RESUMEN
Toll-like receptors (TLRs) are a family of proteins that recognize pathogen associated molecular patterns (PAMPs). Their primary function is to activate innate immune responses while also involved in facilitating adaptive immune responses. Different TLRs exert distinct functions by activating varied immune cascades. Several TLRs are being pursued as cancer drug targets. We discovered a novel, highly potent and selective small molecule TLR8 agonist DN052. DN052 exhibited strong in vitro cellular activity with EC50 at 6.7 nM and was highly selective for TLR8 over other TLRs including TLR4, 7 and 9. DN052 displayed excellent in vitro ADMET and in vivo PK profiles. DN052 potently inhibited tumor growth as a single agent. Moreover, combination of DN052 with the immune checkpoint inhibitor, selected targeted therapeutics or chemotherapeutic drugs further enhanced efficacy of single agents. Mechanistically, treatment with DN052 resulted in strong induction of pro-inflammatory cytokines in ex vivo human PBMC assay and in vivo monkey study. GLP toxicity studies in rats and monkeys demonstrated favorable safety profile. This led to the advancement of DN052 into phase 1 clinical trials.
RESUMEN
A new family of p-quaterphenyls 1-6 laterally substituted with a bulky electron-accepting dimesitylboryl group has been designed and synthesized. These compounds were characterized by X-ray crystallography, UV-vis and fluorescence spectroscopy, and DFT calculations as well as thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), and cyclic voltammetry (CV). X-ray single-crystal analysis revealed that the p-quaterphenyl main chain framework exhibits a twisted structure due to the steric effect of the lateral boryl group, and the intermolecular interactions are effectively suppressed in the solid state. Despite the significantly twisted main-chain structure, these molecules still display efficient intramolecular charge-transfer emissions with large Stokes shifts. An intriguing finding is that all these molecules show bright fluorescence with good to excellent quantum yields in the blue region in the solid state. In addition, the two representative p-quaterphenyls 3 and 4 containing both the electron-accepting boryl group and the electron-donating carbazolyl (3) or diphenylamino group (4) possess high thermal stability and good oxidation-reduction reversibility, which together with their excellent solid-state fluorescence efficiency make them promising bipolar transporting blue emitters.
RESUMEN
We disclose two novel BODIPY dyes, which contain the bulky substituent, [(4-dimesitylboryl)phenyl]ethynyl at 2- and 2,6-positions. The steric bulkiness of the boryl group is effective to suppress the intermolecular interaction in the solid state and thus these two compounds display intense fluorescence not only in solution but also in the solid state. In addition, the BODIPY dyes display sensitive fluorescence responses to fluoride and cyanide anions through the complexation with the boron center of the boryl group and the subsequent decomposition of the BODIPY core, illustrating their potential uses for the fluorescence sensing of fluoride and cyanide ions.
RESUMEN
A new class of organoboron compounds containing a boryl and an amino group at the o,o'-positions of biphenyls display bright through-space intramolecular charge transfer fluorescence owing to the close contact between the boryl and the amino groups. Binding of the fluoride ions results in the remarkable blue shift and color change of the fluorescence, enabling colorimetric and ratiometric fluoride ion sensing.
RESUMEN
Intense solid-state emissions with good to excellent quantum yields were achieved through the introduction of bulky electron-donating diphenylamino groups at the side positions of an electron-accepting para-terphenyl framework.