Isolation and frontier molecular orbital investigation of bioactive quinone-methide triterpenoids from the bark of Salacia petenensis.

The crude dichloromethane bark extract of Salacia petenensis (Hippocrateaceae) from Monteverde, Costa Rica, shows antibacterial and cytotoxic activity. Bioactivity-directed separation led to the isolation of tingenone and netzahualcoyonol as the biologically active materials. Also isolated from the extract were 3-methoxyfriedel-2-en-1-one (a new natural product) and 29-hydroxyfriedelan-3-one. The structures of these compounds were elucidated on the basis of NMR spectral analysis. Molecular orbital calculations have been carried out using the semi-empirical PM3 and Hartee-Fock 3-21G ab initio techniques on the quinone-methide nortriterpenoids tingenone and netzahualcoyonol, as well as on the nucleotide bases adenine, guanine, cytosine, and thymine. The molecular orbital calculations suggest that a possible mode of cytotoxic action of quinone-methide triterpenoids involves quasi-intercalative interaction of the compounds with DNA followed by nucleophilic addition of the DNA base to carbon-6 of the triterpenoid.

Dolastatin 11, a marine depsipeptide, arrests cells at cytokinesis and induces hyperpolymerization of purified actin.

The successful synthesis of dolastatin 11, a depsipeptide originally isolated from the mollusk Dolabella auricularia, permitted us to study its effects on cells. The compound arrested cells at cytokinesis by causing a rapid and massive rearrangement of the cellular actin filament network. In a dose-and time-dependent manner, F-actin was rearranged into aggregates, and subsequently the cells displayed dramatic cytoplasmic retraction. The effects of dolastatin 11 were most similar to those of the sponge-derived depsipeptide jasplakinolide, but dolastatin 11 was about 3-fold more cytotoxic than jasplakinolide in the cells studied. Like jasplakinolide, dolastatin 11 induced the hyperassembly of purified actin into filaments of apparently normal morphology. Dolastatin 11 was qualitatively more active than jasplakinolide and, in a quantitative assay we developed, dolastatin 11 was twice as active as jasplakinolide and 4-fold more active than phalloidin. However, in contrast to jasplakinolide and phalloidin, dolastatin 11 did not inhibit the binding of a fluorescent phalloidin derivative to actin polymer nor was it able to displace the phalloidin derivative from polymer. Thus, despite its structural similarity to other agents that induce actin assembly (all are peptides or depsipeptides), dolastatin 11 may interact with actin polymers at a distinct drug binding site.

Biologically active triterpenoids of Syncarpia glomulifera bark extract from Paluma, north Queensland, Australia.

The crude chloroform bark extract of Syncarpia glomulifera (Myrtaceae) shows antibacterial and cytotoxic activity. Bioactivity-directed separation led to the isolation of oleanolic acid-3-acetate, ursolic acid-3-acetate and betulinic acid. The relatively large abundance (10% of the crude extract) and high degree of activity of betulinic acid are responsible for the bioactivity of the crude bark extract.

A phytochemical investigation of Alchornea latifolia.

A phytochemical investigation of the chloroform leaf extract of Alchornea latifolia has been undertaken. Along with the triterpenoids taraxerone, friedelin, epifriedelinol, and taraxerol, the plant also contains seco-3,4-friedelin (dihydroputranjivic acid) (1) and seco-3,4-taraxerone (2). These A-ring-opened triterpenoids show in vitro cytotoxic activity against Hep-G2 and A-431 human cancer cell lines and are potent inhibitors of topoisomerase II.

Biological activity of the essential oil of Myrcianthes sp. nov. "black fruit" from Monteverde, Costa Rica.

The leaf essential oil of an undescribed species of Myrcianthes has been obtained from Monteverde, Costa Rica. The essential oil exhibits in vitro cytotoxic activity against Hep-G2 and SK-Mel-28 human tumor cell lines. A GC/MS analysis shows the essential oil to be composed of 2-heptanol, alpha-pinene, beta-pinene, limonene, cineole, and alpha-terpineol, alpha-Pinene, beta-pinene, and limonene account for the cytotoxic activity of the leaf essential oil of Myrcianthes sp. nov. "black fruit".

Antibacterial hydroxycinnamic esters from Piper caninum from Paluma, north Queensland, Australia. The crystal and molecular structure of (+)-bornyl coumarate.

The crude chloroform bark extract of Piper caninum (Piperaceae) exhibits antibacterial activity against the Gram-positive bacteria, Bacillus cereus, Staphylococcus aureus, and Streptococcus pneumoniae. The antibacterial agents in this extract have been isolated using bioactivity-directed chromatographic techniques and identified by NMR spectroscopy as (+)-bornyl p-coumarate and bornyl caffeate. A single-crystal X-ray structure has been carried out on (+)-bornyl p-coumarate. The compound crystallizes in the orthorhombic space group P2(1)2(1)2(1) (#19) with a = 12.659(4), b = 13.281(4), and c = 10.177(3) A. Fullmatrix least-squares refinement converged at R = 0.047, and Rw = 0.058.

Lupeol is the cytotoxic principle in the leaf extract of Dendropanax cf. querceti.

The crude ethanol extract from the leaves of Dendropanax cf. querceti (Araliaceae) from Monteverde, Costa Rica, exhibits cytotoxic activity against Hep-G2, A-431, and H-4IIE tumor cell lines. The active component has been isolated by activity-directed separation and identified by 1H- and 13C-NMR spectroscopy as the triterpene lupeol. The mechanism of cytotoxic activity of lupeol has been determined to be inhibition of topoisomerase II.

Stability studies of tetracycline in methanol solution.

The stability of tetracycline in methanol solution was investigated by UV-visible spectroscopy, HPLC and TLC methods. After dissolution in methanol, tetracycline decomposed rapidly under the influence of light and atmospheric oxygen, forming more than fourteen different degradation products. None of the previously reported degradation products, such as the epi- and anhydro-compounds, were detected as the final degradation products. The molecular structures for eight of the compounds were suggested by their product-ion mass spectra. A degradation sequence was proposed for the reactions of tetracycline with methanol. A new HPLC-MS mobile phase was developed, which solved the clogging problem at the interface between the HPLC and MS chamber and enabled a high separation efficiency.

Inhibition of human immunodeficiency virus type 1 transcription and replication by DNA sequence-selective plant lignans.

A plant lignan, 3'-O-methyl nordihydroguaiaretic acid (3'-O-methyl NDGA, denoted Malachi 4:5-6 or Mal.4; molecular weigth 316), was isolated from Larrea tridentata and found to be able to inhibit human immunodeficiency virus (HIV) Tat-regulated transactivation in vivo, induce protection of lymphoblastoid CEM-SS cells from HIV (strain IIIB) killing, and suppress the replication of five HIV-1 strains (WM, MN, VS, JR-CSF, and IIIB) in mitogen-stimulated peripheral blood mononuclear cells, all in a dose-dependent manner. Mal.4 inhibits both basal transcription and Tat-regulated transactivation in vitro. The target of Mal.4 has been localized to nucleotides -87 to -40 of the HIV long terminal repeat. Mal.4 directly and specifically interferes with the binding of Sp1 to Sp1 sites in the HIV long terminal repeat. By inhibiting proviral expression, Mal.4 may be able to interrupt the life cycles of both wild-type and reverse transcriptase or protease mutant viruses in HIV-infected patients.

A cytotoxic diacetylene from Dendropanax arboreus.

The crude ethanol extract from the leaves of Dendropanax arboreus (Araliaceae) from Monteverde, Costa Rica, exhibits cytotoxic activity against Hep-G2, A-431, H-4IIE, and L-1210 tumor cell lines, but is not toxic against normal hepatocytes. The active component has been isolated by activity-directed separation and identified by 1H- and 13C-NMR spectroscopy as the acetylenic compound cis-1,9,16-heptadecatriene-4,6-diyne-3,8-diol.

An antibacterial vitamin E derivative from Tovomitopsis psychotriifolia.

The crude ethanol extract from the leaves of Tovomitopsis psychotriifolia (Clusiaceae) exhibits antibacterial activity against Bacillus cereus, Staphylococcus aureus, and Pseudomonas aeruginosa. The biologically active agent in the extract has been isolated by chromatographic techniques and identified by NMR spectroscopy as trans-delta-tocotrienoloic acid.

Tylophora compounds as Na+/K(+)-ATPase inhibitors.

1. Acetyltylophoroside (AcT) and tylogenin inhibit Na+/K(+)-ATPase in spite of having structures very different from cardiac glycosides (CGs). 2. Calculation of the lowest energy conformations of AcT and tylogenin and superpositions of these with the X-ray conformations of CGs and chlormadinone acetate led to a model for the interaction of these different types of Na+/K(+)-ATPase inhibitors with the receptor.

3-(1-Methyl-1,2,3,6-tetrahydropyrid-4-yl)indole.

C14H16N2, Mr = 212.3, orthorhombic, Pca2(1), a = 19.424 (3), b = 6.770 (1), c = 8.899 (1) A, V = 1170.2 (3) A3, Z = 4, Dx = 1.20 g cm-3, Mo K alpha, lambda = 0.71073 A, mu = 0.7 cm-1, F(000) = 456, T = 296 K, final R = 0.043 for 1162 observed reflections. The pi systems in the title compound (1), a serotonin mimic, are in a 'near-planar' conformation (actually twisted 21 degrees from the transoid conformation) as has been postulated to be essential for activity. Molecular-mechanics calculations indicate that the inactive 2-methyl derivative of (1) has near-planar forms of much higher energy in accordance with expectation.

A new diterpene from Cupressus goveniana var. abramasiana: 5 beta-hydroxy-6-oxasugiol (cupresol).

The petroleum ether-EtOH extract of Cupressus goveniana var. abramasiana (Cupressaceae) yielded sugiol (1) and the new diterpene, cupresol (5 beta-hydroxy-6-oxasugiol), for which structure 2 was established by spectroscopic and chemical means.

Microbial transformations of natural antitumor agents XXII: Conversion of bouvardin to O-desmethylbouvardin and bouvardin catechol.

Bouvardin is a cyclic hexapeptide antitumor agent which undergoes two major microbial transformation reactions. Screening with 220 cultures revealed 17 different strains capable of producing O-desmethylbouvardin in good yield. O-Desmethylbouvardin was isolated and characterized from preparative scale incubations with Streptomyces rutgersensis NRRL B-1256. Four aspergilli and one streptomycete formed bouvardin catechol when O-desmethylbouvardin was used as substrate. Bouvardin catechol was isolated and characterized from a preparative scale incubation with Aspergillus ochraceous UI 398.