ZM-105180

Fluorescent mols. have been used for various applications in biol. system monitoring.Considering the complexity of cellular systems, there is a huge demand for diverse fluorescent organic mol. scaffolds.However, only a limited number of fluorescent scaffolds have been reported due to the lack of a rational design strategy.We serendipitously discovered N4-phenylquinazoline-4,6-diamine as a fluorescent scaffold with turn-on characteristics.To improve the photophys. property of the initial fluorescence mol., we synthesized derivatives of the N4-phenylquinazoline-4,6-diamine and found systematic correlation between electronic d. of the Ph substituent of the scaffold and fluorescence intensity.Through tuning the photophys. property of the scaffold and a rational design strategy, we developed N4-dichlorophenylquinazoline-4,6-diamine as a potential fluorophore for various biol. applications.To prove the value of the developed fluorescent scaffold, we devised formaldehyde (FA) fluorescent sensor by tailoring amine on 6-position of N4-dichlorophenylquinazoline-4,6-diamine to employ a 2-aza-Cope rearrangement as the mol. detection mechanism with double-digit nanomolar detection limits.FA level in live HeLa cells were successfully visualized with the probe, exhibiting that N4-dichlorophenylquinazoline-4,6-diamine can serve as a useful mol. scaffold for offering various fluorescent sensors toward the investigation of physiol. and pathol. processes in live cells.

The abnormal biological functions of HDAC6 were closely related to the occurrence and development of various tumors, making HDAC6 gradually become promising therapeutic target for cancer treatment and inspiring researchers to explore and develop selective HDAC inhibitors. In this study, based on the classical pharmacophore model of HDAC inhibitors, 20 compounds were designed and synthesized by modifying the Cap group, and the biological activities of the target compounds were assessed through anti-proliferation and enzyme inhibition experiments. The title compounds exhibited varying degrees of inhibitory activities against the selected tumor cell lines, especially the compounds 9m, 9q, and 12c, which were further evaluated at the enzymatic level. The enzyme inhibition assay showed that compound 12c exerted broad-spectrum enzyme inhibitory activities and compounds 9m and 9q were more inclined to inhibit HDAC6, exhibiting certain selective inhibitory activities among the representative subtypes. Moreover, the binding modes of compounds 9q and 12c in HDAC1&6 were further explored via computational approaches to elucidate the molecular mechanisms underlying selective inhibitory activities, providing valuable hints for the discovery of novel HDAC6 inhibitors.