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A new polycyclic guanidine alkaloid, ptilomycalin D, and the known crambescidic acid were isolated from the marine sponge Monanchora dianchora collected in Nosy-Be, northwest of Madagascar, in the Indian Ocean. The structures were elucidated using 1- and 2-D NMR and MS data, and their biogenetic implications are discussed.

BackgroundThe natural phloroglucinol hyperforin HF displays anti-inflammatory and anti-tumoral properties of potential pharmacological interest. Acute myeloid leukemia (AML) cells abnormally proliferate and escape apoptosis. Herein, the effects and mechanisms of purified HF on AML cell dysfunction were investigated in AML cell lines defining distinct AML subfamilies and primary AML cells cultured ex vivo.Methodology and ResultsHF inhibited in a time- and concentration-dependent manner the growth of AML cell lines (U937, OCI-AML3, NB4, HL-60) by inducing apoptosis as evidenced by accumulation of sub-G1 population, phosphatidylserine externalization and DNA fragmentation. HF also induced apoptosis in primary AML blasts, whereas normal blood cells were not affected. The apoptotic process in U937 cells was accompanied by downregulation of anti-apoptotic Bcl-2, upregulation of pro-apoptotic Noxa, mitochondrial membrane depolarization, activation of procaspases and cleavage of the caspase substrate PARP-1. The general caspase inhibitor Z-VAD-fmk and the caspase-9- and -3-specific inhibitors, but not caspase-8 inhibitor, significantly attenuated apoptosis. HF-mediated apoptosis was associated with dephosphorylation of active Akt1 (at Ser473) and Akt1 substrate Bad (at Ser136) which activates Bad pro-apoptotic function. HF supppressed the kinase activity of Akt1, and combined treatment with the allosteric Akt1 inhibitor Akt-I-VIII significantly enhanced apoptosis of U937 cells.SignificanceOur data provide new evidence that HF's pro-apoptotic effect in AML cells involved inhibition of Akt1 signaling, mitochondria and Bcl-2 members dysfunctions, and activation of procaspases -9/-3. Combined interruption of mitochondrial and Akt1 pathways by HF may have implications for AML treatment.

The quantification of the total phenolic compounds of Pistacia atlantica showed that the different parts of the tree are rich in natural phenolic compounds. The antioxidant tests proved that the phenolic extracts have a strong antioxidant activity. The positive correlation between the Trolox equivalent antioxidant capacity (TEAC) and the amount of phenolic compounds confirms their contribution to the antioxidant activity. Among the various phenolic compounds isolated and characterized by spectroscopic methods, a new natural antioxidant 1 (methyl 5-(3,4-dihydroxyphenyl)-3-hydroxypenta-2,4-dienoate) derived from hispolone 2 has been isolated from the mushroom Inonotus hispidus growing on Pistacia atlantica. Hispolone 2 (6-(3,4-dihydroxyphenyl)-4-hydroxyhexa-3,5-dien-2-one) and hispidin 3 (6-(2-(3,4-dihydroxyphenyl)vinyl)-4-hydroxy-2H-pyran-2-one) have been also identified using spectroscopic methods, including 2D-NMR and EI-MS.

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