One-pot synthesis of 2,3-bis-(4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl)succinates and arylmethylene-bis-3,3-quinoline-2-ones

In this investigation an efficient synthesis of 2,3-bis-(4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl)succinic acid derivatives was achieved by one-pot reaction of one equivalent of aromatic amines with two equivalents of diethyl malonate in diphenyl ether and catalyzed with triethylamine. In case of applying the previous condition with aromatic amines and diethyl malonate in a ratio of 2:1, no quinolone structure was obtained, whereas N-1,N-3-bis(4-bromophenyl)malonamide, as an example, was obtained in 95% yield. Under the same previous condition, arylmethylene-bis-3,3-quinoline-2-ones were in one pot synthesized via the reaction of equal equivalents of aromatic amines and diethyl malonate together with half equivalent of the corresponding aromatic aldehydes. The structure of the obtained compounds was proved by IR, NMR and mass spectra and X-ray structure analyses. [GRAPHICS] .Peer reviewe

Synthesis of spiro[indoline-3,4'-pyrano[3,2-c]quinolone]-3'-carbonitriles

Quinoline-2,4-diones reacted with 2-(2-oxo-1,2-dihydroindol-3-ylidene)malononitrile in pyridine to give 2'-amino-2,5'-dioxo-5',6'-dihydrospiro(indoline-3,4'-pyrano[3,2-c]quinoline)-3'-carbonitriles in good to excellent yields. The structures of all new products were proven using one- and two-dimensional NMR, IR, and mass spectral data, and in five cases X-ray structural analyses. The possible mechanism for the reaction is also discussed. [GRAPHICS] .Peer reviewe

Synthesis of novel 1,2-bis-quinolinyl-1,4-naphthoquinones : ERK2 inhibition, cytotoxicity and molecular docking studies

Two novel series of N-2,3-bis(6-substituted-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl)naphthalene-1,4-diones 3a-d and substituted N-(methyl/ethyl)bisquinolinone triethyl-ammonium salts 4e,f were successfully synthesized. The synthesized compounds were targeted as new candidates to extracellular signal-regulated kinases 1/2 (ERK1/2) with considerable antineoplastic activity. The synthesis involved the reactions of 2 equivalents of 4-hydroxy-2(1H)-quinolinones la-f and one equivalent of 1,4-naphthoquinone (2) in a mixture of ethanol/dimethylformamide (1:1) as a solvent and 0.5 mL Et3N. In the reaction of 6-methyl-4-hydroxyquinolone 1b with 2, a side product 4b of the second series was obtained. In general, the presence of free NH-quinolone gave a single compound of the first series, whereas reaction of N-methyl/ethyl-quinolones 1e, f with 2 enhanced the formation of compounds of the second series. The structures of the new compounds were proved by different spectroscopic techniques such as IR, NMR (2D-NMR) and mass spectra, elemental analysis, and X-ray crystallography. To further elucidate the mechanism of action of these newly synthesized compounds, compounds 3a, 3b, 4e and 4f were selected to investigate for their MAP Kinases pathway inhibition together with molecular docking using ATP-binding site of ERK2. The results revealed that compounds 3a, 3b and 4f inhibited ETS-1 phosphorylation by ERK2 in a dose dependent manner. Also, compound 4f showed highest potency for ERK2 inhibition with ATPcompetitive inhibition mechanism which was confirmed by the formation of three hydrogen bond in the molecular docking studies. The synthesized compounds were then tested for their in vitro anticancer activity against the NCI-60 panel of tumor cell lines. Interestingly, the selected compounds displayed from modest to strong cytotoxic activities. Compound 3b demonstrated broad spectrum anti-tumor activity against the nine tumor subpanels tested, while compound 3d proved to be lethal to most of the cancer cell lines as shown by their promising GI(50) and TGI values in NCI in vitro five dose testing. These results revealed that the synthesized compounds can potentially serve as leads for the development of novel chemotherapeutic agents and structure improvement will be necessary for some derivatives for enhancing their cellular activities and pharmacokinetic profile.Peer reviewe

Design, synthesis and biological evaluation of fused naphthofuro[3,2-c]quinoline-6,7,12-triones and pyrano[3,2-c]quinoline-6,7,8,13-tetraones derivatives as ERK inhibitors with efficacy in BRAF-mutant melanoma

Approximately 60% of human cancers exhibit enhanced activity of ERK1 and ERK2, reflecting their multiple roles in tumor initiation and progression. Acquired drug resistance, especially mechanisms associated with the reactivation of the MAPK (RAF/MEK/ERK) pathway represent a major challenge to current treatments of melanoma and several other cancers. Recently, targeting ERK has evolved as a potentially attractive strategy to overcome this resistance. Herein, we report the design and synthesis of novel series of fused naphthofuro[3,2-c] quinoline-6,7,12-triones 3a-f and pyrano[3,2-c]quinoline-6,7,8,13-tetraones 5a,b and 6, as potential ERK inhibitors. New inhibitors were synthesized and identified by different spectroscopic techniques and X-ray crystallography. They were evaluated for their ability to inhibit ERK1/2 in an in vitro radioactive kinase assay. 3b and 6 inhibited ERK1 with IC50s of 0.5 and 0.19 mu M, and inhibited ERK2 with IC50s of 0.6 and 0.16 mu M respectively. Kinetic mechanism studies revealed that the inhibitors are ATP-competitive inhibitors where 6 inhibited ERK2 with a K-i of 0.09 mu M. Six of the new inhibitors were tested for their in vitro anticancer activity against the NCI-60 panel of tumor cell lines. Compound 3b and 6 were the most potent against most of the human tumor cell lines tested. Moreover, 3b and 6 inhibited the proliferation of the BRAF mutant A375 melanoma cells with IC50s of 3.7 and 0.13 mu M, respectively. In addition, they suppressed anchorage-dependent colony formation. Treatment of the A375 cell line with 3b and 6 inhibited the phosphorylation of ERK substrates p-90RSK and ELK-1 and induced apoptosis in a dose dependent manner. Finally, a molecular docking study showed the potential binding mode of 3b and 6 within the ATP catalytic binding site of ERK2.Peer reviewe