ABSTRACT
N'-[(4-Chloro-2-oxo-2H-chromen-3-yl)methylene]-2-cyanoacetohydrazide (3) was synthesized in excellent yield from the condensation of 4-Chloro-2-oxo-2H-chromene-3-carbaldehyde with cyanoacetohydrazide. Compound 3 was utilized as a building block to synthesize novel coumarin and heterocycle-fused coumarin derivatives. The chemical structures of all the new coumarin compounds were identified by spectral analyses. Some of the new coumarins compounds were screened in human cancer cell lines (HEPG-2, MCF-7, HCT-116 and PC-3) to learn about their cytotoxic effects in addition to the study of their DNA damage and antioxidant activity. Three of these compounds exhibited remarkable antioxidant and anti-proliferative activities. Moreover, they have the capability to protect DNA from damage induced by bleomycin. Molecular docking, DFT and molecular electrostatic potential studies were performed on the compounds inâ vitro.
Subject(s)
Antineoplastic Agents , Antioxidants , Humans , Antioxidants/pharmacology , Molecular Docking Simulation , Cell Line , Coumarins/chemistry , Antineoplastic Agents/chemistry , Structure-Activity RelationshipABSTRACT
BACKGROUND: Fused heterocyclic containing pyrazolopyridine systems have several medicinal activities including cytotoxic and carcinostatic activities. OBJECTIVE: To investigate the antiproliferative activity and associated mechanism(s) of a novel series of nicotinonitrile derivatives. METHOD: The series has been synthesized by the reaction of hydrazonoyl chlorides with each of 4-(4- methoxyphenyl)-3-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile and 2-amino-4-(4- methoxyphenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carbonitrile in dioxane in basic medium. The assigned structures for each of the new products were identified via elemental and spectral data. Moreover, the cytotoxic activity for some selected products was screened. RESULTS: Derivatives 5g, 7i, 8 and 9 had their IC50 at ~ 1-3 µM and derivatives 7b, 7d, and 7f were similar to 5- fluorouracil and had their IC50 at ~ 5 µM against breast (MCF-7) and colon (HCT-116) cell lines. All derivatives were specific in action and safe to normal fibroblasts (WI38). Only derivative 9 caused some toxicity but at high concentration of 93 µM. These derivatives exerted strong antiproliferative activity through inducing intrinsic apoptosis as indicated from the significant induction of caspases 9 and 3 by 3-6 folds in colon cells and/or inhibiting tyrosine kinase (TK) and hence arresting the cell cycle. CONCLUSION: Compounds 8 and 5g were the most potent anticancer agents inhibiting the TK by 86 and 89% and their IC50 of the enzyme were 311 and 352 nM, respectively. We believe that these derivatives deserve further investigation and these chemical moieties could offer promising anticancer drugs.
Subject(s)
Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Imines/pharmacology , Nitriles/pharmacology , Protein Kinase Inhibitors/pharmacology , Protein-Tyrosine Kinases/antagonists & inhibitors , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Line , Cell Proliferation/drug effects , Cell Survival/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Imines/chemistry , Molecular Structure , Nitriles/chemical synthesis , Nitriles/chemistry , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Protein-Tyrosine Kinases/metabolism , Structure-Activity RelationshipABSTRACT
Coumarins are naturally occurring oxygen heterocyclic compounds having multifarious medicinal properties, hence used as lead compounds for designing new potent analogs. The chromene butenoic acid 3 and the benzochromene butenoic acid 4 which are derived from the reaction of glyoxalic acid with 3-acetylcoumarin and 3-acetylbenzocoumarin, respectively, were reacted with different nitrogen and carbon nucleophiles to give new heterocyclic compounds. The structures of the prepared compounds were elucidated by IR, ¹H-NMR, and mass spectroscopy. Some of the newly prepared compounds were tested in vitro against a panel of four human tumor cell lines namely; hepatocellular carcinoma (liver) HepG2, colon cancer HCT-116, human prostate cancer PC3, and mammary gland breast MCF-7. Also they were tested as antioxidants. Almost all of the tested compounds showed satisfactory activity.
Subject(s)
Antineoplastic Agents/chemistry , Antioxidants/chemistry , Coumarins/chemistry , Neoplasms/drug therapy , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/therapeutic use , Antioxidants/chemical synthesis , Antioxidants/therapeutic use , Benzopyrans/chemistry , Coumarins/chemical synthesis , Coumarins/therapeutic use , DNA Damage/drug effects , Glyoxylates/chemistry , Hep G2 Cells , Humans , Oxidation-Reduction , Proton Magnetic Resonance SpectroscopyABSTRACT
A (pyridazinyl)acetate derivative was reacted with thiosemicarbazide and hydrazine hydrate to yield spiropyridazinone and acetohydrazide derivatives, respectively. The acetohydrazide derivative was used as a starting material for synthesizing some new heterocyclic compounds such as oxoindolinylidene, dimethylpyrazolyl, methylpyrazolyl, oxopyrazolyl, cyanoacetylacetohydrazide and oxadiazolylacetonitrile derivatives. The behavior of the cyanoacetylacetohydrazide and oxadiazolylacetonitrile derivatives towards nitrogen and carbon nucleophiles was investigated. The assigned structures of the prepared compounds were elucidated by spectral methods (IR, ¹H-NMR (13)C-NMR and mass spectroscopy). Some of the newly prepared compounds were tested in vitro against a panel of four human tumor cell lines, namely hepatocellular carcinoma (liver) HePG-2, colon cancer HCT-116, human prostate cancer PC3, and mammary gland breast MCF-7. Also they were tested as antioxidants. Almost all of the tested compounds showed satisfactory activity.
