Exploration of quinolone and quinoline derivatives as potential anticancer agents.

BACKGROUND: Among the different types of cancers, breast cancer, bone cancer and cervical cancer are the most common gender specific cancer types that are affecting the women worldwide. Currently, many enzymatic and cellular pathways are known as drug targets for the treatment of cancer. Even though many improvements have been made in the therapy of various types of cancer, but the major disadvantage of available anti-cancer drugs is their non-selective behavior towards cancer cells as well as normal cells. OBJECTIVES: In the light of this fact, the searching of new compounds with selective behavior only towards cancer cells is critically important. Previously, we have identified several series of compounds as the potential inhibitors of these families. METHODS: Herein, we investigate quinolones and quinolines for their anti-cancer activity against breast cancer cells (MCF-7), bone marrow cancer cells (K-562) and cervical cancer cells (HeLa) by MTT assay. The most effective derivatives were further subjected to flow cytometry analysis followed by fluorescence microscopic analysis by using 4´,6-diamidine-2´-phenylindole (DAPI) and propidium staining (PI) staining. RESULTS: All the tested compounds were found selective only towards cancer cells. The identified compounds also induced either G2 or S-phase cell cycle arrest within the respective cancer cell line, chromatin condensation and the nuclear fragmentation, as well as maximum interaction with DNA. CONCLUSIONS: These results provide evidence that the characteristic chemical features of attached groups are the key factors for their anticancer effects and play a useful role in revealing the mechanisms of action in relation to the known compounds in future research programs. Graphical abstract Flow cytometric analysis of cell cycle using propidium iodide staining. Cell apoptosis observed under fluorescence microscope using DAPI and PI staining.

Anti-proliferative Effects of Chromones: Potent Derivatives Affecting Cell Growth and Apoptosis in Breast, Bone-marrow and Cervical Cancer Cells.

BACKGROUND: Previously, we have identified 3,3'-carbonyl-bis(chromones) (1a-h, 5e) and 3-(5-(benzylideneamino)thiozol-3-yl)-2H-chromen-2-ones (7a-j) as potent inhibitors of tissue non-specific alkaline phosphatase (TNAP). The present study was designed to investigate the cytotoxic and pro-apoptotic effect of the said derivatives. METHODS: The anti-proliferative effect of the derivatives was investigated in three cancer cell lines i.e., MCF-7, K-562, HeLa and normal BHK21 cells using MTT assay. The pro-apoptotic effect of the most potent derivatives was investigated by using flow cytometry, DAPI and PI staining and DNA binding studies. RESULTS: Among all the screened compounds, 1f, 1d, 1c (from 3,3'-carbonyl-bis(chromones), 7c, 7h and 7i (from 3-(5-(benzylideneamino)thiozol-3-yl)-2H-chromen-2-ones) exhibited remarkable growth inhibitory effects. Compounds 1f and 7c were found to be the most potent cytotoxic derivatives against MCF-7; 1d and 7h inhibited most of the proliferation of K-562 cells, whereas 1c and 7i showed maximum growth inhibition in HeLa cells. The identified compounds exerted lower micromolar potency against the respective cell line with significant selectivity over the normal cells (BHK-21). The identified compounds also induced either G2 or S-phase arrest within the respective cancer cells, chromatin condensation and nuclear fragmentation, as well as maximum interaction with DNA. CONCLUSIONS: These results provide evidence that the characteristic chemical features of attached groups are the key factors for their anticancer effects and play a useful role in revealing the mechanisms of action in relation to the known compounds in future research programs.

A domino reaction of 3-chlorochromones with aminoheterocycles. Synthesis of pyrazolopyridines and benzofuropyridines and their optical and ecto-5'-nucleotidase inhibitory effects.

A new and efficient domino reaction of 3-chlorochromones with electron-rich aminoheterocycles was developed which allows for a convenient synthesis of a variety of pyrazolo[3,4-b]pyridines, pyrrolo[2,3-b]pyridines, pyrido[2,3-d]pyrimidines and benzofuro[3,2-b]pyridines. The products exhibit strong fluorescence. In addition, they exhibit significant ecto-5'-nucleotidase inhibition properties and cytotoxic behavior.

Synthesis, alkaline phosphatase inhibition studies and molecular docking of novel derivatives of 4-quinolones.

New and convenient methods for the functionalization of the 4-quinolone scaffold at positions C-1, C-3 and C-6 were developed. The 4-quinolone derivatives were evaluated for their inhibitory potential on alkaline phosphatase isozymes. Most of the compounds exhibit excellent inhibitory activity and moderate selectivity. The IC50 values on tissue non-specific alkaline phosphatase (TNAP) were in the range of 1.34 ± 0.11 to 44.80 ± 2.34 µM, while the values on intestinal alkaline phosphatase (IAP) were in the range of 1.06 ± 0.32 to 192.10 ± 3.78 µM. The most active derivative exhibits a potent inhibition on IAP with a ≈14 fold higher selectivity as compared to TNAP. Furthermore, molecular docking calculations were performed for the most potent inhibitors to show their binding interactions within the active site of the respective enzymes.

Synthesis of 3,3'-carbonyl-bis(chromones) and their activity as mammalian alkaline phosphatase inhibitors.

Hitherto unknown 3,3'-carbonyl-bis(chromones) 8, dimeric chromones bridged by a carbonyl group, were prepared by reaction of chromone-3-carboxylic acid chloride with 3-(dimethylamino)-1- (2-hydroxyphenyl)-2-propen-1-ones 9. The method is generally applicable for the synthesis of novel symmetrical or non-symmetrical products which were found to inhibit mammalian alkaline phosphatases.

2,3-unsubstituted chromones and their enaminone precursors as versatile reagents for the synthesis of fused pyridines.

A divergent and regioselective approach to fused pyridines was developed through formal [3 + 3] cyclocondensations from simple 2,3-unsubstituted chromones or their enaminone precursors.