PTP1B inhibitory and cytotoxic C-24 epimers of Δ28-24-hydroxy stigmastane-type steroids from the brown alga Dictyopteris undulata Holmes.

Ten stigmastane-type steroids bearing unusual Δ28-24-hydroxy side chains, dictyopterisins A-J, including three pairs of C-24 epimers, dictyopterisins B/C, F/G, and I/J, were isolated from the brown alga Dictyopteris undulata Holmes, together with two previously reported analogues, (24S)- and (24R)-saringosterol. Their structures were elucidated on the basis of extensive spectroscopic analysis, with their absolute configurations at the stereogenic center C-24 of the side chain being assigned by a direct comparison of 1H NMR data with those of related known compounds. The absolute configurations of the steroidal nuclei of dictyopterisins A, B, and H were determined using the modified Mosher's method. The mixture of dictyopterisins D and E and dictyopterisin I exhibited promising PTP1B inhibitory activities with IC50 values of 1.88 and 3.47 µM, respectively, comparable to the positive control oleanolic acid (IC50, 2.78 µM). In addition, the mixture of dictyopterisins D and E and dictyopterisins F-J displayed significant cytotoxicities against the human cancer cell lines HL-60 (IC50 from 1.02 to 2.70 µM) and A-549 (IC50 from 1.35 to 2.85 µM).

Compositacins A-K: Bioactive chamigrane-type halosesquiterpenoids from the red alga Laurencia composita Yamada.

Eleven highly halogenated chamigrane sesquiterpenoids, compositacins A-K, including one unusual rearranged chamigrane sesquiterpenoid, compositacin A, were isolated from the red alga Laurencia composita Yamada, along with seven known structural analogues. Compositacins B and D are the first examples of chamigranes bearing an ether bridge involving C-5/C-9 and C-3/C-5, respectively, while compositacins B and C represent the first chamigranes with a C-10 carbonyl group. Their structures were elucidated on the basis of extensive spectroscopic analysis. The absolute configuration of compositacin B was determined by ECD calculation, whereas the absolute configurations of compositacins A and C-L were proposed on biosynthetic grounds by comparison to compositacin B and the related known sesquiterpenoids johnstonol and yicterpene A. We also suggest that the structure of the previously reported sesquiterpenoid laurokamin A should be revised. Cytotoxicity and antifungal activity of these isolates were also investigated. The results showed that compositacin G exhibited good antifungal activity against Microsporum gypseum (Cmccfmza) with a MIC80 value of 4 µg/mL relative to positive controls. Four of the chamigrane halosesquiterpenoids showed marginal cytotoxicity against the A-549 human lung adenocarcinoma cell line with IC50 values ranging from 48.6 to 85.2 µM.

A novel citrinin derivative from the marine-source fungus Penicillium citrinum.

A novel citrinin derivative, penicitrinol L (1), along with two known analogues, penidicitrinin B (2) and pennicitrinone A (3) were isolated from the marine-source fungus Penicillium citrinum. The structure of the new compound was elucidated by spectroscopic methods including one and two-dimensional NMR as well as high-resolution mass spectrometric analysis. Furthermore, compound 1 showed modest cytotoxic activity against HL-60 cell line and compound 3 showed weak cytotoxic activity against A375 cell line.

Bioactive constituents from the green alga Caulerpa racemosa.

Three diterpenoids, including a pair of epimers, racemobutenolids A and B (1 and 2), and 4',5'-dehydrodiodictyonema A (3), an α-tocopheroid, α-tocoxylenoxy (8), and an 28-oxostigmastane steroid, (23E)-3ß-hydroxy-stigmasta-5,23-dien-28-one (11), together with 12 known compounds, were isolated from the green alga Caulerpa racemosa. The structures of the new compounds were elucidated by detailed analysis of spectroscopic data, and by comparison with data for related known compounds. The epimers (1 and 2) are two unusual diterpenoid lactones bearing a ß-methyl-γ-substituted butenolide moiety, and 3 and 8 represent the first naturally occurring natural products with a hematinic acid ester group and 3,5-dimethylphenoxy functionality, respectively. The enzyme inhibitory activities of the isolated compounds were evaluated in vitro against PTP1B and related PTPs (TCPTP, CDC25B, LAR, SHP-1, and SHP-2). Compounds 3, 5, 6, and 9-14 exhibited different levels of PTP1B inhibitory activities with IC50 values ranging from 2.30 to 50.02µM. Of these compounds, 3, 9, and 11 showed the most potent inhibitory activities towards PTP1B with IC50 values of 2.30, 3.85, and 3.80µM, respectively. More importantly, the potent PTP1B inhibitors 3, 9, and 11 also displayed high selectivity over the highly homologous TCPTP and other PTPs. Also, the neuroprotective effects of the isolates against Aß25-35-induced cell damage in SH-SY5Y cells were investigated. Compounds 10, 11, and 14 exhibited significant neuroprotective effects against Aß25-35-induced SH-SY5Y cell damage with 11.31-15.98% increases in cell viability at 10µM. In addition, the cytotoxic activities of the isolated compounds were tested against the human cancer cell lines A-549 and HL-60.

A seco-laurane sesquiterpene and related laurane derivatives from the red alga Laurencia okamurai Yamada.

A ring-cleaved sesquiterpene, named seco-laurokamurone, four laurane-type sesquiterpenes, laurepoxyene, 3ß-hydroperoxyaplysin, 3α-hydroperoxy-3-epiaplysin, and 8,10-dibromoisoaplysin, one laurokamurane-type sesquiterpene, laurokamurene D, and one bisabolane-type sesquiterpene, (5S)-5-acetoxy-ß-bisabolene, have been isolated from a re-collection of the red alga Laurencia okamurai Yamada, together with six other known sesquiterpenes. Their structures, including relative configuration, were elucidated by detailed analysis of spectroscopic data, and by comparison with data for related known compounds. In addition, on the basis of chemical conversions, degradation results, and biogenetic considerations, the absolute configurations of several of these compounds were also tentatively proposed. seco-Laurokamurone possesses an unprecedented carbon skeleton, formed from an oxidative cleavage of the laurokamurane skeleton, and laurokamurene D represents the fourth example of a laurokamurane-type sesquiterpene from a natural source. The in vitro antifungal activity of many of these compounds was evaluated against four fungi (Cryptococcus neoformans, Candida glabrata, Trichophyton rubrum, and Aspergillus fumigatus), as well as assessing cytotoxicity against HL-60 and A-549 human cancer cell lines. The compounds studied displayed moderate activities, relative to controls.

Racemosins A and B, two novel bisindole alkaloids from the green alga Caulerpa racemosa.

Racemosin A (1), a structurally unique bisindole alkaloid possessing the seco-indolo[3,2-a]carbazole skeleton with two uncommon indolinenone units both conjugated with a methyl propenoate moiety, and its unusual cyclized derivative, racemosin B (2), were isolated from the green alga Caulerpa racemosa, together with the most commonly encountered pigment in the genus Caulerpa, caulerpin (3). Their structures were elucidated by extensive spectroscopic analysis and by comparison with data for related known compounds. A plausible biosynthetic pathway of 1 and 2 was proposed. In a neuro-protective assay, compound 1 significantly attenuated the Aß2(5-35)-induced SH-SY5Y cell damage with a 14.6% increase in cell viability at the concentration of 10µM when compared to epigallocatechin gallate (EGCG, 16.57% increase at 10 µM) as the positive control.

Caulerprenylols A and B, two rare antifungal prenylated para-xylenes from the green alga Caulerpa racemosa.

Two new prenylated para-xylenes, named caulerprenylols A (1) and B (2), were isolated from the green alga Caulerpa racemosa, collected from the Zhanjiang coastline, China. The structures of the two metabolites were elucidated on the basis of detailed spectroscopic analysis. This is the first report of prenylated para-xylenes from marine algae and from marine organisms as well. Moreover, caulerprenylol B (2) is also characterized by an uncommon indane ring system. In in vitro bioassays, the new compounds exhibited a broad spectrum of antifungal activity against Candida glabrata (537), Trichophyton rubrum (Cmccftla), and Cryptococcus neoformans (32609) with MIC80 values between 4 and 64 µg/mL when compared to amphotericin B (MIC80 values of 2.0, 1.0, and 4.0 µg/mL, respectively) as a positive control and showed no growth inhibition activity against the tumor cells HL60 and A549.

The alternative medicine pawpaw and its acetogenin constituents suppress tumor angiogenesis via the HIF-1/VEGF pathway.

Products that contain twig extracts of pawpaw (Asimina triloba) are widely consumed anticancer alternative medicines. Pawpaw crude extract (CE) and purified acetogenins inhibited hypoxia-inducible factor-1 (HIF-1)-mediated hypoxic signaling pathways in tumor cells. In T47D cells, pawpaw CE and the acetogenins 10-hydroxyglaucanetin (1), annonacin (2), and annonacin A (3) inhibited hypoxia-induced HIF-1 activation with IC(50) values of 0.02 microg/mL, 12 nM, 13 nM, and 31 nM, respectively. This inhibition correlates with the suppression of the hypoxic induction of HIF-1 target genes VEGF and GLUT-1. The induction of secreted VEGF protein represents a key event in hypoxia-induced tumor angiogenesis. Both the extract and the purified acetogenins blocked the angiogenesis-stimulating activity of hypoxic T47D cells in vitro. Pawpaw extract and acetogenins inhibited HIF-1 activation by blocking the hypoxic induction of nuclear HIF-1alpha protein. The inhibition of HIF-1 activation was associated with the suppression of mitochondrial respiration at complex I. Thus, the inhibition of HIF-1 activation and hypoxic tumor angiogenesis constitutes a novel mechanism of action for these anticancer alternative medicines.

Lipophilic 2,5-disubstituted pyrroles from the marine sponge Mycale sp. inhibit mitochondrial respiration and HIF-1 activation.

The lipid extract of the marine sponge Mycale sp. inhibited the activation of hypoxia-inducible factor-1 (HIF-1) in a human breast tumor T47D cell-based reporter assay. Bioassay-guided isolation and structure elucidation yielded 18 new lipophilic 2,5-disubstituted pyrroles and eight structurally related known compounds. The active compounds inhibited hypoxia-induced HIF activation with moderate potency (IC50 values <10 microM). Mechanistic studies revealed that the active compounds suppressed mitochondrial respiration by blocking NADH-ubiquinone oxidoreductase (complex I) at concentrations that inhibited HIF-1 activation. Under hypoxic conditions, reactive oxygen species produced by mitochondrial complex III are believed to act as a signal of cellular hypoxia that leads to HIF-1alpha protein induction and activation. By inhibiting electron transport (or delivery) to complex III under hypoxic conditions, lipophilic Mycale pyrroles appear to disrupt mitochondrial ROS-regulated HIF-1 signaling.

Molecular-targeted antitumor agents. 19. Furospongolide from a marine Lendenfeldia sp. sponge inhibits hypoxia-inducible factor-1 activation in breast tumor cells.

A natural product chemistry-based approach was employed to discover small-molecule inhibitors of the important tumor-selective molecular target hypoxia-inducible factor-1 (HIF-1). Bioassay-guided isolation of an active lipid extract of a Saipan collection of the marine sponge Lendenfeldia sp. afforded the terpene-derived furanolipid furospongolide as the primary inhibitor of hypoxia-induced HIF-1 activation (IC(50) 2.9 µM, T47D breast tumor cells). The active component of the extract also contained one new cytotoxic scalarane sesterterpene and two previously reported scalaranes. Furospongolide blocked the induction of the downstream HIF-1 target secreted vascular endothelial growth factor (VEGF) and was shown to suppress HIF-1 activation by inhibiting the hypoxic induction of HIF-1α protein. Mechanistic studies indicate that furospongolide inhibits HIF-1 activity primarily by suppressing tumor cell respiration via the blockade of NADH-ubiquinone oxidoreductase (complex I)-mediated mitochondrial electron transfer.