ChemBioChem

The cover picture shows an imaging study of a cytotoxic small molecule AA005, which is able to recognize and enter human cancer cells selectively. Fluorescent labeling of AA005 was successfully accomplished by a bioactivity assessment-aided protocol after examining a number of potential derivative positions in parallel. AA005-flu was found to exhibit similar cell selectivity to its parent molecule AA005. Fluorescent images of AA005-flu show a significant difference in drug distribution between cancerous and normal cells, with accumulation of AA005-flu occurring in the mitochondria of cancers cells. For more information, see the article by Z.-J. Yao et al. on p. 172 ff.

Brief encounter. Zn^II- and Cu^II-induced aggregation of the peptide amyloid-β (Aβ) are considered to be involved in Alzheimer's disease. The present data indicate that Zn^II and Cu^II transiently form a monomeric complex with Aβ40/42 before aggregation, which exhibits no further transiently stable intermediate up to ∼15-mer.

Sugars in a row. A new strategy for carbohydrate microarrays based on photochemical ligation of perfluorophenylazide-derivatized carbohydrates to PEO surfaces is presented. It constitutes a controllable and robust method of array fabrication, on the carbohydrate-chemistry and on the surface-chemistry levels, and the resulting carbohydrate arrays can be efficiently used to reveal the recognition patterns of carbohydrate-binding proteins.

Single strand stands out. A polymerase chain reaction (PCR) with a primer containing a mirror image DNA (L-DNA) sequence tag at the 5′-end produced an L-DNA duplex labeled with a single strand of L-DNA of defined sequence. The PCR products could be directly detected on the surface plasmon resonance (SPR) imaging array where the complementary L-DNA sequences were immobilized.

The potent anticancer agent AA005 has been successfully biolabeled with fluorescein. Of the two compounds synthesized, only AA005-flu retained the selectivity of AA005 for cancerous (e.g., BEL-7404) over normal (e.g., LO2) cells. Fluorescent-imaging studies revealed that AA005-flu's distribution in human normal cells was significantly difference from that in cancer cells, where AA005-flu accumulates in the mitochondria. This direct and visible evidence suggests that membrane recognition of AA005 is involved in its selective action.

Charge less. We show that a novel inhibitor (1) of PTP1B is active in cells at low micromolar concentrations and prevents PTP1B-mediated dephosphorylation of the FLT3-ITD receptor tyrosine kinase (shown). We have synthesized a series of derivatives for basic SAR analysis and have conducted computer-modeling studies to predict its binding mode. This class of uncharged inhibitors could be a starting point for the development of new drugs targeting protein tyrosine phosphatases.

A potential insulin mimetic. Protein tyrosine phosphatase 1B (PTP1B) negatively regulates insulin signaling, and PTP1B inhibitors have been seen as promising therapeutic agents against obesity and type 2 diabetes. Here we report that hyrtiosal, a marine natural product from the marine sponge Hyrtios erectus and newly identified as a PTP1B inhibitor, shows extensive cellular effects on PI3K/AKT activation, glucose transport, and TGFβ/Smad2 signaling.

Finding sialidase natural substrates. Sialoside libraries containing sialosides with different naturally occurring sialic acid forms α2,3- or α2,6-linked to Galβ-pNP or GalNAcβ-pNP have been chemoenzymatically prepared by using a highly efficient one-pot three-enzyme system. Colorimetric high-throughput screening assays on a 96-well plate-based format found diversity in substrate specificity of various bacterial sialidases (see scheme).

Trick of the light. We describe the covalent modification of the SssI DNA methyltransferase (M.SssI) with 4,5-dimethoxy-2-nitrobenzyl-bromide (DMNBB) to obtain M.SssI with a caged active-site Cys residue (see figure). Irradiation of the caged enzyme with near-ultraviolet light restored its catalytic activity. The results indicate that caging by DMNBB can be used for the reversible inactivation of DNA methyltransferases.

Oxylipins are fatty acid-derived molecules that control defense and metabolic activities in attacked plants. They are generated in areas where a leaf is damaged and are therefore ingested by the insect upon feeding. 12-Oxophytodienoic acid (OPDA) is rapidly isomerized by an enzyme in the insect's gut tissue to the planar iso-OPDA (see scheme). This reaction suggests that OPDA is also physiologically active in herbivorous insects, maybe due to its structural similarity to prostaglandins.

Stressed out. Tryptophan derivatives are a target for oxidative stress induced by reactive oxygen and nitrogen species, such as peroxynitrite (ONOO⁻/ONOOH) produced from NO^. and O₂^.−. Beside oxidation, N1-nitrosation is the main reaction of N-blocked Trp derivatives (melatonin, N-acetyl-L-tryptophan and Ac–Asp–Ile–Ile–Trp) with peroxynitrite at physiological pH (see scheme).

Heavy metal fusion. An enzyme with a reactive thiol function within its catalytic cavity, namely papain, was site-specifically modified by several sandwich- or half-sandwich-type organometallic complexes. This approach should be useful for producing efficient heavy-atom derivatives for protein X-ray crystallography.

Accommodating the organopalladium conditions. An aryl iodide tag on the Ras protein was chemoselectively modified by Mizoroki–Heck and Sonogashira reactions (see figure). The Ras protein retained its biological activity under organopalladium conditions. These results were confirmed by Western blot, LC-MS, and in vitro pull-down analyses.

Sugar phosphate cyclases (SPCs) catalyze the cyclization of sugar phosphates to produce a variety of cyclitol intermediates that serve as the building blocks of many primary and secondary metabolites. By using genetic and biochemical approaches, a number of new SPCs have been identified. Further phylogenetic analysis of SPC sequences revealed a new clade of SPCs that might regulate the biosynthesis of a novel set of secondary metabolites.