Chrysanthones, a new source of fungal metabolites with potential antitumor and antiangiogenesis properties.

Chrysanthones are secondary metabolites, isolated from Ascochyta chrysanthemi, with a methyl-benzoisoquinoline or methyl-benzoisochromene system. Three compounds were tested for their cytotoxicity properties on endothelial cells (EC) and two different tumor cell lines and for their ability to inhibit EC migration. Structure-function relationship considerations suggested that the methylisoquinolinic moiety is important for the cytotoxic activity, whereas the methylisochromene moiety confers an endothelial selectivity to the structures. In general, compared to the activity of known antiproliferative and antiangiogenic compounds, chrysanthones showed weaker activities. However, they present a basis for the synthesis of new derivatives.

Structure elucidation of clavilactone D: an inhibitor of protein tyrosine kinases.

Clavilactones D and E were isolated from an agar culture of the Basidiomycetous fungus Clitocybe clavipes, and their structure was elucidated by 1H- and 13C-NMR studies. Clavilactone D is an inhibitor of tyrosine kinases.

Structure and absolute configuration of new acetylenic compounds isolated from cultures of Clitocybe catinus.

Investigations of the extracts of a culture of Clitocybe catinus gave rise to the isolation of new acetylenic diols 1-3. Their structure was determined on the basis of 1H- and 13C-NMR evidence and the absolute configuration elucidated by means of the modified Mosher's method.

Clavilactones, a novel class of tyrosine kinase inhibitors of fungal origin.

Targeting of deregulated protein tyrosine kinases has been proposed as a new approach in the therapeutic intervention against pathological processes including proliferative disorders and cancer. Using a screening approach based on a comparative evaluation of antiproliferative effects in a panel of tumor cells with differential expression of protein tyrosine kinases, three benzoquinoid macrolidic fungal metabolites produced by Clitocybe clavipes, clavilactones A, B, and D (CA, CB, and CD) and two semisynthetic derivatives of these products, diacetyl-CA and dimethyl-CA, were identified as inhibitors of protein tyrosine kinases. Naturally occurring CA, CB, and CD showed inhibitory activity in kinase assays against the Ret/ptc1 and epidermal growth factor receptor (EGF-R) tyrosine kinases, while being less effective against the v-Abl tyrosine kinase and p34(cdc2) serine/threonine kinase (IC(50) 2.8, 5.5, 81.3, and 128 microM respectively, for the most potent compound CD). CB was shown to be a non-competitive inhibitor of EGF-R with respect to ATP or poly(Glu(6)Ala(3)Tyr). CD also preferentially inhibited the growth of A431 cells, which overexpress a constitutively active EGF-R, as opposed to IGROV-1 and SKOV-3 cells, which express low levels of the receptor. Further, EGF-R was shown to be a target for clavilactones in A431 cells, since EGF-induced receptor autophosphorylation was inhibited in the presence of CB, CD, and diacetyl-CA. Both CD and diacetyl-CA displayed weak activity when administered daily (i.p.) to mice bearing ascitic A431 tumor. These findings indicate that clavilactones represent the prototypes of a new structural class of tyrosine kinase inhibitors deserving further investigation.

Tsugicoline E, a new polyoxygenated protoilludane sesquiterpene from the fungus laurilia tsugicola1

Tsugicoline E (3) has been isolated from cultures of the Basidiomycetous fungus Laurilia tsugicola and its structure deduced from 1H and 13C NMR and single-crystal X-ray diffraction studies. The suggested absolute configuration is consistent with biogenetic considerations.

A hydroxytetradecatrienoic acid from Mycosphaerella rubella.

Investigations on the acidic fractions from extracts of a culture of Mycosphaerella rubella led to the isolation of a new unsaturated dihydroxy acid, 6,13-dihydroxytetradeca-2,4,8 trienoic acid, and two of its derivatives, which are probably artifacts. Their structures were determined on the basis of H and C NMR evidence. The absolute configuration of the chiral centres of the new acid was elucidated using the modified Mosher's method.

Marasmane sesquiterpenes from the basidiomycete Clitocybe hydrogramma.

Investigations of solid cultures of Clitocybe hydrogramma gave rise to the isolation of two new alpha, beta-unsaturated dialdehydes having the marasmane skeleton. Their structures have been determined on the basis of 1H and 13C NMR evidence.

Constituents of Dragon's Blood. 5. Dracoflavans B1, B2, C1, C2, D1, and D2, new A-type deoxyproanthocyanidins.

From Dragon's Blood, a resin produced by plants of the genus Daemonorops (Palmae), six new A-type flavanoid deoxyproanthocyanidins have been isolated. Their structure and stereochemistry, established by chemical degradation and extensive NMR analysis, is consistent with a mechanism of formation common to other constituents of the resin, which involves oxidation of a 6-methylflavan to a quinonemethide, followed by coupling with another flavan moiety.

Peritoneal macrophage beta-2 microglobulin production and bacterial peritonitis in CAPD patients.

To evaluate the role of bacterial peritonitis in peritoneal macrophage (PM) Beta-2 Microglobulin (B2M) production, and its relationship with PM Interleukin-1 (IL-1) and Leukotriene B4 (LTB4) release, the authors studied 20 CAPD patients (10 with peritonitis): 1. in vivo plasma and peritoneal dialysis effluent (PDE) B2M, IL-1, and LTB4 levels; 2. in vitro B2M, IL-1, and LTB4 release by PM. Values were compared with those seen in the plasma or with peripheral blood monocytes of 30 hemodialysis (HD) patients (10 treated with Cuprophan [CU]; 10 with Polyacrylonitrile [PAN]; and 10 with Cellulose Acetate [CA]). Results showed that in CAPD patients with bacterial peritonitis B2M, IL-1 and LTB4 concentrations in the PDE were significantly higher than those seen in CAPD patients without peritonitis, or in the plasma of HD patients treated with PAN or CA, but were similar to those seen in HD patients treated with CU. At the same time, in vitro PM from CAPD patients with bacterial peritonitis produced more B2M, IL-1, and LTB4, than did PM from CAPD patients without peritonitis, or peripheral blood monocytes from HD patients treated with PAN or CA. The authors conclude that in CAPD patients, bacterial peritonitis is able to induce PM B2M production, probably via a cytokine mediated process, which may be analogous to what occurs with peripheral blood monocytes of HD patients treated with CU.

Structure of elsinochrome A: a perylenequinone metabolite.

trans-1,2-Diacetyl-1,2-dihydro-5,10-dihydroxy-3,7,8,12- tetramethoxybenzo[ghi]perylene-4,11-dione, C30H24O10, Mr = 544.51, orthorhombic, P2(1)2(1)2(1), Z = 4, a = 12.428 (3), b = 13.048 (3), c = 14.933 (3) A, V = 2421.5 (9) A3, Dx = 1.494, Dm (by flotation) = 1.48 g cm-3, lambda(Mo K alpha) = 0.71069 A, mu = 1.057 cm-1, F(000) = 1136, T = 293 K, R = 0.046 (2065 observed reflections). Elsinochrome A is shown to exist in the solid state as a nonplanar quinone tautomer; the pigment adopts a helical conformation, in analogy with the related cercosporin, but the perylenequinone moiety in elsinochrome A appears to be significantly less skewed.

Structure and biological activity of lipiarmycin B.

Actinoplanes deccanensis ATCC 21983, the producer of antibiotics lipiarmycin A3 and A4, furnished also a related antibiotic designated lipiarmycin B, active against Gram-positive bacteria, including anaerobes, and against Neisseria. The structures of the two major components, B3 and B4, were elucidated from their physico-chemical properties, 1H and 13C NMR spectra and fast atom bombardment mass spectra data in comparison with lipiarmycins A3 and A4.

New secondary metabolites of Aspergillus wentii Wehmer. The positive and negative ion mass spectra produced by electron impact.

The positive and negative ion mass spectra of three secondary metabolites of Aspergillus Wentii Wehmer, namely 15-acetoxyhexadecyl-, 15-oxohexadecyl- and 15-hydroxyhexadecylcitraconic anhydrides are reported and discussed. The positive ion mass spectra, which have been studied in detail by exact mass measurements and metastable ion detection using a defocusing method, show very weak molecular ions and complex fragmentation pathways, strongly influenced by the group on C-15. However, the negative ion mass spectra show very abundant molecular ions and little fragmentation, with the negative charge mainly retained by the anhydride moiety. The behavior of both positive and negative ions is in agreement with the charge localization concept, on the grounds of ionization energy and electron affinity considerations. positive and negative ion mass spectra are largely complementary, thus increasing their analytical value.