ABSTRACT
Polyamine conjugated flavonoid with a naphthalene moiety (ZYY14) displayed excellent therapeutic activity against hepatocellular carcinoma. In this study, three different series of novel flavonoid-polyamine conjugates were designed and screened against tumor cell lines. The structure-activity relationship study demonstrated the importance of the naphthalene moiety (as the B-ring), the basic side chains in the A-ring, and the methoxy group linked to the C-ring. The optimized compound 9b displayed better antitumor potency in vitro and in vivo than the lead compound ZYY14. Fluorescent assays revealed that 9b could enter cancer cells via polyamine transporter (PAT) and locate in mitochondria and endoplasmic reticulum. Compound 9b and ZYY14 demonstrated similar apoptotic mechanism in the cytotoxicity studies and stimulated the expression of apoptosis-related proteins, such as p-p38, p-JNK, p53 and Bax. In addition, 9b can initiate autophagy which inhibited the occurrence of apoptosis. Thus, 9b can be used as a valuable lead for the future development of antitumor agents.
Subject(s)
Antineoplastic Agents/pharmacology , Flavonoids/pharmacology , Naphthalenes/pharmacology , Polyamines/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Flavonoids/chemistry , Hep G2 Cells , Humans , Mice , Mice, Inbred Strains , Molecular Structure , Naphthalenes/chemistry , Neoplasms, Experimental/drug therapy , Neoplasms, Experimental/pathology , Polyamines/chemistry , Structure-Activity RelationshipABSTRACT
A novel series of 7-aminoalkyl-substituted flavonoid derivatives 5a-5r were designed, synthesized and evaluated as potential cholinesterase inhibitors. The results showed that most of the synthesized compounds exhibited potent acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities at the micromolar range. Compound 2-(naphthalen-1-yl)-7-(8-(pyrrolidin-1-yl)octyloxy)-4H-chromen-4-one (5q) showed the best inhibitory activity (IC50, 0.64µM for AChE and 0.42µM for BChE) which were better than our previously reported compounds and the commercially available cholinergic agent Rivastigmine. The results from a Lineweaver-Burk plot indicated a mixed-type inhibition for compound 5q with AChE and BChE. Furthermore, molecular modeling study showed that 5q targeted both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. Besides, these compounds (5a-5r) did not affect PC12 and HepG2 cell viability at the concentration of 10µM. Consequently, these flavonoid derivatives should be further investigated as multipotent agents for the treatment of Alzheimer's disease.
