xiv Contents 8.Miscellaneous Compounds 224 8.I Phidolopin 224 9.Concluding Remarks 228 References 228 9.Bioactive Marine Alkaloids 235 Intro 235 237 3.Pyrroloacridine and Related Alkaloids 247 4.Indole Alkaloids 255 5.Pyrrole Alkaloids 258 6.Is 260 aneo s Alkaloids 6 Concluding R marks 269 References 269 10.Bioactive Marine Peptides 278 1.Introduction 278 ation 279 rine ans 39g29 4.Cone Snail Venoms 299 5.Sea Urchins 300 6.Marine Worms 302 7.Marine Vertebrates 302 8.Mari e Peptides d Related Compounds in Clinical Trials 302 8.1 n10 8.3 Cematodin 30 85 lidin 9.Miscellenous Peptides 308 10.Concluding Remarks 316 References 317
xiv Contents 8. Miscellaneous Compounds 224 8.1 Phidolopin 224 9. Concluding Remarks 228 References 228 9. Bioactive Marine Alkaloids 235 1. Introduction 235 2. Pyridoacridine Alkaloids 235 2.1 Occurrence and chemical properties 236 2.2 Assignment of structure 237 2.3 Structural subtypes 237 3. Pyrroloacridine and Related Alkaloids 247 4. Indole Alkaloids 255 5. Pyrrole Alkaloids 258 6. Isoquinoline Alkaloids 260 7. Miscellaneous Alkaloids 260 8. Concluding Remarks 269 References 269 10. Bioactive Marine Peptides 278 1. Introduction 278 2. Peptides Conformation 279 3. Bioactive Marine Peptides 280 3.1 Marine algae 280 3.2 Sponges 283 3.3 Tunicates 292 3.4 Ascidians 293 3.5 Coelenterates 297 3.6 Molluscs 298 4. Cone Snail Venoms 299 5. Sea Urchins 300 6. Marine Worms 302 7. Marine Vertebrates 302 8. Marine Peptides and Related Compounds in Clinical Trials 302 8.1 Dolastatin 10 303 8.2 Soblidotin 303 8.3 Cematodin 304 8.4 Synthadotin 304 8.5 Applidine 305 8.6 Kahalalide F 305 8.7 Hemiasterlin 307 9. Miscellenous Peptides 308 10. Concluding Remarks 316 References 317
Contents xv 11.Marine Prostaglandins 329 1.Introduction 329 2.Marine Organisms 335 3.Mammalian-Type Prostaglandins in Marine Organisms 347 4.Biosynthesis 349 5.Concluding Remarks 351 References 351 AUTHOR INDEX 355 SUBJECT INDEX 365
Contents xv 11. Marine Prostaglandins 329 1. Introduction 329 2. Marine Organisms 335 2.1 Plexaura homomalla 335 2.2 Clavularia viridis QUOY and GAIMARA 338 2.3 Labophyton depressum 343 2.4 Telesto riisei 343 2.5 Gracilaria lichenoides 346 3. Mammalian-Type Prostaglandins in Marine Organisms 347 4. Biosynthesis 349 5. Concluding Remarks 351 References 351 AUTHOR INDEX 355 SUBJECT INDEX 365
1 Bioactive Metabolites of Marine Algae,Fungi and Bacteria Abstract The chapter deals with the bioactive metabolites of marine algae,bacteria and fungi.The chemistry and biological activities of the bioactive brominated compounds. 1.Introduction About 30,000 species of algae are found the world over which occur at all heeight and moisture and ar found in abundance in o the bio are a sc rce of food for fishes,cattl and man.Algae are also used as medicine and fertilizers.A few algae that excrete toxic substances pollute marine water. A majority of red algae and almost all the genera of brown algae except Bodanella,Pleurocladia and Heribaudiella occur in salt water.Many macroscopic green algae like Codium.Caulerpa.Ulva and Enteromorph grow in shallow waters.The species of some genera.for example Prasiol Enteromorpha and Cladophora grow both in fresh water and sea water.In sea water,many algae grow as phytoplankton(especially the dinoflagellates and certain blue-green algae).Other marine algae grow as benthos,epiphyte on other algae,parts of higher plants,rocks,stones,gravels,sand and mud. A small group of algae occurs in brackish water
1 Bioactive Metabolites of Marine Algae, Fungi and Bacteria Abstract The chapter deals with the bioactive metabolites of marine algae, bacteria and fungi. The chemistry and biological activities of the bioactive brominated compounds, nitrogen heterocyclics, nitrogen-sulphur heterocyclics, sterols, terpenoids and sulfated polysaccharides isolated from marine algae, fungi and bacteria have been reviewed. 1. Introduction About 30,000 species of algae are found the world over which occur at all places where there is light and moisture and are found in abundance in sea. They supply oxygen to the biosphere, are a source of food for fishes, cattle and man. Algae are also used as medicine and fertilizers. A few algae that excrete toxic substances pollute marine water. A majority of red algae and almost all the genera of brown algae except Bodanella, Pleurocladia and Heribaudiella occur in salt water. Many macroscopic green algae like Codium, Caulerpa, Ulva and Enteromorpha grow in shallow waters. The species of some genera, for example Prasiola, Enteromorpha and Cladophora grow both in fresh water and sea water. In sea water, many algae grow as phytoplankton (especially the dinoflagellates and certain blue-green algae). Other marine algae grow as benthos, epiphyte on other algae, parts of higher plants, rocks, stones, gravels, sand and mud. A small group of algae occurs in brackish water
2 Bioactive Marine Natural Products 2.Secondary Metabolites of Marine Algae Extensive work has been done on the secondary metabolites of marine algae. The work carried out on Laurencia species,2 blue-green algae and dinoflagellates have been reviewed.Reports are available dealing with amino acids from marine algae,'guanidine derivatives,phenolic substances, mneei 3.Bioactive Metabolites Chemically the bioactive metabolites of marine flora include brominated phenols,oxygen heterocyclics,nitrogen heterocyclics,sulphur nitrogen heterocyclics. sterols te enoids polysaccharides,peptidesand The che prote chemitry and biological activiies of the compounds isoted have been 3.1 Brominated Phenols The green.brown and red algae had been extensively analyzed for antibacterial dctivities The active prinipessm gracilis Rhodomela lari and Polysiphon alcohol, 4.5-disulphate dipotassium s salt (1),2.3-dibromc dihydroxybenzaldehyde(2).2,3-dibromo-4.5-dihydroxybenzyl alcohol(3) 3,5-dibromo-p-hydroxybenzyl alcohol (4)and the 5-bromo-3,4- dihydroxybenzaldehyde(5).Virtually nothing is known about the physiological he mechanism of bioynthesis of the bromo phenols.Their y suggests that they may play a role in the regulation epiphytes and endophytes.The bromo phenols may be biosynthesised through the shikimate pathway,and bromination may occur in the presence of suitable peroxide
2 Bioactive Marine Natural Products 2. Secondary Metabolites of Marine Algae Extensive work has been done on the secondary metabolites of marine algae.1 The work carried out on Laurencia species,2 blue-green algae3 and dinoflagellates4 have been reviewed. Reports are available dealing with amino acids from marine algae,5 guanidine derivatives,6 phenolic substances,7 bioluminescence,8 carotenoids,9 diterpenoids,10 biosynthesis of metabolites,11 indoles,12 bioactive polymers13 and halogenated compounds.14,15 3. Bioactive Metabolites Chemically the bioactive metabolites of marine flora include brominated phenols, oxygen heterocyclics, nitrogen heterocyclics, sulphur nitrogen heterocyclics, sterols, terpenoids, polysaccharides, peptides and proteins. The chemistry and biological activities of the compounds isolated have been reviewed.16 3.1 Brominated Phenols The green, brown and red algae had been extensively analyzed for antibacterial and antifungal activities. The active principles isolated from Symphyocladia gracilis, Rhodomela larix and Polysiphonia lanosa were: 2,3-dibromobenzyl alcohol, 4,5-disulphate dipotassium salt (1), 2,3-dibromo-4,5- dihydroxybenzaldehyde (2), 2,3-dibromo-4,5-dihydroxybenzyl alcohol (3), 3,5-dibromo-p-hydroxybenzyl alcohol (4) and the 5-bromo-3,4- dihydroxybenzaldehyde (5). Virtually nothing is known about the physiological importance and the mechanism of biosynthesis of the bromo phenols. Their antialgal activity suggests that they may play a role in the regulation of epiphytes and endophytes. The bromo phenols may be biosynthesised through the shikimate pathway, and bromination may occur in the presence of suitable peroxide.17 1 2, R = CHO 3, R = CH2OH 4 5 HO
Bioactive Metabolites of Marine Algae,Fungi and Bacteria 3 3.2 Brominated Oxygen Heterocyclics brominated oxygen heterocyclic compounds,laurencin (6)22 and laureatin (7)23,respectively.Laurencin (CI7H2 BrO),m.p.73-74C:[alp +70.2 (CHCIa)was isolated from the neutral fraction from methanol extract of the algae.The IR of the e pur of a term methine (Vma an ether (1168 and 1080 cm)functions and trans and cis double bonds (3040,950 and 750 cm-).The UV (in EtOH),mx 224 nm 16,400)and 232 nm (e 11,000)showed the presence of a conjugated diene or enyne.The NMR spe ctrum of the nd indicated the pres en of four pro ons an acetoxyl a cthylgroup The presence of ethy group wa confirmed by isolation of CH-CH2-CHO on ozonization of laurencin. Laurencin consumed four moles of hydrogen over platinum in ethyl acetate toyield octahydrolaurencin (C).On mild hydrolysis with KOH laurencin gave deacetyl la rencin (CisH2 BrO2)which was reconverted int original ester in good yield by treatment with acetic anhydride/pyridine Reduction of octahydrolaurencin with LiAlH,afforded a debromoalcohol (CIsH30O2).Extensive NMR studies and spin decoupling experiments of the parent compound and the degradation products established structure(6)for Laureatin()m.p.82-83C:[(CCl)has been isolated from the Japanese seaweed.UV absorption x223 nm(e12,800),229 nm (e10,400)and IR peaks at Vmax3300,2100,1140,1045,975and965cm indicated that laureatin is an ether having a conjugated enyne group and contains neither hydroxyl nor carbonyl functions.NMR and spin decoupling experiments confirmed the presence of-CH2- CH=CH-C-CH and-CH-CH2-CH3 groups.NMR spectrum of the compound also contained peaks for 6 protons att 5.0,6.5;three one-proton septets att5.12 and 5.87,a broad quartet at 5.62 and two multiplets tered at 6.2 and 6.35. These absorptions were ascribed to protonson carbons bearing an ethe oxygen or a bromine atom.Laureatin consumed three moles of hydrogen over platinum catalyst in ethanol to yield hexahydrolaureatin.On treatment with zinc in refluxing acetic acid and then with dilute alkali hexahydrolaureatin
Bioactive Metabolites of Marine Algae, Fungi and Bacteria 3 3.2 Brominated Oxygen Heterocyclics The red algae Laurencia sp. have produced the diverse class of natural products.18–22 L. glandulifera19 and L. nipponica23 had furnished two brominated oxygen heterocyclic compounds, laurencin (6) 22 and laureatin (7) 23, respectively. Laurencin (C17H23BrO3), m.p. 73–74°C; [α]D + 70.2° (CHCl3) was isolated from the neutral fraction from methanol extract of the algae. The IR of the purified compound suggested the presence of a terminal methine (νmax 3285 and 2180 cm–1), an acetoxyl (1735 and 1235 cm–1) and an ether (1168 and 1080 cm–1) functions and trans and cis double bonds (3040, 950 and 750 cm–1). The UV (in EtOH), λmax 224 nm (ε 16,400) and 232 nm (ε 11,000) showed the presence of a conjugated diene or enyne. The NMR spectrum of the compound indicated the presence of four olefinic protons and an acetoxyl and ethyl groups. The presence of ethyl group was confirmed by isolation of CH3—CH2—CHO on ozonization of laurencin. Laurencin consumed four moles of hydrogen over platinum in ethyl acetate to yield octahydrolaurencin (C17H31BrO3). On mild hydrolysis with KOH laurencin gave deacetyl laurencin (C15H21BrO2) which was reconverted into original ester in good yield by treatment with acetic anhydride/pyridine. Reduction of octahydrolaurencin with LiAlH4 afforded a debromoalcohol (C15H30O2). Extensive NMR studies and spin decoupling experiments of the parent compound and the degradation products established structure (6) for laurencin. Laureatin (C15H20Br2O2) m.p. 82-83°C; [α]D+ 96° (CCl4) has been isolated from the Japanese seaweed.18 UV absorption λmax 223 nm (ε12,800), 229 nm (ε10,400) and IR peaks at νmax 3300, 2100, 1140, 1045, 975 and 965 cm–1 indicated that laureatin is an ether having a conjugated enyne group and contains neither hydroxyl nor carbonyl functions. NMR and spin decoupling experiments confirmed the presence of —CH2—CH=CH—C≡CH and —C | H—CH —CH 2 3 groups. NMR spectrum of the compound also contained peaks for 6 protons at τ 5.0, 6.5; three one-proton septets at τ 5.12 and 5.87, a broad quartet at 5.62 and two multiplets centered at 6.2 and 6.35. These absorptions were ascribed to protons on carbons bearing an ether oxygen or a bromine atom. Laureatin consumed three moles of hydrogen over platinum catalyst in ethanol to yield hexahydrolaureatin. On treatment with zinc in refluxing acetic acid and then with dilute alkali hexahydrolaureatin 6 7 4 5 6 9 1 2 3 4 6 7