ABSTRACT
Eleven novel NNN Cu(II) complexes supported by a tridentate bis(imidazo[1,2-α]pyridin-2-yl)pyridine ligand were synthesized and characterized by elemental analysis, HRMS, and X-ray determination. Target prediction and docking studies indicated that these pincer complexes formed hydrogen bonds with Asp33 and Gly35 of Cathepsin D protein, which is highly associated with prognosis of advanced prostate cancer. Furthermore, they exhibited anti-proliferation activity in both androgen-sensitive and androgen-insensitive prostate cancer cells according to WST-1 assay results. Mechanistic study showed that pincer complexes arrested cell cycle progression at G0/G1 phase and inhibited Cathepsin D regulated signaling pathways. Most importantly, new pincer copper complexes significantly inhibited xenograft prostate cancer growth along with a promising in vivo safety profile. In summary, these results suggest the applicability of the developed novel pincer copper complexes as promising anticancer agents for prostate cancer treatment.
Subject(s)
Antineoplastic Agents , Coordination Complexes , Neoplasms , Humans , Copper/chemistry , Cathepsin D , Androgens , Crystallography, X-Ray , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Coordination Complexes/pharmacology , Coordination Complexes/chemistryABSTRACT
Human neutrophil elastase (HNE) has been identified as a potential therapeutic target for the discovery of anti-inflammatory drugs for decades. However, little progress has been made on assays measuring the activity of HNE, especially on synthetic substrates which play essential role in determination of HNE activity. Herein, a small-molecule compound, 2,2,3,3,3-pentafluoro-N-(2-oxo-4-(trifluoromethyl)-2H-chromen-7-yl)-propanamide (compound 4), has been successfully designed as the first ever non-peptide-based fluorogenic substrate for HNE. A "turn-on" fluorometric assay based on 4 has been successfully developed for rapid determination of HNE activity and the inhibitory kinetic study. Most importantly, the probe 4 shows highly specific response for HNE among seven tested hydrolases or proteins and can be directly used to detect the elevated HNE activity in the serum of chronic obstructive pulmonary disease (COPD) patients compared to that of healthy controls. This specific and cost-effective probe will facilitate future high-throughput discovery of HNE inhibitors and clinical diagnosis of elastase-related diseases.
