New Leukotriene B₄ Receptor Antagonist: Leucettamine A and Related Imidazole Alkaloids from the Marine Sponge Leucetta microraphis

Abstract

Three new imidazole alkaloids, leucettamines A [1] and B [2] and leucettamidine [31, have been isolated from the Palauan sponge Leucetta microraphis. Their structures were established on the basis of extensive spectral analyses. Leucettamine A showed potent leukotriene B4 receptor binding activity (K¡ =1.3 µ ), while leucettamine B was essentially inactive (K¡ = 100 µ ) and leucettamidine showed significant activity (K¡ = 5.3 µ ). With leucettamine A identified as a pure LTB4 receptor antagonist, a new structure lead is presented to inflammation therapy.

A Distinctive Structural Twist in the Aminoimidazole Alkaloids from a Calcareous Marine Sponge: Isolation and Characterization of Leucosolenamines A and B

“…This array was confirmed by gHMBC correlations illustrated in Figure 1 and further justified by comparison of NMR properties of A to the parallel peaks of leucettamine B (2). 11 The remaining observed protons were identified as Nmethyl singlets at δ 3.39 and 3.24 that flanked the intense water peak.…”

“…A partial formula for 5 of C 17 H 13 O 2 N 3 was supported by (a) the 13 C and DEPT NMR data (Table 1) showing 10 quaternary, three methine, two methylene, and two methyl carbons, (b) the ä C 160.1 characteristic of a guanidine residue of a 2-amino imidazole group, and (c) the ä C /ä H 100.5/5.90 (s, 2H's) indicative of the 1,3 dioxolane ring as seen in leucettamine B (2). 11 Successive sets of high-resolution mass spectrometry data were needed to finalize the molecular formula of 5 as C 17 . At this point in the analysis (i) was favored; however, the ultrahigh-resolution data indicated the best match was with (ii) because of the following pattern of ¢ mmu vs calc: (ii) = 0.04, (iii) = 47.2, and (i) = 48.0.…”

“…The structures of naamine C (1), 10 leucettamine B (2), 11 spirocalcaridine A (3), 8c and 2-amino-2-deoxykealiiquinone (4) 12 provide illustrations of these structural features.…”

Natural product-like combinatorial libraries

“…Several imidazole alkaloids of marine origin, as naamine D, 200 leucettamine A 201 and leucetatamidine 201 have proved to possess interesting biological activities, including antifungal and nitric oxide synthase inhibitory activity, leukotriene B4 receptor binding activity, and LTB4 receptor antagonism. Aiming the discovery of new antifungal agents, Saha and co-workers 202 described a combinatorial chemistry approach to 4-substituted imidazole sulfonamides using 4-formyl-imidazole (193) as the starting material.…”

“…14, No. 5,2003 substituent (201). Cascade radical annulation with an isonitrile (202) bearing the A-ring substituent then produces the mappicine analogues.…”