The biological screening results in this study established the importance of the nitrogen atom at the ortho position as well as the beneficial effect of a methyl substituent at the 4- or 5-position of the pyridine ring. Two pyridine epothilone B analogs (i.e. compounds 3 and 4) possessing higher potencies against drug-resistant tumor cells than epothilone B, the most powerful of the naturally occurring epothilones, were identified.

The macrolactonization-based strategy for the total synthesis of epothilones has been streamlined and improved to a high level of efficiency and stereoselectivity. This strategy has been applied to the construction of vinyl iodide 19 which served as a common intermediate for the synthesis of a series of natural and designed epothilones including an epothilone B10 (3), epothilone F (5), 16-desmethylepothilone B (14), pyridine epothilones 57a-57g, dimeric epothilones 59 and 61, and benzenoid epothilones 63a-63g.

Introduction The [3,3]‐Sigmatropic Rearrangements The [2,3]‐Sigmatropic Rearrangements The Dyotropic Rearrangements The B amberger Rearrangements The B eckmann Rearrangements The N eber Rearrangements The L ossen Rearrangement Other Rearrangements

The eucalyptus weevil, Gonipterus platensis (Coleoptera, Curculionidae), is a major pest of eucalyptus plantations worldwide. To date, no pheromones have been identified for this species, despite their valuable potential as tools in monitoring or control strategies. Here we report the detection and identification of pheromones candidates of G. platensis. The weevil's volatile compounds were collected by solid phase micro extraction (SPME) and monolithic material sorption extraction (MMSE). Using Gas Chromatography coupled to Mass Spectrometry (GC/MS) analysis, eleven insect specific compounds were detected and identified: verbenene, cis‐verbenol, trans‐verbenol, verbenone, 2‐oxo‐1,8‐cineole, 9‐hydroxy‐1,8‐cineole, 2‐α‐hydroxy‐1,8‐cineole, 3‐oxo‐1,8‐cineole, 2‐β‐hydroxy‐1,8‐cineole, 3‐α‐hydroxy‐1,8‐cineole and 7‐hydroxy‐1,8‐cineole. Three of these compounds, verbenene, cis‐verbenol and trans‐verbenol, were shown to be male‐specific. Antennal sensitivity towards ten compounds emitted by G. platensis was detected using Gas Chromatography–Mass Spectrometry/Electroantennographic Detection (GC‐MS/EAD). Extracts from virgin males proved to be attractive to virgin females in olfactometer bioassays. Further behavioural bioassays showed that both virgin females and virgin males were attracted to the male‐specific compound cis‐verbenol and that virgin females were attracted to trans‐verbenol. Verbenone was attractive to mated females. Regarding 2‐α‐hydroxy‐1.8‐cineole and 2‐oxo‐1,8‐cineole, which are produced by both sexes, the alcohol was attractive to virgin males and both the alcohol and the ketone were repellant to mated females. This is, to our knowledge, the first identification of pheromones candidates in Gonipterus spp. and also the first evidence of cineole metabolites acting as semiochemicals.

Hypoxia-inducible factor 1 (HIF-1) is the central mediator of cellular responses to low oxygen and has recently become an important therapeutic target for solid tumor therapy. Inhibition of HIF-1 is expected to result in the attenuation of hypoxia-inducible genes, which are vital to many aspects of tumor biology, including adaptative responses for survival under anaerobic conditions. To identify small molecules inhibiting the HIF-1 pathway, we did a biological screen on a 10,000-membered natural product-like combinatorial library. The compounds of the library, which share a 2,2-dimethylbenzopyran structural motif, were tested for their ability to inhibit the hypoxic activation of an alkaline phosphatase reporter gene under the control of hypoxia-responsive elements in human glioma cells. This effort led to the discovery of 103D5R, a novel small-molecule inhibitor of HIF-1α. 103D5R markedly decreased HIF-1α protein levels induced by hypoxia or cobaltous ions in a dose- and time-dependent manner, whereas minimally affecting global cellular protein expression levels, including that of control proteins such as HIF-1β, IκBα, and β-actin. The inhibitory activity of 103D5R against HIF-1α was clearly shown under normoxia and hypoxia in cells derived from different cancer types, including glioma, prostate, and breast cancers. This inhibition prevented the activation of HIF-1 target genes under hypoxia such as vascular endothelial growth factor (VEGF) and glucose transporter-1 (Glut-1). Investigations into the molecular mechanism showed that 103D5R strongly reduced HIF-1α protein synthesis, whereas HIF-1α mRNA levels and HIF-1α degradation were not affected. 103D5R inhibited the phosphorylation of Akt, Erk1/2, and stress-activated protein kinase/c-jun-NH2-kinase, without changing the total levels of these proteins. Further studies on the mechanism of action of 103D5R will likely provide new insights into its validity/applicability for the pharmacologic targeting of HIF-1α for therapeutic purposes.

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New gamma-amino esters and amides were prepared by a radical 1,4-addition of carbon radicals to acrylic derivatives. Alpha-amino acids derivatives holding chiral auxiliaries as radical precursors and different chiral olefins were used and chiral induction on the C-gamma center was discussed.