ABSTRACT
A novel series of 6-benzyl substituted 4-aminocarbonyl-1,4-diazepane-2,5-diones were explored as human chymase inhibitors using structure-based drug design according to the X-ray cocrystal structure of chymase and compound 1. The optimization focused on the prime site led to the attainment of compounds that showed potent inhibitory activity, and among them, 18R shows a novel interaction mode.
Subject(s)
Azepines/chemical synthesis , Chymases/antagonists & inhibitors , Drug Design , Enzyme Inhibitors/chemistry , Ethylmorphine/chemical synthesis , Azepines/chemistry , Azepines/pharmacology , Catalytic Domain , Crystallography, X-Ray , Enzyme Activation/drug effects , Enzyme Inhibitors/pharmacology , Ethylmorphine/chemistry , Ethylmorphine/pharmacology , Humans , Inhibitory Concentration 50 , Molecular Structure , Structure-Activity RelationshipABSTRACT
Naphtho[2,1-α]pyrrolo[3,4-c]carbazole-5,7(6H,12H)-dione (NPCD) is known to be a very potent and selective cyclin D1-CDK4 inhibitors and could induce strong G1 phase arrest in breast tumor cell lines. In this work, the synthesis of five NPCD glycosides and their cytotoxic activities against eight tumor cell lines are presented, as well as the investigation of their cell cycle arrest profiles. The results showed that the introduction of a sugar moiety onto NPCD did not affect much of their cytotoxic activities, while the subtle structure of the sugar moiety affected the underlying mechanism strongly. In addition, NPCD showed distinct cell-cycle arrest profiles in BxPC3 prostate cells and MCF-7 breast cells, while NPCD glycosides shared similar cell cycle arrest profiles in MCF-7 and BxPC3 cells, which also indicated that not only the indolocarbazole framework as well known before but the sugar moiety can have a profound impact on the mechanism of action for these types of compounds.
Subject(s)
Antineoplastic Agents , Cell Cycle/drug effects , Glycosides , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Antineoplastic Agents/toxicity , Carbazoles/chemical synthesis , Carbazoles/chemistry , Carbazoles/pharmacology , Cell Line, Tumor , Cell Survival , Ethylmorphine/chemical synthesis , Ethylmorphine/chemistry , Ethylmorphine/pharmacology , Glycosides/chemical synthesis , Glycosides/chemistry , Glycosides/pharmacology , Glycosides/toxicity , Humans , Molecular Structure , Naphthols/chemical synthesis , Naphthols/chemistry , Naphthols/pharmacology , Pyrroles/chemical synthesis , Pyrroles/chemistry , Pyrroles/pharmacologyABSTRACT
2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine has been prepared in 26% yield from 3-amino-2-phenylpropenal and creatinine which were heated with N,O-bis(trimethylsilyl)acetamide at 120 degrees C for 2 h. Under certain other conditions, the main product was a pyrimidine derivative.
