A new marine-derived macrolide designated as neopeltolide (1) has been isolated from a deep-water sponge of the family Neopeltidae. Its structure was elucidated on the basis of spectroscopic data interpretation. Neopeltolide (1) is a potent inhibitor of the in vitro proliferation of the A-549 human lung adenocarcinoma, the NCI-ADR-RES human ovarian sarcoma, and the P388 murine leukemia cell lines, with IC50's of 1.2, 5.1, and 0.56 nM, respectively. Neopeltolide (1) also inhibited the growth of the fungal pathogen Candida albicans with a minimum inhibitory concentration of 0.62 microg/mL.

Leiodermatolide is a structurally unique macrolide, isolated from the deep-water marine sponge Leiodermatium sp., which exhibits potent antiproliferative activity against a range of human cancer cell lines (IC50 <10 nM) and dramatic effects on spindle formation in mitotic cells. Its unprecedented polyketide skeleton and stereochemistry were established using a combination of experimental and computational (DP4) NMR methods, and molecular modelling.

Meridine [1], a polycyclic alkaloid derived from the marine sponge Corticium sp., was found to inhibit the growth of Candida albicans and Cryptococcus neoformans. Activity was also observed against Trichophyton mentagrophytes and Epidermophyton floccosum. Studies of the mechanism of action of this agent have shown an inhibition of nucleic acid biosynthesis.

Marine macrolides that selectively disrupt cell cycle events continue to occupy a central position as lead compounds in the ongoing search for novel anticancer agents, [1,2] highlighted by the recent FDA approval of Halaven (eribulin mesylate, a fully synthetic analogue of the halichondrins) for the treatment of advanced breast cancer. [3] Lithistid sponges have proven to be a particularly fertile source [4] of such biologically relevant polyketide metabolites, including dictyostatin [5] and discodermolide. [5d, 6] As part of a continued program aimed at the discovery of novel bioactive natural products from deepwater marine invertebrates, we have examined the relatively unexplored [7] lithistid sponge Leiodermatium. A crude extract of Leiodermatium sp. was found to exhibit substantial activity in an assay which identifies antimitotic agents through detection of phosphonucleolin, a marker of mitosis. [8] Bioassay-guided fractionation led to the isolation of leiodermatolide (1, Figure 1), whose unprecedented 16-membered macrolide skeleton, featuring an unsaturated side chain terminating in a d-lactone, has been elucidated through a combination of extensive NMR spectroscopic analysis, comparative DFT GIAO NMR shift calculations, and molecular modeling. Leiodermatolide was found to exhibit potent and selective antimitotic activity (IC 50 < 10 nm) against a range of human cancer cell lines by inducing G2/M cell cycle arrest, and represents a promising new lead for anticancer drug discovery.A specimen of Leiodermatium (1.04 kg) was collected at a depth of 401 m off the coast of Fort Lauderdale, Florida, using the Johnson Sea Link submersible. The frozen sponge was exhaustively extracted using a mixture of EtOAc/EtOH (9:1) followed by partitioning of the dried extract residue between EtOAc and H 2 O. Vacuum column chromatography of the organic partition on a silica gel stationary phase followed by reverse-phase HPLC of the active fraction led to the isolation of leiodermatolide (11.8 mg, 0.0011 % wet weight) as an amorphous white powder with ½a 24 D ¼À84.2 (c = 0.34, MeOH). [9] HRDART MS analysis of leiodermatolide (1) provided a [M+H] + ion at m/z 602.3705, appropriate for a molecular formula of C 34 H 51 NO 8 (calcd for [M+H], 602.3693, D = 1.2 mmu), requiring 10 sites of unsaturation. [10] Optimum NMR signal dispersion was realized in CD 2 Cl 2 ; inspection of the 13 C NMR spectrum revealed a total of 34 resonances in agreement with the HRMS formula. 13 C NMR resonances attributable to two ester groups (d C = 172.4, 170.4 ppm), one carbamate (d C = 157.6 ppm), and 10 olefinic carbons (d C = 137.9, 137.5, 134.2, 131.8, 130.0, 128.8, 128.5, 126.4, 125.9, 124.7 ppm) accounted for eight of the 10 sites of unsaturation, suggesting the presence of two rings.Interpretation of the 2D DQF-COSY spectrum coupled with the edited g-HSQC spectrum led to the assignment of seven isolated spin systems (A-G, Figure 2). These spin systems and their connectivity with the remaining atoms enabled assembly into the final planar struct...