Antibiotics from Marine Bacteria.

This review discusses main directions and results of the studies on antibiotics produced by bacteria living in the marine environment. In recent years many obligate marine species and strains were studied, diverse metabolites were isolated, and their chemical structures were elucidated. Among them here were natural compounds toxic against tumor cells, pathogenic bacteria, viruses, and malaria plasmodial species; these compounds often had no analogues among the natural products of terrestrial origin. Some isolated compounds form a basis of active ingredients in medicinal preparations used in clinic practice, while others are under different stages of preclinical or clinical studies. Much attention has been paid in recent years to producers of marine-derived antibiotics isolated from the deep-sea habitats, from the surface of marine invertebrates and algae, as well as from symbiotic microorganisms.

Pibocin B, the first N-O-methylindole marine alkaloid, a metabolite from the Far-Eastern ascidian Eudistoma species.

Pibocin B (2), the first representative of marine alkaloids with a unique structural feature, an N-O-methylindole group, was isolated from the Far-Eastern ascidian Eudistoma sp. Its structure has been established as (8 beta)-2-bromo-N-O-methyl-6,8-dimethylergoline on the basis of NMR data, FAB and MALDI-TOF MS, and chemical correlations. Pibocin B showed moderate cytotoxic activity against mouse Ehrlich carcinoma cells.

Two new diterpenoids, sarcophytins B and C, from the Indian Ocean soft coral Sarcophyton species.

Two new diterpenoids, sarcophytins B and C (1, 2), and the previously known sarcophytin (4) have been isolated from the Indian Ocean soft coral Sarcophyton sp. Structures of 1 and 2 were established by spectral data and supported by X-ray analysis of 1.

New polar steroids from the sponges Trachyopsis halichondroides and Cymbastela coralliophila.

Fractions of trisulfated trihydroxysteroids from the sponges Trachyopsis halichondroides (two different collections) and Cymbastela coralliophila have been isolated and investigated. Ten triacetates were obtained from these fractions by desulfatation/acetylation followed by chromatographic separation, and their structures have been established. Four of these derivatives--namely, triacetates of 5 alpha-pregnane-2 beta,3 alpha,6 alpha-triol (3c), 23,24-dinor-5 alpha-cholane-2 beta,3 alpha,6 alpha-triol (4c), 5 alpha-cholest-22-ene-2 beta,3 alpha,6 alpha-triol (7c), and 24-isopropyl-5 alpha-cholestane-2 beta,3 alpha,6 alpha-triol (11c)-- are described as new derivatives of natural steroids.

Varacin and three new marine antimicrobial polysulfides from the far-eastern ascidian Polycitor sp.

Varacin [1] and three new antimicrobial marine polysulfides, varacins A-C [3-5], have been isolated from the Far Eastern ascidian Polycitor sp. Their structures have been elucidated by spectroscopic methods and by chemical transformations.

Structure of cucumarioside G2, a novel nonholostane glycoside from the sea cucumber Eupentacta fraudatrix.

The new triterpene glycoside cucumarioside G2 [1] has been isolated from the sea cucumber Eupentacta fraudatrix. Glycoside 1 is the first triterpene glycoside with the 23,24,25,26,27-pentanorlanostane type of aglycone. Its structure has been established by chemical transformations as well as 13C- and 1H-nmr, eims, and liquid sims studies.

Biosynthetic studies of marine lipids. 42. Biosynthesis of steroid and triterpenoid metabolites in the sea cucumber Eupentacta fraudatrix.

The saponins, conjugated sterols, and free sterols of the sea cucumber Eupentacta fraudatrix were examined. A total of 85 steroids, twelve of them new, were identified in the free sterol, sulfated sterol, and sterol-xyloside fractions. The free sterol fraction contained 4 alpha,14 alpha-dimethylcholest-9(11)-en-3 beta-ol(6) and 14 alpha-methylcholest-9(11)-en-3 beta-ol(7) together with 18 minor sterols. Examination of the aglycone moieties of the sterol-beta-xyloside fraction afforded 31 different sterols. Cholestan-3 beta-ol (15) and 24-methylcholesta-7,22-dien-3 beta-ol (20) were the major sterols in this group. Cholestanol sulfate (74) and cholesterol sulfate (64) were identified as the major components among the 34 different sterol sulfates present. Finally, cucumariosides G1 (1), C1 (2), C2 (3), H (4), and G2 (5) were isolated from the saponin fraction. Radiolabeling experiments indicated that there are two pathways of sterol biosynthesis in E. fraudratix. The first involves transformation of squalene to produce lanosta-9(11),24-dien-3 beta-ol(parkeol) which is subsequently demethylated to form 4 alpha,14 alpha-dimethylcholest-9(11)-en-3 beta-ol (6) and 14 alpha-methylcholest-9(11)-en-3 beta-ol (7). The second proceeds through squalene to lanosterol which is further metabolized to produce the triterpene saponins, 5 alpha-cholest-7-en-3 beta-ol (19) and its xyloside (49).

Sarcochromenol sulfates A-C and sarcohydroquinone sulfates A-C, new natural products from the sponge Sarcotragus spinulosus.

New Na+,K(+)-ATPase inhibitors, sarcochromenol sulfates A [1], B [2], and C [3] and sarcohydroquinone sulfates A [4], B [5], and C [6], have been isolated from the sponge Sarcotragus spinulosus. Four of them (1, 4-6) and all six corresponding acetates 1a-6a have been isolated, and their structures have been established by spectral methods and chemical transformations.

Inhibitory characteristics of 3,5-dibromo-1-acetoxy-4-oxo-2,5-cyclohexadien-1-acetonitrile, a semisynthetic derivative of aeroplysinin-1 from sponges (Aplysinidae), on Na+ - K+-ATPase.

3,5-Dibromo-1-acetoxy-4-oxo-2,5-cyclohexadien-1-acetonitrile (dienone A) inhibited Na+ - K+-ATPase with a half-maximal inhibition concentration (I50) equal to 2.9 X 10(-6)M. Inhibition was time- and pH-dependent and complete after 20-30 min preincubation within a range of pH from 7.0 to 9.0. Kinetic evaluation of the cationic substrate activation of Na+ - K+-ATPase indicated mixed type inhibition with regard to Na+ and K+ and competitive inhibition with regard to ATP activation of the enzyme. The presence of Mg2+ caused an increased inhibition. Also, K+-p-nitrophenyl phosphatase activity was altered by dienone A and mixed type inhibition with regard to p-nitrophenyl phosphate and K+ was demonstrated. Inhibition was partially restored by repeated washing. Preincubation with sulfhydryl reagents protected the enzyme from inhibition. A significant linear correlation between reactive enzyme sulfhydryl contents [SH] and Na+ - K+-ATPase activity in the presence of varying concentrations of dienone A was observed. One of the factors causing cytotoxic activity of this compound might be its interaction with some thiol groups of the membrane-bound Na+ - K+-ATPase.

Steroids in Porifera. II. Steroid derivatives from two sponges of the family Halichondriidae. Sokotrasterol sulfate, a marine steroid with a new pattern of side chain alkylation.

A trisulfated derivative of 24,25,26,26-tetramethyl-5 alpha-cholest-23E-ene-2 alpha, 3 beta, 6 alpha-triol (sokotrasterol sulfate) has been isolated from the sponge Halichondriidae gen. sp., collected near Sokotra Island (Arabian Sea), and its structure has been elucidated. The side chain of the new steroid involves a "normal" alkylation at C-24 and the unprecedented addition of two extra methyl groups at C-26 and one extra methyl group at C-25. A free sterol fraction contained only 24-isopropyl-5-cholesten-3 beta-ol and 24-isopropyl-5, 22E-cholestadien-3 beta-ol. 24-Isopropyl-5, 22E-cholestadien-3 beta-ol as sole monohydroxy sterol and halistanol sulfate as major polyhydroxylated steroid derivative have been detected in Halichondria sp., a Madagascar sponge.

Inhibiting effect of cytotoxic bromine-containing compounds from sponges (Aplysinidae) on Na+ -K+-ATPase activity.

The bromine-containing compounds from sponges of the Aplysinidae family inhibit, in vitro, the Na+ -K+ -ATPase activity of the rat brain microsomal fraction. The extent of inhibition is dependent on concentration and chemical structure of the compounds. The substances containing the dienone fragment, such as 3,5-dibromo-1-hydroxy-4-oxo-2,5-cyclohexadien-1-acetamide (IV), 3,5-dibromo-1-acetoxy-4-oxo-2,5-cyclohexadien-1-acetonitrile (V) and 3,5-dibromo-1-hydroxy-4-oxo-2,5-cyclohexadien-1-ethylacetate (VI), are powerful inhibitors of Na+ -K+ -ATPase.