Inhibition of the hypoxia-inducible factor 1α (HIF-1α) pathway by disrupting its association with the transcriptional coactivator p300 inhibits angiogenesis and tumor development. Development of HIF-1α/p300 inhibitors has been hampered by preclinical toxicity; therefore, we aimed to identify novel HIF-1α/p300 inhibitors. Using a cell-free assay designed to test compounds that block HIF-1α/p300 binding, 170 298 crude natural product extracts and prefractionated samples were screened, identifying 25 active extracts. One of these extracts, originating from the marine sponge Latrunculia sp., afforded six pyrroloiminoquinone alkaloids that were identified as positive hits (IC50 values: 1-35 μM). Luciferase assays confirmed inhibition of HIF-1α transcriptional activity by discorhabdin B (1) and its dimer (2), 3-dihydrodiscorhabdin C (3), makaluvamine F (5), discorhabdin H (8), discorhabdin L (9), and discorhabdin W (11) in HCT 116 colon cancer cells (0.1-10 μM, p < 0.05). Except for 11, all of these compounds also reduced HIF-1α transcriptional activity in LNCaP prostate cancer cells (0.1-10 μM, p < 0.05). These effects occurred at noncytotoxic concentrations (<50% cell death) under hypoxic conditions. At the downstream HIF-1α target level, compound 8 (0.5 μM) significantly decreased VEGF secretion in LNCaP cells (p < 0.05). In COLO 205 colon cancer cells no activity was shown in the luciferase or cytotoxicity assays. Pyrroloiminoquinone alkaloids are a novel class of HIF-1α inhibitors, which interrupt the protein-protein interaction between HIF-1α and p300 and consequently reduce HIF-related transcription.

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Three new phytoecdysteroids, ajugacetalsterones C (1) and D (3) and breviflorasterone (2), were isolated from the roots of Ajuga macrosperma var. breviflora along with five known compounds, namely, 20-hydroxyecdysone, cyasterone, makisterone A, 20-hydroxyecdysone 3-acetate, and 20-hydroxyecdysone 2-acetate. The structures of 1-3 were elucidated on the basis of extensive 1D and 2D NMR spectroscopic studies. The new compounds possess acetal oxygen bridges between C-26 and C-20/C-22, or C-26/C-23, or a lactone bridge between C-26 and C-23.

Different neo-clerodane diterpenoids were isolated from a dichloromethane extract of Ajuga bracteosa depending on the isolation procedure used, owing to the labile nature of these tetrahydrofurofuran derivatives. Under "hydroxyl-free" purification conditions, both clerodin- and dihydroclerodin-type diterpenes were obtained [four new compounds, ajubractins A-D (1-4), along with clerodin (5), 3-epi-caryoptin (6), ajugapitin (7), 14,15-dihydroclerodin (8), 3-epi-14,15-dihydrocaryoptin (9), ivain II (10), and 14,15-dihydroajugapitin (11)]. When methanol-water mixtures were used for a C18 reversed-phase prepurification procedure and for semipreparative HPLC, the new ajubractin E (12) was also isolated along with 3 and 8-11, as previously, but 7 was the only tetrahydrofurofuran derivative obtained. Epimeric (15R and 15S) mixtures were obtained instead of 14-hydro-15-hydroxyclerodin derivatives [15-hydroxyajubractin C (13), 14-hydro-15-hydroxyajugachin A (14), and 14-hydro-15-hydroxyajugapitin (15)], along with 15-epi-lupulin B (16). The structures of the new compounds were elucidated by NMR and MS data analysis and by comparison with values previously reported. Antifeedant activity against Spodoptera littoralis larvae was evaluated for the compounds obtained.

neo-Clerodane diterpenes of plant origin are molecules difficult to monitor due to their nonspecific UV/vis absorption. The present work describes for the first time the application of the LC-MS-SPE-NMR technique for the isolation and characterization of three new neo-clerodane diterpenes, 3beta-hydroxyteucroxylepin and teuluteumin A and teuluteumin B, from Teucrium luteum subsp. flavovirens, harvested from two different locations.

Endophytic fungi are plant tissue-associated fungi that represent a rich resource of unexplored biological and chemical diversity. As part of an ongoing effort to characterize Amazon rainforest-derived endophytes, numerous fungi were isolated and cultured from plants collected in the Yasuní National Park in Ecuador. Of these samples, phylogenetic and morphological data revealed a previously undescribed fungus in the order Pleosporales that was cultured from the tropical tree Duroia hirsuta. Extracts from this fungal isolate displayed activity against Staphylococcus aureus and were thus subjected to detailed chemical studies. Two compounds with modest antibacterial activity were isolated, and their structures were elucidated using a combination of NMR spectroscopic analysis, LC-MS studies, and chemical degradation. These efforts led to the identification of stelliosphaerols A (1) and B (2), new sesquiterpene-polyol conjugates that are responsible, at least in part, for the S. aureus inhibitory activity of the fungal extract.

This review focuses on the occurrence and structural elucidation of neo-clerodane type diterpenes from Verbenaceae (no matter if recently reclassified based on phylogenetic research) and the semisynthetic compounds of closely related structure obtained. Biological activities of crude extracts and isolated diterpenes will be briefly discussed.

Six new naturally occurring ajugarin-like neo-clerodane diterpenoids, ajugaflorins A-F, along with six known compounds [the parent ajugarin I, ajugalides B and C, ajugamarin F4, ajugamacrin E, and ajugatakasin B] were isolated from A. macrosperma var. breviflora. The structures were elucidated by extensive NMR spectroscopic and MS analyses and comparison with data previously reported.