Fungal Metabolites in Forestry and Agriculture : Isolation, Characterization and Applications

Note:The fungus Pisolithus tinctorius was found to produce the antifungal metabolites p-hydroxybenzoylformic acid and (R)-(-)-p-hydroxymandelic acid. The absolute stereochemistry of the latter compound was established via stereospecific synthesis of both (R) and (S) enantiomers and NMR techniques. The structure-activity relationship was examined through the use of related compounds. Both of the natural products and a few of their analogues were found to inhibit spore germination and cause cell-specific disintegration (hyphallysis) to a number of phytopathogenic and dermatogenic fungi. It was concluded that P. tinctorius, which exists symbiotically on the roots of most forest trees, provides protection to its host trees against disease causing fungi. The fungus Suillus cavipes was shown to promote dichotomous branching and root development in hypocotyl cuttings of coniferous seedlings by inducing the biosynthesis of the phytohormone ethylene. […]Il a été découvert que les métabolites fongicides, l'acide p-hydroxybenzoylformique et l'acide (R)-(-)-p-hydroxymandélique, sont produits par le champignon Pisolithus tinctorius. La configuration absolue de l'acide p- hydroxymandélique a été établie par la synthèse stéréospécifique des énantiomères et par la résonance magnétique nucléaire du proton (RMN) de dérivés. La relation entre la structure et l'activité biologique des métabolites et de composes similaires a été examinée. Les produits naturels et quelques analogues préviennent la germination des spores et causent la désintégration cellulaire spécifique de certains champignons phytopathogènes et dermatogènes. Il a été conclu que le P. tinctorius, qui existe en symbiose sur les racines des arbres forestiers, protège son hôte contre les effects d'organismes pathogènes. Il a été démontré que le champignon SuilIus cavipes stimule la division dichotomisée et la rhizogénèse des boutures hypocotyles des jeunes conifères. Le S. cavipes induit la biosynthèse d'une phytohormone, l’éthylène. […

Mutant lamin A links prophase to a p53 independent senescence program

<p>Expression of oncogenes or short telomeres can trigger an anticancer response known as cellular senescence activating the p53 and RB tumor suppressor pathways. This mechanism is switched off in most tumor cells by mutations in p53 and RB signaling pathways. Surprisingly, p53 disabled tumor cells could be forced into senescence by expression of a mutant allele of the nuclear envelope protein lamin A. The pro-senescence lamin A mutant contains a deletion in the sequence required for processing by the protease ZMPSTE24 leading to accumulation of farnesylated lamin A in the nuclear envelope. In addition, the serine at position 22, a target for CDK1-dependent phosphorylation, was mutated to alanine, preventing CDK1-catalyzed nuclear envelope disassembly. The accumulation of this mutant lamin A compromised prophase to prometaphase transition leading to invaginations of the nuclear lamina, nuclear fragmentation and impaired chromosome condensation. Cells exited this impaired mitosis without cytokinesis and re-replicated their DNA ultimately arresting in interphase as polyploid cells with features of cellular senescence including increased expression of inflammatory gene products and a significant reduction of tumorigenicity <i>in vivo</i>.</p

Modular Assembly of Purine-like Bisphosphonates as Inhibitors of HIV‑1 Reverse Transcriptase

Bisphosphonates can mimic the pyrophosphate leaving group of the nucleotidyl transfer reaction and effectively inhibit RNA/DNA polymerases. In a search of HIV-1 reverse transcriptase (RT) inhibitors, a new chemotype of nonhydrolyzable purine diphosphate mimic was synthesized. A modular synthetic protocol was developed, utilizing 2-amino-6-(methylthio)-4-(trimethylsilyl)­nicotinonitrile as the key synthon in the preparation of highly substituted 2-aminonicotinonitriles. These building blocks were subsequently elaborated to the pyrido­[2,3-<i>d</i>]­pyrimidine bisphosphonates (PYPY-BPs). Biochemical screening identified analogs of PYPY-BPs that inhibit HIV-1 RT-catalyzed DNA synthesis

Crystallographic and thermodynamic characterization of phenylaminopyridine bisphosphonates binding to human farnesyl pyrophosphate synthase

<div><p>Human farnesyl pyrophosphate synthase (hFPPS) catalyzes the production of the 15-carbon isoprenoid farnesyl pyrophosphate. The enzyme is a key regulator of the mevalonate pathway and a well-established drug target. Notably, it was elucidated as the molecular target of nitrogen-containing bisphosphonates, a class of drugs that have been widely successful against bone resorption disorders. More recently, research has focused on the anticancer effects of these inhibitors. In order to achieve increased non-skeletal tissue exposure, we created phenylaminopyridine bisphosphonates (P<i>N</i>P-BPs) that have bulky hydrophobic side chains through a structure-based approach. Some of these compounds have proven to be more potent than the current clinical drugs in a number of antiproliferation assays using multiple myeloma cell lines. In the present work, we characterized the binding of our most potent P<i>N</i>P-BPs to the target enzyme, hFPPS. Co-crystal structures demonstrate that the molecular interactions designed to elicit tighter binding are indeed established. We carried out thermodynamic studies as well; the newly introduced protein-ligand interactions are clearly reflected in the enthalpy of binding measured, which is more favorable for the new P<i>N</i>P-BPs than for the lead compound. These studies also indicate that the affinity of the P<i>N</i>P-BPs to hFPPS is comparable to that of the current drug risedronate. Risedronate forms additional polar interactions via its hydroxyl functional group and thus exhibits more favorable binding enthalpy; however, the entropy of binding is more favorable for the P<i>N</i>P-BPs, owing to the greater desolvation effects resulting from their large hydrophobic side chains. These results therefore confirm the overall validity of our drug design strategy. With a distinctly different molecular scaffold, the P<i>N</i>P-BPs described in this report represent an interesting new group of future drug candidates. Further investigation should follow to characterize the tissue distribution profile and assess the potential clinical benefits of these compounds.</p></div

Bisphosphonate inhibitors of hFPPS.

<p>Carbon hydrogens in the R₂ side chains are omitted for simplicity. IC₅₀ values were reported previously [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0186447#pone.0186447.ref009" target="_blank">9</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0186447#pone.0186447.ref010" target="_blank">10</a>]. SASA (total solvent accessible surface area) and FOSA (hydrophobic component of SASA) were calculated with QikProp 3.2 by using a virtual probe of 1.4 Å radius.</p

Crystallization conditions.

<p>Crystallization conditions.</p