fragment, indicating that herbamide B (3) and barbamide have the same configuration at this center.

Figure 3

(A) The distinctive spatial arrangements of the fatty acyl moieties of dragonamide E (1) and dragonamide C, and (B) dragonamide E as a precursor for either the R or S configuration of the fatty acyl moiety, present in dragonamides A and B, dragomabin, and majusculamide B (S moiety) and almiramide A–C and majusculamide A (R moiety).

Figure 4