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212 Vassilios Roussis et al. Cytotoxic metabolites from chlorophyta OH CH 2 OH CH 2 OH CH 2 OMe Br OH Br OH C-1 OHBr OH OH OH Br Br OH Br OH C-2 HO Br Br OH OH Br OH Br OH HO C-3 H H H H H H H H O H Val-2 D-alloIleu-1 D-alloIleu-2 Thr-1 L-Orn D-Pro Val-3 N N N N O N O O O N H 2 N N O O O N N O N O O N O HO N O N Val-4 Thr-2 Val-5 L-Phe H O O Val-1 Z-Dhb H H C-4 OAc AcO OAc C-5 OAc CHO H A H B OAc C-6 HO C-7 OAc AcO OAc O C-8 HO R 2 R 1 R 1 R 2 H H O O OOH H OH H C-9 C-10 C-11 C-12 OH O C-13 HO OOH C-14 OBr HO H Br C-15 cytotoxic, indicating that oxidation increases the activity. Four additional oxygenated desmosterols (R-8 to R-11) were isolated from the same organism and exhibited significant cytotoxicity against P-388, KB, A-549 and HT-29 cancer cell lines, with ED 50 values within the range of 0.11–2.37 gmL Ϫ1 . From the red algae Gigartina tenella a sulfolipid (R-12) that belongs to the class of sulfoquinovosyldiacyl glycerol was isolated. The compound potently inhibited the activities of mammalian DNA polymerase ␣ and  and terminal deoxynucleotidyl transferase (TdT), and enhanced the cytotoxicity of bleomycin. Complete inhibition doses of each were achieved at 1.0–2.0 M for polymerase ␣ and TdT and 7.5M for polymerase . Three new Malyngamides: Malyngamide M (R-13), Malyngamide N (R-14) and Malyngamide I acetate (R-15) were isolated from the Hawaiian red alga Gracilaria coronopifolia. Malyngamide N and Malyngamide I acetate showed moderate cytotoxicity to mouse neuroblas- toma (NB) cells in the tissue culture. The IC 50 values of R-14 and R-15 were 12 M (4.9 gmL Ϫ1 ) and 12 M (7.1gmL Ϫ1 ), respectively. In contrast Malyngamide M showed rather weak cytotoxicity to NB cells (IC 50 Ͼ20M). Malyngamides are known as metabolites of blue green algae, in particular Lyngbya majuscula. Furthermore it has been reported that epi- phytes such as blue green algae grow on Gracilaria. Therefore the true origin of R-13 to R-15 is likely a blue green alga that grows on Gracilaria coronopifolia. A cytotoxic oxysterol, 16-hydroxy-5a-cholestane-3,6-dione (R-16) was isolated from the red alga Jania rubens and was found to be significantly cytotoxic towards the KB tumor cell line with an ID 50 value 0.5 gmL Ϫ1 . Cytotoxic metabolites from marine algae 213 OBr HO H Br C-16 H CHO CHO CHO H C-17 Br HO H C-18 OH Br C-19 B OH r C-20 H H O C-21 HOH H H OSO 3 Na OSO 3 Na OSO 3 Na NaO 3 SO NaO 3 SO NaO 3 SO C-22 O H H H C-23 Callicladol (R-17), a brominated metabolite has been isolated from the red alga Laurencia calliclada. This compound displayed cytotoxic activity in vitro against P-388 murine leukemia cell with IC 50 value 1.75 gmL Ϫ1 . Six chamigrane derivatives (R-18 to R-23) isolated from Laurencia cartilaginea, were screened for toxicity. All metabolites have shown remarkable results against various cancer cell lines at low concentrations, especially to HT-29. The IC 50 values for the compounds R-18 to R-23 were 1.0, 1.0, 1.0, 1.0, 5.0 and 5.0gmL Ϫ1 for the P-388 cell line, 0.1, 1.0, 1.0, 1.0, 5.0 and 1.0gmL Ϫ1 for the A-549 cell line, 0.1, 0.025, 0.025, 0.25, 0.5 and 0.25gmL Ϫ1 for the HT-29 cell line and 0.1, 1.0, 1.0, 1.0, 10.0 and 1.0gmL Ϫ1 for the MEL-28 cell line, respectively. Majapolene A (R-24), a dioxabicyclo[2.2.2]-alkene, was isolated from the red alga Laurencia majuscula. It displayed modest mean response parameter values for all NCI 60-cell lines of 0.4 M for GI 50 (50% net growth inhibition, relative to controls), 0.9 M for TGI (net total growth inhibition) and 2.8 M for LC 50 (50% net cell death). Thyrsiferyl 23-acetate (R-25) has been isolated from the red alga Laurencia obtusa, which showed strong cytotoxicity against mammalian cells. Actually, TF23A is a specific inhibitor of protein phosphatase 2A (PP2A) activity. Red seaweeds of genus Laurencia is known to produce interesting active polyether squalene-derived metabolites, which possess strong cytotoxic properties. Mechanisms of growth inhibition by the novel marine compound Dehydrothyrsiferol (DHT) (R-26), iso- lated from the red alga Laurencia viridis and Laurencia pinnatifida, were investigated in a sen- sitive and an MDR ϩ human epidermoid cancer cell line. DHT was found to circumvent multidrug resistance mediated by P-glycoprotein. Cell cycle analysis revealed an accumula- tion in S-phase. Growth inhibition in KB cancer cells is not mediated by apoptosis but by growth retardation. The IC 50 values of DHT in all investigated cell lines were, although in the M range, found to be higher than the ones determined for the clinically established chemotherapeutic compound Doxorubicin and the cytotoxic compound Colchicine. The IC 50 values determined in tumor cell lines derived from different primary tissues support the notion that the cytotoxicity mediated by DHT may be more tissue related than correlated to a single mechanism of growth inhibition throughout the various cancer systems. Screening for cytotoxicity was performed on compounds R-26 to R-36 with a battery of cultured tumor cell lines: P-388, suspension culture of a lymphoid neoplasm from a DBA/2 mouse; A-549, monolayer culture of a human lung carcinoma; HT-29, monolayer culture of a human colon carcinoma; MEL-28, monolayer culture of a human melanoma. This assay proved them to possess a potent and selective activity against P-388 cells. Compounds Thyrsiferol (R-27), Dehydrothyrsiferol (R-26), Dehydrovenustatriol (R-28), Isodehydrothyrsiferol (R-31) and Thyrsenol B (R-36) had IC 50 ϭ0.01gmL Ϫ1 . This activity was significantly higher than that of 15–16-dehydrovenustatriol (R-29), Thyrsenol A (R-35), (IC 50 ϭ0.25gmL Ϫ1 ), 16-hydroxydehydrothyrsiferol (R-32), 10-epi-15–16-dehydrothyrsiferol (R-33), (IC 50 ϭ0.50gmL Ϫ1 ), 10-epidehydrothyrsiferol (R-34) (IC 50 ϭ1.00gmL Ϫ1 ) and predehydrovenustatriol acetate (R-30) (IC 50 ϭ1.20gmL Ϫ1 ), establishing that small chemical changes in the molecule greatly affect the cytotoxicity. Moreover compound R-31 showed selective activity against P-388 mouse lymphoid neoplasm. Martiriol (R-37) along with three other derivatives of dehydrothyrsiferols (R-38 to R-40) were isolated from Laurencia viridis and tested for their cytotoxicity against different cancer cell lines. The results showed that Martiriol (R-37) was inactive at concentrations lower than 10 gmL Ϫ1 and compounds R-38 to R-40 were inactive at concentrations lower than 1 gmL Ϫ1 . 214 Vassilios Roussis et al. From the tropical marine red alga Plocamium hamatum two polyhalogenated monoterpenes (R-41, R-42) were isolated. Compound R-41 was moderately cytotoxic (IC 50 : Lu1 12.9gmL Ϫ1 , KB 13.3 gmL Ϫ1 , ZR-75–1 7.8 gmL Ϫ1 ) as was compound R-42 (IC 50 : KB-V (-VBL) 5.3 gmL Ϫ1 , KB 12.4 gmL Ϫ1 , LNCaP 14.8 gmL Ϫ1 ). An array of similar halogenated monoterpenes has been isolated by other researchers from Plocamium sp. According to Mynderse and Faulker (1978) the observed chemical variability is not caused from extraction decompositions but is depended on the algae geographic location. The polyhalogenated acyclic monoterpene Halomon, (R-43) was obtained as a major component of the organic extract of the red algae Portieria hornemannii. It exhibited highly dif- ferential cytotoxicity against the NCI’s new in vitro human tumor cell line screening panel; brain tumor, renal, and colon tumor cell lines were most sensitive, while leukemia and melanoma cell lines were relatively less sensitive. On the basis of its unprecedented cytotoxicity profile on the NCI primary screen this compound has been selected by the NCI Decision Network Committee for preclinical drug development. Pharmacological studies of Halomon have been conducted concerning the in vitro metabolism, pharmacokinetics, bioavailability and tissue distribution in mice. A second collection of Portieria hornemannii yielded a monocyclic 3-halogenated monoterpene (1-[3-(1-chloro-2(E)-propenyl)]-2,4-dichloro-3,3-dimethylcyclohex-5-ene, R-44), which proved to be one order of magnitude less potent than R-43 and devoid of differential activity. Isohalomon R-45, an isomer of Halomon, R-43, with a diatropic rearrangement of the halo- gens at C-6 and C-7, dehydrobromo derivative of isohalomon R-46, dehydrochloro derivative of Halomon R-47 and the monocyclic halogenated monoterpene R-48 uniformly exhibited the unique differential cytotoxicity profile reported earlier for Halomon against the NCI panel of 60 human tumor cell lines, with comparable panel-averaged potency. The monocyclic halogenated monoterpene R-48 was more comparable in overall (panel-averaged) potency to Halomon, however, there was little differential response of the cell lines, and consequently no significant correlation to the profile of the Halomon R-43. Mean panel response (Valuesϫ10 Ϫ6 M): R-43 GI 50 ϭ0.676, LC 50 ϭ11.5; R-44 GI 50 ϭ20.0, LC 50 Ͼ100; R-45 GI 50 ϭ1.32, LC 50 ϭ16.2; R-46 GI 50 ϭ0.741, LC 50 ϭ17.0; R-47 GI 50 ϭ0.691, LC 50 ϭ13.5; R-48 GI 50 ϭ1.15, LC 50 ϭ20.0. A structure/activity relationship study with compounds R-43, and R-45 to R-48 exhibited a similar cytotoxicity profile, displaying higher activity than R-49 to R-53. These results suggest that halogen on C-6 is essential for this characteristic activity profile. Three agglutinins have been isolated from the aqueous ethanolic extract of the marine red alga Solieria robusta. These proteins, designated solnins A, B and C, were monomeric glycopro- teins with a similar MW and they share predominant amino acids as Gly, Asx and Glx. Solnins showed mitogenic activity for mouse splenic lymphocytes, while they inhibited the growth in vitro of mouse leukemia cells L-1210 and mouse FM3A tumor cells. Four sulfated triterpenoids R-54 to R-57 were isolated from brine shrimp-toxic fractions of the methanolic extract of the red alga Tricleocarpa fragilis. Compounds R-54 and R-55 were the most active, showing 55.7 Ϯ8.7% and 47.1 Ϯ15.1% immobilization of brine shrimp respec- tively, at 17 gmL Ϫ1 . Compounds R-56 and R-57 showed 39.1 Ϯ11.0% and 35.5 Ϯ12.8% immobilization respectively, at 50 gmL Ϫ1 . Toxicity toward P-388, A-549, MEL-28 and HT- 29 cell lines was also evaluated. IC 50 values for R-54 and R-55 were Ͼ10gmL Ϫ1 and for R-56 and R-57Ͼ1 gmL Ϫ1 against all cell lines tested. Cytotoxic metabolites from marine algae 215 Table 4.6 Cytotoxic metabolites from rhodophyta Source Metabolite Code Literature Ceratodictyon spongiosum cis,cis-Ceratospongamide R-1 Tan et al., 2000a trans,trans-Ceratospongamide R-2 Galaxaura marginata Oxygenated desmosterols R-3 to R-7 Sheu et al., 1996 R-8 to R-11 Sheu et al., 1997a Gigartina tenella Sulfoquinovosyldiacyl glycerol R-12 Ohta et al., 1999 Gracilaria coronopifolia Malyngamide M R-13 Kan et al., 1998 Malyngamide N R-14 Malyngamide I acetate R-15 Jania rubens 16-Hydroxy-5a-cholestane-3,6-dione R-16 Ktari et al., 2000 Laurencia calliclada Callicladol R-17 Suzuki et al., 1995 Laurencia cartilaginea Chamigrane deriv. R-18 to R-21 Juagdan et al., 1997 Ma’ilione R-22 Allo-isoobtusol R-23 Laurencia majuscula Majapolene A R-24 Erickson et al., 1995 Laurencia obtusa Thyrsiferyl 23-acetate R-25 Matsuzawa et al., 1994 Laurencia viridis Dehydrothyrsiferol (DHT) R-26 Pec et al., 1998, 1999 Dehydrothyrsiferol (DHT) R-26 Fernández et al., 1998 Thyrsiferol R-27 Dehydrovenustatriol R-28 15–16 Dehydrovenustatriol R-29 Predehydrovenustatriol acetate R-30 Isodehydrothyrsiferol R-31 16-Hydroxydehydrothyrsiferol R-32 10-epi-15,16 Dehydrothyrsiferol R-33 10-epi-Dehydrothyrsiferol R-34 Thyrsenol A R-35 Norte et al., 1996, 1997 Thyrsenol B R-36 Martiriol R-37 Manriquez et al., 2001 Dehydrothyrsiferol derivatives R-38 to R-40 Plocamium hamatum Polyhalogenated monoterpenes R-41, R-42 Coll et al., 1988 Koenig et al., 1999 Portieria hornemannii 6(R)-Bromo-3(S)-(bromomethyl)-7- R-43 Fuller et al., 1992 methyl-2,3,7-trichloro-1-octene (Halomon) 1-[3-(1-chloro-2(E)-propenyl)]-2,4- R-44 dichloro-3,3-dimethylcyclohex-5-ene Portieria hornemannii Isohalomon R-45 Fuller et al., 1994 Dehydrobromo derivative of Egorin et al., 1996, 1997 Isohalomon R-46 Dehydrochloro derivative of Halomon R-47 Monocyclic halogenated monoterpene R-48 Acyclic halogenated monoterpene R-49 Acyclic halogenated monoterpene R-50 Acyclic halogenated monoterpene R-51 Acyclic halogenated monoterpene R-52 Monocyclic halogenated monoterpene R-53 Solieria robusta Isoagglutinins Hori et al., 1988 Solnins A-C Tricleocarpa fragilis Triterpenoid sulfates R-54 to R-57 Horgen et al., 2000 218 Vassilios Roussis et al. Cytotoxic metabolites from rhodophyta N O O N N O N S N O N N O O H H H Phe-2 Pro-1 Ile Phe-1 Pro-2 cis-cis trans-trans R-1 R-2 HO R OOH R= OOH OH OH R= R= R= R-3 R-4 R-5 R-6 O OH O R-7 OOH R= OOH O OH R R-8 R-9 OOH R= OOH R O O Me OCH 3 OCH 3 OCH 3 CH 3 CH 3 CH 3 R-10 R-11 O H OH OH O O H 2 C O C C C H H H H O O O S OO OH R-12 N Cl O HO OAc R-13 N Cl O Me O R-14 N Cl O Me O O O R-15 O O H OH H H R-16 O H H O O Br H OH O OH H O H R-17 Cl HO Br R-18 HO Br Br R-19 HO Br Br R-20 HO Br R-21 HO Br O R-22 Cytotoxic metabolites from marine algae 219 HO Br Cl Me Br R-23 HOH 2 C O O Br CH 3 CH 3 R-24 O O O HH Br H H OH OH O OAc H R-25 H H H OH H O O O Br O H OH R-26 O O O HOH O H OH Br HH H HO R-27 O O O H O H OH Br HH OH H R-28 OH HH Br O H OH O O H O R-29 HO O O H O H OH HH OAc R-30 O O O H Br H H OH O HH HO R-31 O O O H O H OH Br HH OH OH R-32 OH HH Br O H OH O O H O R-33 O O O H O H OH Br HH OH R-34 OH H H Br O H OH O O H HOCH 2 OH O R-35 O O O H HO CH 2 OH O H OH Br H H OH R-36 O O O O HO H H OH H OH H R-37 O O O OH OH H H O HO HH H R-38 O O O O OH Br OH H H H H H R-39 O O O Br H H H HO H OH OH H R-40 220 Vassilios Roussis et al. BrH 2 C Cl Cl Cl Br R-41 Cl Br CH 2 Cl BrH 2 C Br Cl R-42 Br Cl Br Cl Cl R-43 Cl Cl Cl R-44 Cl Br Br Cl Cl R-45 Cl Cl Br Cl R-46 Cl Br Cl Br R-47 Br Cl Cl Cl R-48 Cl Br Cl H R-49 Cl Br R-50 Br Br Cl Cl R-51 Br Cl R-52 Cl Br – O 3 SO – O 3 SO R 1 R 1 R 2 R 2 HOH R-53 CH 3 CH 3 H CH 2 OH COOCH 3 COOCH 3 R-54 R-55 R-56 O COOCH 3 R-57 4.4 Cytotoxic metabolites from phaeophyta From the brown algae Bifurcaria bifurcata five linear diterpenes (B-1 to B-5) and two terminally cyclized derivatives (B-6, B-7) were isolated and revealed potent cytotoxicity to fertilized sea urchin eggs. Bifurcanol (B-4) and bifurcane (B-6) were the most active from the compounds tested with an ED 50 4 and 12gmL Ϫ1 , respectively. Eleganediol (B-1), 12-(S)-hydroxygeranylgeraniol (B-2) and 12-(S)-hydroxy-geranylgeranic acid (B-3) exhibited an ED 50 36, 18 and 60gmL Ϫ1 , respec- tively, while the two compounds (B-5 and B-7) did not exhibit significant cytotoxic activity. The Et 2 O extract of Cystoseira mediterranea, containing meroterpenoids, possess antineoplastic activity attributable to Mediterraneol A, one of its major components. Mediterraneol A (B-8), Mediterraneone (B-9) and Cystoseirol (B-10) were tested by the crown-gall potato disc bioassay, as a high correlation between this test and the mouse P-388 leukemia protocol has been demon- strated. While Didemnin B, a potent antitumor cyclic depsipeptide, inhibited 100% the tumor growth (number of tumors per leaf disc), Mediterraneol A, Mediterraneone and Cystoseirol inhibited tumor growth by 88%, 76% and 73%, respectively. Four meroterpenes have been isolated from the brown alga Cystoseira usneoides, Usneoidone E (B- 11), Usneoidone Z (B-12), Usneoidol E (B-13) and Usneoidol Z (B-14). The antitumoral activity of compound B-11 and B-12 was tested against P-388, A-549, HeLa and B-16 cell lines with an IC 50 0.8, 1.25, 1.0 and 1.0gmL Ϫ1 and 1.5, 1.4, 1.3 and 1.5gmL Ϫ1 , respectively. The other two com- pounds were tested against P-388, L-1210 and A-549 cell lines and were also found to be cytotoxic. Bicyclic diterpenes, which possess a decalin skeleton, have been isolated from the brown algae Dictyota dichotoma and Pachydictyon coriaceum and their cytotoxicity was tested against murine B16 melanoma cells. It was found that Dictyotin A (B-15), Dictyotin B (B-16), Dictyotin C (B-17), Dictyotin B methyl ether (B-32) and Dictyotin D methyl ether (B-33) had IC 50 values 8, 3, 15, 10 and 19 gmL Ϫ1 , respectively. Xenicane and norxenicane diterpenes (B-18 to B-21) have been isolated from the brown alga Dictyota dichotoma and their cytotoxicity was tested against murine B16 melanoma cells. It was found that 4-acetoxydictyolactone (B-18), Dictyotalide A (B-19), Dictyotalide B (B-20) and nordictyotalide (B-21) had IC 50 values 1.57, 2.57, 0.58 and 1.58 gmL Ϫ1 , respectively. Four Dolabellane (B-22 – B-25) and one hydroazulenoid (B-26) diterpenes, isolated from Dictyota dichotoma, were tested against the following cancer cell lines: P-388 mouse lymphoma, A-549 Human Lung Carcinoma, HT-29 Human Colon Carcinoma and MEL-28 Human Melanoma. Compounds B-23 to B-26 were mildly active with ED 50 5gmL Ϫ1 in all cases, whereas B-22 exhibited the greatest activity with ED 50 equal to 1.2gmL Ϫ1 against P-388 and A-549 tumor cell lines and 2.5gmL Ϫ1 against HT-29 and MEL-28 tumor cell lines. Dolabellane B-27 was found to possess interesting bioactivities among them cytotoxicity against KB cancer cells. Metabolites Dilopholide (B-28), hydroxyacetyldictyolal (B-29), acetylcoriacenone (B-31), and isoacetylcoriacenone (B-30) were isolated from the brown alga Dilophus ligulatus. These metabolites displayed cytotoxic activity to several types of mammalian cells in culture (KB, P-388, P-388/DOX, and NSCLC-N6). Especially, Dilopholide (B-28) showed significant cyto- toxic activity (ED 50 Ͻ4gmL Ϫ1 ) against KB (human nasopharynx carcinoma), NSCLC-N6 (human lung carcinoma) cells, and P-388 (murine leukemia) cells. 24-Hydroperoxy-24 –vinyl cholesterol (B-34) was isolated from the dichloromethane extract of the brown alga Padina pavonica and was found to be cytotoxic toward the KB tumor cell line. The ID 50 was approximately 6.5 gmL Ϫ1 (14. 10 Ϫ3 M). Fucoidan (GIV-A) B-35, a hexouronic acid containing L-fucan sulfate was isolated from Sargassum thunbergii and showed antimetastatic effect when examined on an experimental model of lung metastases induced by LLC in mice. Cytotoxic metabolites from marine algae 221 [...]... ether 24-Hydroperoxy-24-vinyl-cholesterol Bifurcaria bifurcata Padina pavonica Pachydictyon coriaceum Dilophus ligulatus Dictyota dichotoma Cystoseira usneoides Cystoseira mediterranea Metabolite Source Table 4.7 Cytotoxic metabolites from phaeophyta B-1 B-2 B-3 B-4 B-5 B-6 B-7 B -8 B-9 B-10 B-11 B-12 B-13 B-14 B-15 B-16 B-17 B- 18 B-19 B-20 B-21 B-22 to B-25 B-26 B-27 B- 28 B-29 B-30 B-31 B-32 B-33 B-34... Schizothrix calcicola Oscillatoria nigroviridis Oscillatoria acutissima Microcystis aeruginosa NO-1 5-1 84 0 Nostoc sp ATCC 53 789 Source Table 4 .8 (Continued) Code M- 38 M-39 M-40 M-41 M-42 M-43 M-44 M-45 M-46 M-47 M- 48 M-49 M-50 M-51 M-52 M-53 M-54 M-55 M-56 M-57 M-22 M- 58 M-59 M-60 M-57 M-22 M-31 M-36 M-41 and M-42 Metabolite Malyngamide H Laxaphycin A Laxaphycin B Yanucamide A Yanucamide B Grenadadiene... (2R)-Phe O (2S)-Hse HN H N (2R)-Leu (3R )- -Ade HN (2S)-Thr NH O O M- 38 O H O (2S)-Thr Cl M-37 O HO (2S)-Pro OH N O O O Dhoya L-Hiv O O O L-Val N H O (2S)-Gln M-41 O N-Me-(2S, 3S)-Ile O (2R, 3R)-Asn(3-OH) β-Ala H N O Dhoya D-N-MePhe N O O O H M-42 O O O L-Hiv H O H O O H Br H O M-43 L-allo-Ile N H OH L-Tyr Ahp H2N OH O OMe O M-44 O HO O O NH OH O NH NH O O OH L-Gln D-p-OH-PLac L-Thr O NH N O O L-Leu... cells to cytotoxic drugs Cyano nucleoside Toyocamycin- 5- -D-glucopyranoside (M-73), closely related to Tubercidin-5-D glucopyranose (M- 58) , was isolated from Tolypothrix tenuis and was assayed on KB and HL-60 cell lines showing MICs 12 and 6 g mLϪ1, respectively M-20 M-21 M-22 M-22 M-23 M-24 M-25 M-26 M-27 M- 28 M-29 M-30 M-31 M-32 M-33 M-34 M-35 M-36 M-37 Welwistatin Hormothamnione Debromoaplysiatoxin... OCH3 O OH O B-13 O OH B-14 OH OH H OH H R1 R2 R1 = Me, R2 = OH H H B-16 R1 = OH, R2 = Me B-15 H OH B-17 B-32 R1 = Me, R2 = OMe H H OMe OAc H B-33 H H H B- 18 O O 226 Vassilios Roussis et al O O B-19 B-20 CHO OAc O O H O B-21 R1O O H R2 O R1 R2 Ac OH Ac H H B-22 B-25 OAc B-23 B-24 H H HO O HO H O O B-26 B-27 H HO H OAc O OAc C B- 28 B-29 OH OHC O RЈ O R R RЈ OAc H B-30 H C OAc B-31 HOO B-34 HO OH O O... Symploca hydnoides M-61 M-61 M-61 M-62 to M-65 M-66 M-67 M- 68 M-69 M-22 M-70 M-71 M-72 M-73 M-66 M-61 M-60 Tolytoxin Tolytoxin Tolytoxin Scytophycins A – D Tubercidin Symbioramide Symplostatin 1 Symplostatin 2 Debromoaplysiatoxin Tolyporphin Tolyporphin J Tolyporphin K Toyocamycin-5-D glucopyranose Tubercidin Tolytoxin Tubercidin-5-D glucopyranose Mynderse et al., 1977 Mayer, 19 98; Minehan et al., 1999... zonale B-35 B-36 B-37 B- 38 B-39 B-40 B-41 B-42 B-43 B-44 B-45 B-46 Fucoidan Sargaol Sargadiol-I Sargadiol-II Sargasal-I Sargasal-II Hydroxysargaquinone Kjellmanianone Fucosterol Spatol 14-Keto-stypodiol diacetate Stypoldione Sargassum thunbergii Sargassum tortile Code Metabolite Source Table 4.7 (Continued) Gerwick et al., 1 980 Depix et al., 19 98 Mori and Koga, 1992; Gerwick and Fenical, 1 981 O’Brien... H N O O Cl Cl 2 38 Vassilios Roussis et al O HN O N H S OMe N S O O M-36 N O O Cl N H Cl H (2S)-Leu OMe O O N H H N HN (2R,3S)-Ile O O HN Gly O O (2R )- -Aoc N H O NH (2S, 3S)-Ile O (2S)-Val N N H O HO O (2R)-Leu HN NH O OO N H OH HO H N OO OH O H N NH2 NCH3 NH M-39 OH O (2S, 4R)-Pro(4HO) OH (2S)-Hse D-N-MePh e H N β-Ala (2S)-Ala M-40 NH (2R, 3S),-Leu(3-OH) O NH2 O E-Dhb (2S,3S)-Leu(3-OH) OH O HN OH... the chromenes Sargaol (B-36), Sargadiol-I (B-37), Sargadiol-II (B- 38) , Sargasal-I (B-39), Sargasal-II (B-40), hydroxysargaquinone (B-41), Kjellmanianone (B-42) and Fucosterol (B-43) Among them, hydroxysargaquinone (B-41) and Sargasals-I and ϪII (B-37, B- 38) demonstrated significant (ED50 ϭ 0.7 g mLϪ1) and marginal (ED50 ϭ 5 .8 and 5.7 g mLϪ1) cytotoxicity against cultured P- 388 lymphotic leukemia cells,... B-35 OH H3C O O a OH O H3C – O3SO O HC OH 3 OH O HO – O3SO OH b R HO R: H R: OH B-36 B-37 Cytotoxic metabolites from marine algae 227 OH O B- 38 HO O R= CHO B-39 R= O CHO B-40 R HO O OH HO B-41 MeO B-42 C O O OMe OH O B-43 B-44 H O HO O O B-45 HO OAc B-46 H O H OAc O O R R B-49 B-47 R= R= B- 48 O O B-50 O HOO OH HOO HOO COOH B-51 B-52 HO 4.5 Cytotoxic metabolites from microalgae Amphidinolides A (M-1), . monoterpenes R-41, R-42 Coll et al., 1 988 Koenig et al., 1999 Portieria hornemannii 6(R)-Bromo-3(S )-( bromomethyl )-7 - R-43 Fuller et al., 1992 methyl-2,3,7-trichloro-1-octene (Halomon) 1-[ 3-( 1-chloro-2(E)-propenyl) ]-2 , 4- R-44 dichloro-3,3-dimethylcyclohex-5-ene Portieria. H H H H H H H H O H Val-2 D-alloIleu-1 D-alloIleu-2 Thr-1 L-Orn D-Pro Val-3 N N N N O N O O O N H 2 N N O O O N N O N O O N O HO N O N Val-4 Thr-2 Val-5 L-Phe H O O Val-1 Z-Dhb H H C-4 OAc AcO OAc C-5 OAc CHO H A H B OAc C-6 HO C-7 OAc AcO OAc O C -8 HO R 2 R 1 R 1 R 2 H H O O OOH H OH H C-9 C-10 C-11 C-12 OH O C-13. rhodophyta N O O N N O N S N O N N O O H H H Phe-2 Pro-1 Ile Phe-1 Pro-2 cis-cis trans-trans R-1 R-2 HO R OOH R= OOH OH OH R= R= R= R-3 R-4 R-5 R-6 O OH O R-7 OOH R= OOH O OH R R -8 R-9 OOH R= OOH R O O Me OCH 3 OCH 3 OCH 3 CH 3 CH 3 CH 3 R-10
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