Tolyporphins J and K, two further porphinoid metabolites from the cyanobacterium Tolypothrix nodosa.

Two new porphinoids, tolyporphins J (1) and K (2), have been isolated from the terrestrial cyanobacterium, Tolypothrix nodosa (HT-58-2) and identified by NMR and mass spectral analysis. The activities of tolyporphins J and K in cell sensitization and drug accumulation assays for multidrug resistance (MDR) reversal were compared with those of tolyporphin A. Unusual NMR spectroscopic shifts were observed for tolyporphin J (1) in CDCl3.

Tolyporphin: a natural product from cyanobacteria with potent photosensitizing activity against tumor cells in vitro and in vivo.

Tolyporphin (TP), a porphyrin extracted from cyanobacteria, was found to be a very potent photosensitizer of EMT-6 tumor cells grown both in vitro as suspensions or monolayers and in vivo in tumors implanted on the backs of C.B17/Icr severe combined immunodeficient mice. Thus, during photodynamic treatment (PDT) of EMT-6 tumor cells in vitro, the photokilling effectiveness of TP measured as the product of the reciprocal of D50 (the light dose necessary to kill 50% of cells) and the concentration of TP is approximately 5000 times higher than that of Photofrin II (PII), the only PDT photosensitizer thus far approved for clinical trials. TP almost exclusively localizes in the perinuclear region and specifically in the endoplasmic reticulum (ER), as shown by microspectrofluorometry on single living EMT-6 cells costained with the ER and/or Golgi fluorescent vital probes, 3,3'-dihexyloxacarbocyanine iodide and N-[4,4-difluoro-(5,7-dimethyl-BODIPY)-1-pentanoyl]-D-erythro-sphin gosine (Molecular Probes, Eugene, OR). As a result, the singlet oxygen-mediated photodynamic activity of TP induces an effective inactivation of the acyl CoA:cholesterol-O-acyltransferase, a sensitive marker of ER membrane integrity and alterations of the nuclear membrane. In vivo, with the EMT-6 mouse tumor model, an exceptional effectiveness is also observed as compared to that of PII and other second generation photosensitizers of the pheophorbide class, which are themselves much more potent than PII. The outstanding PDT activity of TP observed in vivo may be due to its unique biodistribution properties, in particular much less extraction by the liver, resulting in a higher delivery to other tissues, including tumor.

Tolypodiol, an antiinflammatory diterpenoid from the cyanobacterium Tolypothrix nodosa.

A new diterpenoid, tolypodiol (1), has been isolated from the terrestrial cyanobacterium Tolypothrix nodosa (HT-58-2) and identified by NMR and mass spectral analysis. The monoacetate derivative 2 was prepared. Tolypodiol (1) and its monoacetate derivative 2 show potent antiinflammatory activity in the mouse ear edema assay.

Reversal of multiple drug resistance by tolyporphin, a novel cyanobacterial natural product.

The effects of a novel porphyrin, tolyporphin, on P-glycoprotein-mediated multiple drug resistance in human ovarian and breast cell lines were characterized. Compared with parental SKOV3 and MCF-7 cells, the P-glycoprotein-overexpressing sublines SKVLB1 and MCF-7/ADR were 5- and 1.3-fold less sensitive to the cytotoxic effects of tolyporphin. Subtoxic doses of tolyporphin increased the sensitivity of the SKVLB1 and MCF-7/ADR cells to P-glycoprotein-transported drugs, but did not increase the antiproliferative effects of nontransported drugs. Tolyporphin also enhanced the accumulation of [3H]-vinblastine in SKVLB1 and MCF-7/ADR cells at doses approximately 10-fold lower than those required for similar responses to verapamil. In contrast, tolyporphin did not affect drug accumulation in SKOV3 or MCF-7 cells. Tolyporphin reduced [3H]-vinblastine efflux from SKVLB1 cells, reduced [3H]-vinblastine binding to membranes from SKVLB1 cells, and blocked the ability of [3H]-azidopine to photoaffinity-label P-glycoprotein in these membranes. These results indicate that tolyporphin binds to P-glycoprotein and inhibits the transport of cytotoxic natural product drugs. This novel natural product, and related compounds, may be useful for the reversal of multiple drug resistance and for further definition of the drug binding site(s) of P-glycoprotein.

Westiellamide, a bistratamide-related cyclic peptide from the blue-green alga Westiellopsis prolifica.

The isolation and structural elucidation of westiellamide [1] from the terrestrial blue-green alga Westiellopsis prolifica is described. This moderately cytotoxic cyclic peptide appears to be identical with a bistratamide-type marine natural product from the aplouso-branch ascidian Lissoclinum bistratum.

New cytotoxic beta-carboline alkaloids from the marine bryozoan, Cribricellina cribraria.

Bioactivity-directed separations led to the isolation of the new alkaloid, 1-vinyl-8-hydroxy-beta-carboline [1], as the major cytotoxic component of the marine bryozoan Cribricellina cribraria. Another new beta-carboline alkaloid 2 with the novel sulfone structure was isolated, together with a number of known beta-carboline compounds. Cytotoxicity and antimicrobial effects are reported for these compounds and for other synthesized beta-carbolines.