Francis J. Schmitz

Enzyme Inhibitors: New and Known Polybrominated Phenols and Diphenyl Ethers from Four Indo-Pacific Dysidea Sponges

Extracts and pure compounds isolated from four samples of Dysidea sp. sponges collected from two geographically distinct regions of the Indo-Pacific (Chuuk Atoll and Fiji) were assayed against five different enzyme assays, four of which are relevant to anticancer drug discovery and one of which (15-lipoxygenase) may detect compounds significant in modulating the development of atherosclerotic plaque. The pure compounds that inhibited various enzymes were polybrominated phenols and polybrominated phenoxyphenols. Fourteen of these phenols were isolated, six of which were new compounds. A variety of the phenols inhibited inosine monophosphate dehydrogenase (IMPDH), guanosine monophosphate synthetase, and 15-lipoxygenase. No activity was observed with protein tyrosine kinase pp60v-src or matrix metalloprotease.

Comparison of fascaplysin and related alkaloids: a study of structures, cytotoxicities, and sources.

The fascaplysin class of compounds have been further investigated from six organisms consisting of four sponge collections (Fascaplysinopsis reticulata) and two tunicate collections (Didemnum sp.). This work is an extension of an earlier communication and reports the isolation of 12 new fascaplysin derivatives: 10-bromofascaplysin (7), 3,10-dibromofascaplysin (8), homofascaplysate A (9), homofascaplysin B-1 (11), 3-bromohomofascaplysins B (12), B-1 (13), and C (15), 7,14-dibromoreticulatine (17), reticulatol (20), 14-bromoreticulatol (21), and 3-bromosecofascaplysins A (22) and B (23), along with known compounds: fascaplysin (1), reticulatine (4), 3-bromofascaplysin (6), and homofascaplysin C (14). Selected compounds were screened in a cell-based cytotoxicity assay with compounds 1, 6, and fascaplysin A (24) also screened in the NCI 60 cell line panel. A biogenetic pathway for the brominated fascaplysins and brominated related alkaloids is proposed and discussed.

Antitumor and Cytotoxic Compounds from Marine Organisms

An earlier review of antitumor and cytotoxic compounds from marine organisms which covered the literature into early 1986 was published in 1987 by Munro et al. (1987). The current review is intended to provide a comprehensive review of the field from the beginning of 1986 to early 1991. The primary aim was to include all the marine natural products reported to have any type of cytotoxic or antitumor activity. In addition to compounds reported to be toxic to a variety of cultured cancer cell lines, we have included compounds that show activity in the brine shrimp assay or which inhibit development of fertilized sea urchin or starfish eggs, simple assays which correlate to some extent with cytotoxicity. A considerable literature has developed regarding some of the most promising marine antitumor agents, such as didemnin B, the bryostatins, and the dolastatins. Information on some of the pharmacologic and mechanistic studies of these compounds has been included. The chapter is organized according to structural type, although in some cases a given compound could be assigned equally well to different categories.

Inhibition of protein phosphatases-1 and -2A with acanthifolicin: Comparison with diarrhetic shellfish toxins and identification of a region on okadaic acid important for phosphatase inhibition

Acanthifolicin (9,10‐epithio‐okadaic acid from Pandoras acanthifolium) inhibited protein phosphatase‐1 (PP1) similarly to okadaic acid (IC50 = 20 nM and 19 nM, respectively) but was slightly less active against protein phosphatase‐2A (PP2A) (IC50 1 nM and 0.2 nM, respectively). Methyl esterification of acanthifolicin sharply reduced its activity. PP2A was inhibited with an IC50 = 5.0 μM, whilst PP1 was inhibited < 10% at 250 μM toxin. Okadaic acid methyl ester was similarly inactive whereas dinophysistoxin‐1 (35‐methyl okadaic acid) inhibited PP1/2A almost as potently as okadaic acid. Pure acanthifolicin/okadaic acid methyl ester may be useful as specific inhibitors of PP2A at 1–10 μM concentrations in vitro and perhaps in vivo. The data also indicate that a region on these toxins important for PP1/2A inhibition comprises the single carboxyl group.

Marine natural products: fistularin-1, -2 and -3 from the sponge Aplysina fistularis forma fulva

Three new high molecular weight bromotyrosine-related metabolites, 3a, 4a and 5a, were isolated from the sponge Aplysina ( Verongia) fistularis forma fulva, and their structures were determined from high resolution 1H NMR and other spectroscopic data. The new metabolites are formally derived by combination of major segments of two known Aplysina metabolites 1a and 2.

Marine natural products. Xenicin: a diterpenoid possessing a nine-membered ring from the soft coral, Xenia elongata.

Der neue Naturstoff (I) fand sich erstaunlicherweise nur in Bestanden, die vor Heron Island (Australien) gesammelt wurden, nicht dagegen inExemplaren von der Picnic Bay, Magnetic Island (Australien) oder von den Fidschiinseln.

Structures and cytotoxicities of fascaplysin and related alkaloids from two marine phyla—Fascaplysinopsis sponges and Didemnum tunicates

The structural variations and bioactivity properties of the alkaloids in the fascaplysin (1) and the reticulatine (3) families were examined. Four organisms were analyzed consisting of two collections of the sponge Fascaplysinopsis reticulata and two collections of the tunicate Didemnum sp. Reported are the isolation of three new compounds: 3-bromofascaplysin (2), 14-bromoreticulatine (4), and 14-bromoreticulatate (6) along with reticulatate (5) previously known as a semi-synthetic product of 1. Compounds 1 and 5 showed selectivity in a cell based cytotoxicity assay.

1,2,3,4-TETRAHYDRO-8-HYDROXYMANZAMINES, ALKALOIDS FROM TWO DIFFERENT HAPLOSCLERID SPONGES

Abstract The isolation and characterization of two new sponge alkaloids, 1,2,3,4-tetrahydro-2-N-methyl-8-hydroxymanzamine A (2) and 1,2,3,4-tetrahydro-8-hydroxymanzamine A (3), is described. These compounds were obtained from Papua New Guinea sponges of the genera Petrosia and Cribochalina, which are in different families of the order Haplosclerida. These new manzamines are close in structure to 8-hydroxymanzamine (4) recently reported from Pachypellina, a Haplosclerid sponge belonging to a different family than that of the two preceding sponges. The cytotoxicity of 2 is described and the biogenetic relationship of 2 or 3 to manzamine A (1) and to nine other related polycyclic diamine and one monoamine type alkaloids is described.

Chemistry of 2-bromoleptoclinidinone, structure revision

Abstract The structure of 2-bromoleptoclinidinone has been revised on the basis of selective long-range 1 H/ 13 C polarization transfer experiments and chemical correlation with ascididemin. Both alkaloids have the same pentacyclic aromatic skeleton.

The search for inosine 5′-Phosphate dehydrogenase (IMPDH) inhibitors from marine sponges. Evaluation of the bastadin alkaloids

Abstract Six known bastadins, compounds 1 – 6 , and one new one, bastadin 18 ( 8 ), have been isolated from the marine sponge Ianthella Basta collected in Papua New Guinea. A mixture of 2 and 3 was also isolated from I. flabelliformis . Two of these compounds, bastadins 8 ( 5 ) and 10 ( 6 ), were found to be moderate inhibitors of IMPDH. A discussion of the enzyme assay is included.