Salinosporamide A (1, NPI-0052) is a potent proteasome inhibitor in development for treating cancer. In this study, a series of analogues was assayed for cytotoxicity, proteasome inhibition, and inhibition of NF-kappaB activation. Marked reductions in potency in cell-based assays accompanied replacement of the chloroethyl group with unhalogenated substituents. Halogen exchange and cyclohexene ring epoxidation were well tolerated, while some stereochemical modifications significantly attenuated activity. These findings provide insights into structure-activity relationships within this novel series.

A series of chlorinated bisindole pyrroles, lynamicins A-E (1-5), was discovered from a novel marine actinomycete, NPS12745, which was isolated from a marine sediment collected off the coast of San Diego, California. Close to full length 16S rRNA sequence analysis indicated that NPS12745 is a novel strain of a recently described marine actinomycete with the proposed genus name Marinispora. The antimicrobial spectrum of these compounds was evaluated against a panel of 11 pathogens, which demonstrated that these substances possess broad-spectrum activity against both Gram-positive and Gram-negative organisms. Significantly, compounds 1-5 were active against drug-resistant pathogens such as methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium.

Salinosporamide A (NPI-0052; 3), a highly potent inhibitor of the 20S proteasome, is currently in phase I clinical trials for the treatment of cancer. During the course of purifying multigram quantities of 3 from Salinispora tropica fermentation extracts, several new salinosporamides were isolated and characterized, most of which represent modifications to the chloroethyl substituent at C-2. Specifically, 3 was isolated along with the known compound salinosporamide B (4), the previously undescribed methyl congener salinosporamide D (7), and C-2 epimers of 3 and 7 (salinosporamides F (9) and G (10), respectively). Salinosporamide I (13), in which the methyl group at the ring junction is replaced with an ethyl group, and the C-5 deshydroxyl analogue salinosporamide J (14), were also identified. Replacement of synthetic sea salt with sodium bromide in the fermentation media produced bromosalinosporamide (12), 4, and its C-2 epimer (11, salinosporamide H). In addition to these eight new salinosporamides, several thioester derivatives were generated semisynthetically. IC50 values for cytotoxicity against human multiple myeloma cell line RPMI 8226 and inhibition of the chymotrypsin-like (CT-L) activity of purified rabbit 20S proteasomes were determined for all compounds. The results indicate that thioesters may directly inhibit the proteasome, albeit with reduced potency compared to their beta-lactone counterparts.

A collection of Lyngbya majuscula from Palau contained the peptides dolastatin 3 (1), homodolastatin 3 (2), and kororamide (3), together with aplysiatoxin (4), debromoaplysiatoxin (5), and oscillatoxin A (6). The structures of the new peptides homodolastatin 3 (2) and kororamide (3) were determined by interpretation of spectroscopic data and chemical degradation.As part of a collaborative effort to discover new inhibitors of HIV-1 integrase from marine organisms, 1 we screened a collection of crude extracts of marine organisms from Palau. Among the few extracts that showed activity, most of which were from marine sponges, was an extract of the macroscopic cyanophyte Lyngbya majuscula that had been collected because it was fouling corals. L. majuscula has previously yielded a wide variety of natural products 2 that include the antiproliferative agents, curacin A 3 and debromoaplysiatoxin, 4 and both acyclic 5 and cyclic 6 peptides. In this paper we report the HIV-1 integrase inhibition assayguided isolation of dolastatin 3 (1), which had previously been reported from the sea hare Dolabella auricularia, 7 and the structure elucidation of two new cyclic peptides, homodolastatin 3 (2) and kororamide (3).The specimen of L. majuscula (90-95% homogeneous) was collected in shallow water in the lagoon near Big Goby marine lake, Palau, and was immediately frozen. The crude methanolic extract of the cyanophyte was found to inhibit HIV-1 integrase in the terminal-cleavage and strandtransfer assays, 8 but did not inhibit molluscum contagiosum virus (MCV) topoisomerase. 9 The ethyl acetate-soluble material from the methanolic extract was subjected to repeated chromatography on reversed-phase supports to obtain dolastatin 3 (1, 4 × 10 -5 % wet wt), homodolastatin 3 (2, 4.8 × 10 -5 % wet wt), and kororamide (3, 4 × 10 -5 % wet wt), in addition to the known metabolites aplysiatoxin (4), debromoaplysiatoxin (5), and oscillotoxin (6). 4,10 Each fraction obtained during the separation procedure was screened for activity against HIV-1 integrase, and it was shown that the only active material present was dolastatin 3 (1), which was identified by comparison of its spectral data with literature values. 7 Homodolastatin 3 (2) was obtained as a white solid. The molecular formula, C 30 H 42 N 8 O 6 S 2 , obtained from a highresolution mass measurement of the [M + Na] + ion, suggested that 2 differed from dolastatin 3 (1) by the addition of a methylene group. Analysis of the 1 H and 13 C NMR spectra revealed signals that were characteristic of an isoleucine residue in place of the valine residue of dolastatin 3. The sequence of the amino acid residues was confirmed by analysis of the HMBC experiment. The absolute configuration of the L-isoleucine, L-proline, and L-leucine residues was determined by hydrolysis followed by GC-MS analysis of the derivatized residues on a chiral column and that of the remaining center was determined by treatment with ozone followed by hydrolysis and derivatization to obtain a peak corresponding to L-glutamate,...