Enigmazole C: A Cytotoxic Macrocyclic Lactone and Its Ring-Opened Derivatives from a New Species of Homophymia Sponge

Abstract

A new macrolide, enigmazole C ( 1 ), and two additional analogues, enigmazoles E ( 2 ) and D ( 3 ), were obtained from a new species of the Homophymia genus as part of an ongoing discovery program at PharmaMar to study cytotoxic substances from marine sources. The structures were fully characterized by cumulative analyses of NMR, IR, and MS spectra, along with density functional theory computational calculations. All three of the new compounds feature an unusual 2,3-dihydro-4 H -pyran-4-one moiety, but only enigmazoles C ( 1 ) and D ( 3 ) showed cytotoxic activity in the micromolar range against A-549 (lung), HT-29 (colon), MDA-MB-231 (breast), and PSN-1 (pancreas) tumor cells.

Enigmazole Phosphomacrolides from the Marine Sponge Cinachyrella enigmatica

“…4 Photooxidation of Enigmazole B (1) and 15-OMe Enigmazole A (7). A solution of 15-OMe enigmazole A (1.0 mg, 1.6 × 10 −6 mol) in CD 3 OD (180 μL) was placed in a 3 mm NMR tube and irradiated by a flood lamp (250 W) at rt for 6 h. The reaction mixture was purified by C 18 HPLC to afford enigmimide A (5). In a similar manner, 1 was irradiated for 24 h and purified by HPLC to afford enigmimide B (4) together with cis-enigmimide B (data not shown).…”

“…In a previous study, we reported on three cytotoxic phosphomacrolides, enigmazole A ( 6 ), 15-OMe enigmazole A ( 7 ), and its analogues, from a Papua New Guinea marine sponge Cinachyrella enigmatica . Subsequently, enigmazoles C–E were isolated as cytotoxic components from an Indonesian Homophymia sponge . During our further study of the organic-soluble portion of an aqueous extract from C.…”

“…4 Subsequently, enigmazoles C−E were isolated as cytotoxic components from an Indonesian Homophymia sponge. 5 During our further study of the organic-soluble portion of an aqueous extract from C. enigmatica, a new macrolide enigmazole B (1), two enigmazole B derivatives (2 and 3), and two imide-type analogues named enigmimides (4 and 5) were obtained. Here, we report the isolation and structure elucidation of 1−5, as well as the structure−cytotoxicity relationship of enigmazoles.…”

Connection of Isolated Stereoclusters by Combining 13C-RCSA, RDC, and J-Based Configurational Analyses and Structural Revision of a Tetraprenyltoluquinol Chromane Meroterpenoid from Sargassum muticum

“…Trying to establish the relative configuration at C3, we followed the i J /DP4 protocol of Daranas, Sarotti et al, involving a conformational search within a 5-kcal/mol interval, and then calculated the theoretical chemical shifts at the B3LYP/6-31G(d,p) level [ 36 , 37 , 38 ]. Contrasting calculated vs. experimental chemical shifts gave rise to a better DP4 score for the (3 R *,7 S *,11 R *)-1b diastereoisomer (C/DP4: 94.25%, H/DP4: 100%).…”

Total Synthesis of (−)-Enigmazole B

“…2 Very recently, Jimeńez, Rodri ́guez, 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. 3 It was reported that (−)-enigmazole A (1) showed significant cytotoxicity against the National Cancer Institute (NCI) panel of human cancer cell lines with an average GI 50 value of 1.7 μM, albeit with essentially no selectivity among the tested cell lines. Meanwhile, (−)-enigmazole B (4) has a characteristic dihydropyran ring substituted with an α,β-unsaturated ester as an acid-, base-, and light-sensitive substructure.…”