Catalytic-Type Excited-State N-H Proton-Transfer Reaction in 7-Aminoquinoline and Its Derivatives.

7-Aminoquinoline (7AQ) and various amino derivatives thereof (-NHR) have been strategically designed and synthesized to study their excited-state proton-transfer (ESPT) properties. Due to the large separation between the proton donor -NHR and the acceptor -N- site, ESPT in 7AQ derivatives, if available, should proceed under protic solvent catalysis. ESPT is found to be influenced by the acidity of -NHR and the basicity of the proton-acceptor -N- in the quinoline moiety. The latter is varied by the resonance effect at the quinoline -N- site induced by the -NHR substituent. For those 7AQ derivatives undergoing ESPT, increased quinoline basicity results in a faster rate of ESPT, implying that proton donation from methanol to the quinoline moiety may serve as a key step in the process. Our studies also indicate the existence of an equilibrium between cis and trans arrangements of -NHR in terms of its hydrogen-bond (H-bond) configuration with methanol, whereby only the cis-H-bonded form undergoes methanol-assisted ESPT. With one exception, the interconversion between cis and trans configurations is much faster than the rate of ESPT, yielding amino-type (normal form) and imine-type (proton-transfer tautomer) emissions with distinct relaxation dynamics.

Liposomal PHD2 Inhibitors and the Enhanced Efficacy in Stabilizing HIF-1α.

Prolyl hydroxylase domain-containing protein 2 (PHD2) inhibition, which stabilizes hypoxia-inducible factor (HIF)-1α and thus triggers adaptation responses to hypoxia in cells, has become an important therapeutic target. Despite the proven high potency, small-molecule PHD2 inhibitors such as IOX2 may require a nanoformulation for favorable biodistribution to reduce off-target toxicity. A liposome formulation for improving the pharmacokinetics of an encapsulated drug while allowing a targeted delivery is a viable option. This study aimed to develop an efficient loading method that can encapsulate IOX2 and other PHD2 inhibitors with similar pharmacophore features in nanosized liposomes. Driven by a transmembrane calcium acetate gradient, a nearly 100% remote loading efficiency of IOX2 into liposomes was achieved with an optimized extraliposomal solution. The electron microscopy imaging revealed that IOX2 formed nanoprecipitates inside the liposome's interior compartments after loading. For drug efficacy, liposomal IOX2 outperformed the free drug in inducing the HIF-1α levels in cell experiments, especially when using a targeting ligand. This method also enabled two clinically used inhibitors-vadadustat and roxadustat-to be loaded into liposomes with a high encapsulation efficiency, indicating its generality to load other heterocyclic glycinamide PHD2 inhibitors. We believe that the liposome formulation of PHD2 inhibitors, particularly in conjunction with active targeting, would have therapeutic potential for treating more specifically localized disease lesions.