Enigmazole Phosphomacrolides from the Marine Sponge Cinachyrella enigmatica

Abstract

Enigmazole B (1) and four new analogues, cis-enigmazole B (2), dehydroenigmazole B (3), enigmimide B (4), and enigmimide A (5), were isolated from the marine sponge Cinachyrella enigmatica. Their planar structures were elucidated by detailed NMR and MS data analyses, which established 1–3 to be oxazole-substituted 18-membered phosphomacrolides, while 4 and 5 were oxazole ring-opened congeners. The relative and absolute configurations in 1 were determined by a combination of chemical transformations and spectroscopic analyses. Photooxidation of the oxazole moiety in 1 gave enigmimide B (4), thus establishing that 4 has the same absolute configuration of 1. Enigmazole B (1) along with analogues 2 and 3 showed cytotoxicity against murine IC-2 mast cells with IC50 values of 3.6–7.0 μM. The enigmimides (4 and 5) and dephosphoenigmazoles did not show cytotoxicity (IC50 > 10 μM), implying that both the oxazole moiety and the phosphate group are necessary for the cytotoxicity of the enigmazole class macrolides.

Total Synthesis of (−)-Enigmazole A by the Macrocyclization/Transannular Pyran Cyclization Strategy

“…(−)-Enigmazole A ( 1 ), the representative member, was reported to exhibit significant cytotoxicity against the NCI-60 panel of human cancer cell lines, although it appears to be a nonselective cytotoxin. Other members of this family of natural products, including enigmazole B, C, and D, also showed considerable to moderate cytotoxic activity.…”

“…Macrolide natural products of marine origin are fascinating members of polyketide secondary metabolites in that they represent an important and promising source of new cancer chemotherapeutics . (−)-Enigmazole A, B, and their congeners ( 1 – 4 , Figure ), new members of marine macrolide natural products, were isolated by Gustafson and co-workers from a Papua New Guinean sponge Cinachyrella enigmatica . Additional congeners, enigmazoles C–E ( 5 – 7 ), were recently identified by Jiménez and Rodríguez et al from a new Indonesian sponge that belongs to the Homophymia genus .…”

Total Synthesis of (−)-Enigmazole B

“…Meanwhile, (−)-enigmazole B ( 4 ) has a characteristic dihydropyran ring substituted with an α,β-unsaturated ester as an acid-, base-, and light-sensitive substructure . Moreover, 4 was suggested to show selective and potent cytotoxic activity in mutant c-Kit expressing cells. , Activating mutations in the receptor tyrosine kinase c-Kit are frequently found in acute myelogenous leukemia and gastrointestinal stromal tumors, which cause overexpression or constitutive activation of c-Kit and enhance the proliferation and invasion of cancer cells . Understanding the structural basis of the biological activity and mode-of-action of enigmazoles in detail may be helpful for the development of chemotherapeutics that target the c-Kit signaling pathway.…”

“…Cytotoxic macrolide natural products of marine origin are a potential source of new chemotherapeutic agents for the treatment of human cancers . The Gustafson group disclosed the identification of a series of characteristic phosphomacrolides, enigmazoles ( 1 – 4 , Figure ), from the marine sponge Cinachyrella enigmatica collected along the south coast of Papua New Guinea . Very recently, Jiménez, Rodríguez, and co-workers from PharmaMar reported the isolation of additional enigmazole congeners, designated as enigmazole C–E ( 5 – 7 ), from a new Indonesian sponge that belongs to the Homophymia genus .…”