In biology-oriented synthesis the underlying scaffold classes of natural products selected in evolution are used to define biologically relevant starting points in chemical structure space for the synthesis of compound collections with focused structural diversity. Here we describe a highly enantioselective synthesis of natural-product-inspired 3,3'-pyrrolidinyl spirooxindoles--which contain an all-carbon quaternary centre and three tertiary stereocentres. This synthesis takes place by means of an asymmetric Lewis acid-catalysed 1,3-dipolar cycloaddition of an azomethine ylide to a substituted 3-methylene-2-oxindole using 1-3 mol% of a chiral catalyst formed from a N,P-ferrocenyl ligand and CuPF(6)(CH(3)CN)(4). Cellular evaluation has identified a molecule that arrests mitosis, induces multiple microtubule organizing centres and multipolar spindles, causes chromosome congression defects during mitosis and inhibits tubulin regrowth in cells. Our findings support the concept that compound collections based on natural-product-inspired scaffolds constructed with complex stereochemistry will be a rich source of compounds with diverse bioactivity.

Colorectal cancer (CRC) metastatic dissemination to the liver is one of the most life‐threatening malignancies in humans and represents the leading cause of CRC‐related mortality. Herein, we adopted a gene transfer strategy into mouse hematopoietic stem/progenitor cells to generate immune‐competent mice in which TEMs—a subset of Tie2+ monocytes/macrophages found at peritumoral sites—express interferon‐alpha (IFNα), a pleiotropic cytokine with anti‐tumor effects. Utilizing this strategy in mouse models of CRC liver metastasis, we show that TEMs accumulate in the proximity of hepatic metastatic areas and that TEM‐mediated delivery of IFNα inhibits tumor growth when administered prior to metastasis challenge as well as on established hepatic lesions, improving overall survival. Further analyses unveiled that local delivery of IFNα does not inhibit homing but limits the early phases of hepatic CRC cell expansion by acting on the radio‐resistant hepatic microenvironment. TEM‐mediated IFNα expression was not associated with systemic side effects, hematopoietic toxicity, or inability to respond to a virus challenge. Along with the notion that TEMs were detected in the proximity of CRC metastases in human livers, these results raise the possibility to employ similar gene/cell therapies as tumor site‐specific drug‐delivery strategies in patients with CRC.

Turning the motor off: A malachite green based assay leads to the identification of BTB‐1 (see picture), the first small‐molecule inhibitor of the mitotic motor protein Kif18A. BTB‐1 reversibly inhibits the ATPase activity of the recombinant motor domain of Kif18A in vitro (see picture; red microtubules, blue/black structure =Kif18A) and will be a valuable tool to dissect the mechanochemical properties of Kif18A.

A synthesis of novel pyrazolopyridine, benzopyranopyrazolopyridine, and oxygen-bridged pyrazolo-, tetrazolo-, benzimidazo-, and thiazolopyrimidines via Hantzsch- and Biginelli-like condensations has been developed. The ability of these compounds to inhibit Eg5 activity has been examined. The results indicate that synthetic manipulations in the monastrol thiourea moiety are inefficient.

Motor abgewürgt: Mithilfe eines auf Malachitgrün beruhenden Assays gelang die Identifizierung von BTB‐1 (siehe Bild), dem ersten niedermolekularen Inhibitor von Kif18A. BTB‐1 hemmt die ATPase‐Aktivität der rekombinanten Motordomäne von Kif18A in vitro reversibel (rot=Mikrotubulus, blau‐schwarze Struktur=Kif18A) und wird ein nützliches Hilfsmittel für die Analyse der mechanochemischen Eigenschaften von Kif18A sein.

No abstract

No abstract