ABSTRACT
This study was conducted to design and synthetize highly efficient, specific, non-resistant small MEK inhibitors. Based on active small molecules which have been reported, we studied the action mode with MEK protein using Autodock 4.2, generated innovative and feasible design method, designed novel small MEK protein inhibitors with a reference to molecular modeling and docking. The anti-tumor activities of four kinds of cells including MCF-7, PANC-1, SY5Y, A549 were tested with MTT method in vitro. The structure of 10 new small molecules has been determined with 1H NMR and 13C NMR. The compounds 4, 6, 7, 8, 10 had high antitumor activities, the compounds 1, 3, 5 also showed good activity, and the compounds 2, 9 showed cell selectivity in killing tumor.
Subject(s)
Antineoplastic Agents/chemistry , Drug Design , Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Cell Line, Tumor , Cell Proliferation , Drug Screening Assays, Antitumor , Humans , Models, Molecular , Molecular Structure , Structure-Activity RelationshipABSTRACT
Diosgenin can inhibit the growth of A375 and K562 cell lines and induce their apoptosis with an effect on pro-apoptotic members of Bcl-2 family. To study the SAR of diosgenin derivatives, and to improve the anti-tumor activity of diosgenin, a series of novel diosgenin derivatives were designed and synthesized. Their anti-tumor activities in vitro were evaluated. The results revealed that most of the new derivatives had potent effects against K562, A375 and A549 (three tumor cell lines) in vitro, and had no or less effect against H293 and L02 (two normal cell lines). Particularly, some compounds (e.g. 1, 6-8) showed excellent activities on K562 with IC50 values ranging from 1.96 to 4.35 micromol x L(-1).
Subject(s)
Antineoplastic Agents/chemical synthesis , Diosgenin/chemical synthesis , Drug Design , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Diosgenin/analogs & derivatives , Diosgenin/chemistry , Diosgenin/pharmacology , HumansABSTRACT
The purpose of this paper is to clarify the structure-activity relationship of anti-tumor activity of diosgenin derivatives in vitro. Study has found that diosgenin can inhibit the reproduction of tumor cells by inducing apoptosis and the main target spot of this effect is Bcl-2. Based on the characteristics of pharmacophoric points' of the three-dimensional pharmacophore for Bcl-2 inhibitors, we have docked lots of diosgenin derivatives with Bcl-2, then synthesized 31 compounds of them, finally assessed the anti-tumor activity of the diosgenin derivatives in vitro against A375, A549, HepG-2 and K562. Preliminary studies of SAR have indicated that the aliphatic esters, and aromatic esters of diosgenin without F ring have no anti-tumor activity in vitro. The triazole bromides of diosgenin all achieve fairly good anti-tumor activity in vitro, and those with larger hydrophobic group have the better activity. The stronger is the hydrogen bonding interaction and dipole-dipole interaction of the heterocyclic of diosgenin and diosgenin without F ring and the acid ester of diosgenin without F ring, the better is the activity of derivatives.
Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Apoptosis/drug effects , Diosgenin/analogs & derivatives , Diosgenin/pharmacology , Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitors , Antineoplastic Agents, Phytogenic/chemical synthesis , Antineoplastic Agents, Phytogenic/chemistry , Cell Line, Tumor , Diosgenin/chemical synthesis , Diosgenin/chemistry , Humans , Structure-Activity RelationshipABSTRACT
AIM: To investigate the chemical constituents of the bulbs of Fritillaria wabuensia. METHODS: Chromatography techniques were used to isolate the chemical constituents. EI-MS, 1HNMR, 13 CNMR and DEPT were used to determine the structures of the isolated constituents. RESULTS: Three alkaloids were isolated from the bulbs of Fritillaria wabuensia, and were identified as imperialine (I), imperialine-beta-N-oxside (II), isoverticine-beta-N-oxide (III). CONCLUSION: Isoverticine-beta-N-oxide was isolated from the bulbs of Fritillaria wabuensia for the first time. Isoverticine-beta-N-oxide is a new alkaloid.
