Syntheses and characterization of non-bisphosphonate quinoline derivatives as new FPPS inhibitors

• Published in: Biochimica et biophysica acta Vol. 1840; no. 3; pp. 1051 - 1062
• Main Authors: Liu, Jinggong, Liu, Weilin, Ge, Hu, Gao, Jinbo, He, Qingqing, Su, Lijuan, Xu, Jun, Gu, Lian-quan, Huang, Zhi-shu, Li, Ding
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.03.2014
• Subjects: active sites; Allosteric site; Amino Acid Sequence; binding capacity; biosynthesis; Bisphosphonate; Cancer; cholesterol; Diphosphonates - pharmacology; enzyme inhibition; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - pharmacology; Enzyme Inhibitors - therapeutic use; Farnesyl pyrophosphate synthase; fluorescence; fluorescence microscopy; Geranyltranstransferase - antagonists & inhibitors; hydroxyapatite; image analysis; Imidazoles - pharmacology; membrane permeability; Microscopy, Fluorescence; Models, Molecular; molecular models; Molecular Sequence Data; neoplasm cells; neoplasms; Neoplasms - drug therapy; post-translational modification; proteins; quinoline; Quinoline derivative; Quinolines - chemical synthesis; Quinolines - pharmacology; Quinolines - therapeutic use; synergism; titration; BSA; Bisphosphonate; Farnesyl pyrophosphate synthase; BPs; DTT; Allosteric site; HAP; Quinoline derivative; FPPS; MTT; Tris; Cancer; hydroxyapatite; tris(hydroxymethyl)aminomethane; 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide; DL-dithiothreitol; bisphosphonates; bovine serum albumin
• ISSN: 0304-4165; 0006-3002; 1872-8006
• DOI: 10.1016/j.bbagen.2013.11.006

Farnesyl pyrophosphate synthase (FPPS) is a key regulatory enzyme in the biosynthesis of cholesterol and in the post-translational modification of signaling proteins. It has been reported that non-bisphosphonate FPPS inhibitors targeting its allosteric binding pocket are potentially important for the development of promising anti-cancer drugs. The following methods were used: organic syntheses of non-bisphosphonate quinoline derivatives, enzyme inhibition studies, fluorescence titration assays, synergistic effect studies of quinoline derivatives with zoledronate, ITC studies for the binding of FPPS with quinoline derivatives, NMR-based HAP binding assays, molecular modeling studies, fluorescence imaging assay and MTT assays. We report our syntheses of a series of quinoline derivatives as new FPPS inhibitors possibly targeting the allosteric site of the enzyme. Compound 6b showed potent inhibition to FPPS without significant hydroxyapatite binding affinity. The compound showed synergistic inhibitory effect with active-site inhibitor zoledronate. ITC experiment confirmed the good binding effect of compound 6b to FPPS, and further indicated the binding ratio of 1:1. Molecular modeling studies showed that 6b could possibly bind to the allosteric binding pocket of the enzyme. The fluorescence microscopy indicated that these compounds could get into cancer cells. Our results showed that quinoline derivative 6b could become a new lead compound for further optimization for cancer treatment. The traditional FPPS active-site inhibitors bisphosphonates show poor membrane permeability to tumor cells, due to their strong polarity. The development of new non-bisphosphonate FPPS inhibitors with good cell membrane permeability is potentially important. •Farnesyl pyrophosphate synthase (FPPS) is a key regulatory enzyme in biosynthesis of cholesterol.•We synthesized a series of quinoline derivatives as FPPS inhibitors targeting its allosteric site.•Compounds 6b had potent inhibition to FPPS without significant hydroxyapatite binding affinity.•The inhibition was studied through ITC, molecular modeling, and combination with zoledronate.•Fluorescence microscopy indicated that the compounds could get into cancer cells.