Ring-opening polymerisation of alkyl-substituted ε-caprolactones:kinetic effects of substitution position†

Ring-opening polymerisation (ROP) of lactones has been proven as a powerful technique to generate polyesters with high levels of control over molar mass and polymer dispersity. However, the introduction of functional groups on the monomer ring structure can dramatically influence the ability of a monomer to undergo ROP. Therefore, understanding the structure–reactivity relationship of functional monomers is essential to gain access to materials with chemical functionality via direct polymerisation. Herein, we report how structural modifications of alkyl-substituted ε-caprolactones affected their reactivity towards the ring-opening of the functional monomer. We observed that the reactivity was strongly influenced by the substituent position, wherein the δ-substituted monomer exhibited the fastest polymerisation kinetics. In contrast, a substituent placement in the ε-position significantly reduced polymerisation time compared to other substituent positions. Moreover, the thermal properties of the resultant functional ε-polycaprolactones were investigated and showed no significant change in the thermal transitions. This demonstrates that functional caprolactone monomers with sterically demanding functional groups can still undergo direct ring-opening polymerisation and that careful positioning of these functional groups enables control of the rate of polymerisation, a crucial parameter to be considered for the design of new prospective functional monomers and their industrial applications

Napabucasin and Related Heterocycle-Fused Naphthoquinones as STAT3 Inhibitors with Antiproliferative Activity against Cancer Cells

Napabucasin (<b>6</b>) and its angularly anellated isomer (<b>7</b>), for which the synthesis is described, together with related plant-derived naphthoquinones, were evaluated in vitro against human breast cancer (MDA-MB-231) and chronic myelogenous leukemia (K562) cells. As observed for β-lapachone (<b>3</b>), the active naphthoquinones all induced apoptosis in a cell-cycle-independent fashion. In contrast to the pyran-fused β-lapachone (<b>3</b>), however, the most potent furan-fused naphthoquinones were able to redox cycle and generate superoxide in cell-based assays, which was independent of NAD­(P)­H:quinone oxido-reductase 1. In a homogeneous time-resolved fluorescence (HTRF) assays with MDA-MB-231 cells, both napabucasin (<b>6</b>) and isonapabucasin (<b>7</b>) were identified as targeting STAT3 phosphorylation. In addition, drug affinity responsive target stability assays were performed to validate a direct interaction of the naphthoquinones with STAT3. Isonapabucasin (<b>7</b>) turned out to be twice as potent against STAT3 as napabucasin (<b>6</b>) in the HTRF assay, with an EC₅₀ in the submicromolar range, which was in excellent agreement with the potency of both agents to inhibit the growth of MDA-MB-231 cells. Moreover, molecular docking experiments predicted different binding modes to the STAT3 SH2 domain for the linearly anellated napabucasin (<b>6</b>) and its angularly anellated isomer (<b>7</b>)