Natural products as angiogenesis modulators.

Cancer remains one of the major causes of death worldwide. Anti-angiogenic therapy is one of the new approaches to anticancer therapy. Out of 22 angiogenesis inhibitors currently under clinical trials there are 11 natural products or were modeled on a natural product parent. This review shows the potential of natural products for the discovery of new anti-angiogenic leads.

Marine natural products as lead anti-HIV agents.

Current anti-HIV drugs have extreme side effects and resistance to these drugs develops rapidly. The marine environment holds an unprecedented number of unusual chemical structural classes with activity against HIV. We review the literature on anti-HIV activity of marine natural products and discuss the efficacy of different structural classes.

Effect of Echinostoma liei infection on alterations of protein content and some enzymes in Biomphalaria alexandrina snails.

The survival rate and fecundity of B. alexandrina were greatly reduced when exposed to E. liei miracidia. Also, exposure of B. alexandrina snails to E. liei miracidia induced a disruption in the snail metabolism and this effect was more pronounced in 20-days post-miracidial exposure group than in 10-days group. Protein content was significantly reduced in all exposed snail groups than in the control group. A significant elevation in the levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) enzymes was recorded also in exposed snails than unexposed ones (control snails). The results indicated also that there were significant increases in the levels of acid and alkaline phosphatases enzymes in exposed snails.

Effect of ammonium chloride on Biomphalaria alexandrina and on its infection with Schistosoma mansoni and Echinostoma liei miracidia.

Ammonium chloride (NH4Cl) has molluscicidal activity against B. alexandrina. The LC50 and LC90 recorded of this salt were found to be 90 ppm and 130 ppm, respectively. Maintaining of B. alexandrina at low concentrations of NH4Cl (5, 10, 15 and 20 ppm) greatly reduced their survival rate and fecundity. The net reproductive rate (Ro) [sigmaIx Mx] was deleteriously affected. This rate was significantly reduced than that of control snails in all tested snail groups. The reduction in Ro was 86.9%, 90.8%, 93.9% and 96.9%, respectively. The susceptibility of B. alexandrina to infection with S. mansoni and E. liei miracidia and infectivity of these two parasites were greatly reduced. Increasing the salt concentration increased this reduction. The magnitude of reduction in infection rate was lower in case of E. liei than that in S. mansoni indicating that E. liei is more tolerant to the effect of this salt than S. mansoni.

New manzamine alkaloids with potent activity against infectious diseases.

The isolation of the new enantiomers of 8-hydroxymanzamine A (1), manzamine F (2), along with the unprecedented manzamine dimer, neo-kauluamine from an undescribed genus of Indo-Pacific sponge (family Petrosiidae, order Haplosclerida) is reported. The relative stereochemistry of neo-kauluamine was established through detailed analysis of NOE-correlations combined with molecular modeling. The significance of the manzamines as in vivo antimalarial agents with superior activity to the clinically used drugs artemisinin and chloroquine is discussed along with the activity in vitro against the AIDS-opportunistic infectious diseases tuberculosis and toxoplasmosis. Reexamination of the sponges identified as Prianos, and Pachypellina, in earlier publications has confirmed that these are members of the same genus as the sponge described here, but differ at the species level.

A pseudoguaiane sesquiterpene xylopyranoside from Echinops hussoni.

A new pseudoguaiane sesquiterpene xylopyranoside ester, named echusoside (1), was isolated from the aerial parts of Echinops hussoni Boiss. (Asteraceae) collected from the southeastern border of Egypt. The structure elucidation of echusoside was based primarily on 1D, 2D-NMR analyses and chemical derivatization. This is the first report for a pseudoguainane sesquiterpene in the genus Echinops.

Antimalarial, antiviral, and antitoxoplasmosis norsesterterpene peroxide acids from the Red Sea sponge Diacarnus erythraeanus.

A new norsesterterpene acid, named muqubilone (1), along with the known sigmosceptrellin-B and muqubilin were isolated from the Red Sea sponge Diacarnus erythraeanus. The structure determination of 1 was based primarily on 1D and 2D NMR analyses. Sigmosceptrellin-B exhibits significant in vitro antimalarial activity against Plasmodium falciparum (D6 and W2 clones) with IC(50) values of 1200 and 3400 ng/mL, respectively. Muqubilin and 1 show in vitro antiviral activity against herpes simplex type 1 (HSV-1) with ED(50) values of 7.5 and 30 microg/mL, respectively. Muqubilin and sigmosceptrellin-B display potent in vitro activity against Toxoplasma gondii at a concentration of 0.1 microM without significant toxicity.

Microbial transformation of hypoestenone.

Preparative-scale fermentation of hypoestenone (1) with Mucor ramannianus (ATCC 9628) has resulted in the isolation of 8(9)alpha-epoxyhypoestenone (2) and the new metabolites 8(9)alpha-epoxy-12,13-anhydrohypoestenone (3), 17-hydroxyhypoestenone (4), 13alpha,18-dihydroxyhypoestenone (5), and 13beta,18-dihydroxyhypoestenone (6). Structure elucidation of these metabolites was based primarily on 1D and 2D NMR analyses.

Transformation of jervine by Cunninghamella elegans ATCC 9245.

Preparative-scale fermentation of the known C-nor-D-homosteroidal jerveratrum alkaloid jervine with Cunninghamella elegans (ATCC 9245) has resulted in the isolation of (-)-jervinone as the major metabolite. In addition, C. elegans ATCC 9245 was able to epimerize C-3 of jervine, producing 3-epi-jervine. This epimerization reaction was similar to that reported for tomatidine, the known spirosolane-type Solanum alkaloid. The structure elucidation of both metabolites was based primarily on 1D- and 2D-NMR analyses.

Bioactive 12-oleanene triterpene and secotriterpene acids from Maytenus undata.

The aerial parts of Maytenus undata yielded four new 12-oleanene and 3,4-seco-12-oleanene triterpene acids, namely, 3-oxo-11alpha-methoxyolean-12-ene-30-oic acid (1), 3-oxo-11alpha-hydroxyolean-12-ene-30-oic acid (2), 3-oxo-olean-9(11), 12-diene-30-oic acid (3), and 3,4-seco-olean-4(23),12-diene-3, 29-dioic acid (20-epi-koetjapic acid) (5), together with the known 3, 11-dioxoolean-12-ene-30-oic acid (3-oxo-18beta-glycyrrhetinic acid) (4), koetjapic acid (6), and the 12-oleanene artifact 3-oxo-11alpha-ethoxyolean-12-ene-30-oic acid (7). Koetjapic acid (6) inhibited the growth of Staphylococcus aureus, methicillin-resistant S. aureus, and Pseudomonas aeruginosa, with an MIC range of 3.125-6.25 microg/mL. The new 3,4-secotriterpene acid 20-epi-koetjapic acid (5) potently inhibited rat neonatal brain microglia phorbol ester-stimulated thromboxane B(2) (IC(50) = 0.5 microM) and superoxide anion (IC(50) = 1.9 microM) generation.

Microbial transformation of papaveraldine.

Preparative-scale fermentation of papaveraldine (1), the known benzylisoquinoline alkaloid, with Mucor ramannianus 1839 (sih) has resulted in a stereoselective reduction of the ketone group and the isolation of S-papaverinol (2) and S-papaverinol N-oxide (3). The structure elucidation of both metabolites was based primarily on 1D-, 2D-NMR analyses and chemical transformations. The absolute configuration of 2 was determined using Horeau's method of asymmetric esterification. These metabolism results were consistent with the previous plant cell transformation studies on papaverine and isopapaverine.

Microbial models of mammalian metabolism: microbial transformation of naproxen.

Preparative-scale fermentation of S-naproxen, the known antiinflammatory, analgesic and antipyretic drug, with Cunninghamella elegans ATCC 9245 afforded S-demethylnaproxen, the known human active metabolite of naproxen, in a 90% yield. Demethylnaproxen was also detected as the major metabolite of naproxen using Cunninghamella blakesleeana ATCC 8688a. A review of the previous microbial metabolism studies using the fungi Cunninghamella species suggested that it could be a plausible in vitro predictor for mammalian metabolism.

New pyrrole alkaloids from Solanum sodomaeum.

Two new pyrrole alkaloids, solsodomine A and B, were isolated from the fresh berries of Solanum sodomaeum L., collected from the Libyan desert. The structures of these compounds were established by 2D-NMR, including 15N NMR spectroscopy and chemical degradation. Solsodomine A (1) shows activity against Mycobacterium intracellulare. This is the first report of pyrrole alkaloids from the genus Solanum.

Microbial biotransformation of veratramine.

Preparative-scale fermentation of the known C-nor-D-homosteroidal alkaloid veratramine (1) with Nocardia species ATCC 21145 has resulted in the isolation of three new metabolites, 2-4. The structure elucidation of these compounds was conducted primarily by 2D NMR analysis. The microbe Nocardia species ATCC 21145 was able to metabolize rings A and B of veratramine but failed to metabolize its nitrogen-containing side chain, an observation consistent with previous fermentation studies on steroidal alkaloids.

Phytochemical analysis of Geigeria alata and Francoeuria crispa essential oils.

Phytochemical analyses of Geigeria alata (Benth. & Hook.) and Francoeuria crispa (Forssk., Cas.) (Asteraceae) essential oils were performed. G. alata oil showed moderate in vitro cytotoxicity (IC50, micrograms/ml against tumor cells; P388: 2.0, A-549: 2.5 and HT-29: 5.0), and also showed weak anti-HIV activity. S-Carvotanacetone, the major component of F. crispa oil (93.0%), was isolated and its structure was elucidated by 2D-NMR analysis.

A new norcembranoid dimer from the red sea soft coral Sinularia gardineri.

A study of Sinularia gardineri (Pratt) (Alcyoniidae), collected in the Red Sea, revealed a new heptacyclic norcembranoid dimer singardin (1). The structure of singardin was deduced by spectroscopic analysis. A known sesquiterpene, guaianediol (2), and the known cembranolides (1R,5S,8R,10S,11R)-11-hydroxy-1-isoprenyl-8-methyl-3,6-dioxo -5,8-epoxycyclotetradec-12-ene 10,12-carbolactone (5-epi-sinuleptolide) and sinuleptolide were also isolated. Compounds 1 and 2 show cytotoxicity to murine leukemia (P-388), human lung carcinoma (A-549), human colon carcinoma (HT-29), and human melanoma cells (MEL-28).

Time course and inhibition of stavaroside K, veratramine and cevine-induced hemolysis by other pregnane glycosides and Veratrum alkaloids.

Stavaroside K, veratramine and cevine induce hemolysis, whereas 7 other pregnane stavarosides and 8 Veratrum alkaloids are not hemolytic. On the other hand, erythrocytes pretreated or incubated with low concentrations of stavarosides D-F or with the 8 other Veratrum alkaloids were resistant to hemolysis induced by authentic saponin, stavaroside K, cevine or veratramine. Veratridine, zygadenine and angeloylzygadenine (the known Na-Channel-Gate toxins) revealed the most potent reduction of hemolytic activity.

Pregnane glycosides from Stapelia variegata.

Eleven new pregnane ester glycosides have been isolated from the aerial parts of Stapelia variegata. Eight of the recognized compounds were established to possess the same trioside moiety, viz. 3-O-[3-O-methyl-6-deoxy-beta-D-allopyranosyl-(1-4)-beta-D- cymaropyranosyl-(1-4)-beta-D-cymaropyranoside]. These compounds were identified as: stavaroside A: 12-O-beta-angeloyl-20-O-benzoyl sarcostin; stavaroside B: 12-O-beta-angeloyl-20-O-tigloyl sarcostin; stavaroside C: 11 alpha-acetoxy 2 beta-benzoxy-3 beta,8 beta, 14 beta-trihydroxy-pregn-5-ene-20-one; stavaroside D: 11 alpha-acetoxy- 12 beta-tigloxy-3 beta,8 beta,14 beta-trihydroxy-pregn-5-ene-20-one; stavaroside E: 12-O-beta-benzoyl sarcostin; stavaroside F: 11 alpha-acetoxy-12 beta-acetoxy-3 beta,8 beta,14 beta-trihydroxy-pregn-5- ene-20-one; stavaroside G: 12-O-beta,20-O-diacetyl sarcostin and stavaroside H: 3 beta, 8 beta, 11 alpha, 12 beta, 14 beta-pentahydroxy-pregn-5- ene-20-one. The other three compounds were shown to possess the same tetraside sugar moiety, viz. 3-O-[beta-D-glucopyranosyl- (1-4)-3-O-methyl-6-deoxy-beta-D-allopyranosyl-(1-4)-beta-D-cymaropyra nosyl- (1-4)-beta-D-cymaropyranoside]. These compounds were identified as: stavaroside I: 1 alpha, 12 beta-angeloxy and benzoxy-3 beta,8 beta,14 beta-trihydroxy- pregn-5-ene-20-one; stavaroside J: 11 alpha-acetoxy-12 beta-benzoxy-3 beta, 8 beta,14 beta-trihydroxy-pregn-5-ene-20-one and stavaroside K: 11 alpha-acetoxy-12 beta-tigloxy-3 beta,8 beta,14 beta-trihydroxy-pregn-5-ene- 20-one. The structural elucidation of the isolated compounds was aided significantly on the basis of the chemical and spectral evidence. The decisive assignments of the ester positions were based on the Inverse Detected-Heteronuclear Multiple Bond Connectivity (HMBC) experiments.