mannich-bases and Neoplasms

A recently proposed strategy to overcome multidrug resistance (MDR) in cancer is to target the collateral sensitivity of otherwise resistant cells. We designed a library of 120 compounds to explore the chemical space around previously identified 8-hydroxyquinoline-derived Mannich bases with robust MDR-selective toxicity. We included compounds to study the effect of halogen and alkoxymethyl substitutions in R5 in combination with different Mannich bases in R7, a shift of the Mannich base from R7 to R5, as well as the introduction of an aromatic moiety. Cytotoxicity tests performed on a panel of parental and MDR cells highlight a strong influence of experimentally determined p

Topics: Antineoplastic Agents; Chelating Agents; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Humans; Mannich Bases; Neoplasms; Oxyquinoline; Structure-Activity Relationship

In this study, new Mannich bases, 2-(4-hydroxy-3-methoxy-5-((substitutedpiperazin-1-yl)methyl)benzylidene)-2,3-dihydro-1H-inden-1-one (1, 2, 4, 5, 8), 2-(3-((substituted)piperazin-1-yl)methyl)-4-hydroxy-5-methoxybenzylidene)-2,3-dihydro-1H-inden-1-one (3, 6, 7) were synthesized with the reaction of vanilin derived chalcone compound (2-(4-hydroxy-3-methoxybenzylidene)indan-1-one), paraformaldehyde and suitable amine in 1:1.2:1 mol ratios. Amine part was changed as N-methylpiperazine (1), N-phenylpiperazine (2), N-benzylpiperazine (3), 1-(2-methoxyphenyl)piperazine (4), 1-(3-methoxyphenyl)piperazine (5), 1-(2-fluorophenyl)piperazine (6), 1-(4-fluorophenyl)piperazine (7), and 1-(3-trifluoromethyl)phenyl piperazine (8). Compounds were evaluated in terms of cytotoxic/anticancer and CA inhibitory effects. According to the results obtained, the compounds 2 and 8 had the highest potency selectivity expression (PSE) values (60.6 and 19.2, respectively). On the other hand, the compounds 3 (Ki = 209.6 ± 70.2 pM) and 5 (Ki = 342.66 ± 63.72 pM) had the lowest Ki values in CA inhibition experiments towards hCA I and hCA II, respectively. In conclusion, the compounds 2 (with cytotoxic/anticancer activity), 3 (with hCA I inhibiting activity) and 5 (with hCA II inhibiting activity) can be leading compounds of the study for further designs and evaluations.

Topics: Antineoplastic Agents; Apoptosis; Carbonic Anhydrase I; Carbonic Anhydrase II; Carbonic Anhydrase Inhibitors; Cell Proliferation; Drug Screening Assays, Antitumor; Humans; Mannich Bases; Neoplasms; Piperazines; Structure-Activity Relationship; Tumor Cells, Cultured

New mono Mannich bases, (2-(4-hydroxy-3-((4-substituephenylpiperazin-1-yl)methyl)benzylidene)-2,3-dihydro-1H-inden-1-one), were prepared to evaluate their cytotoxic/anticancer properties and also their inhibitory effects on human carbonic anhydrase I and II isoenzymes (hCA I and II). Amine part was changed as [N-phenylpiperazine (1), N-benzylpiperazine (2), 1-(2-fluorophenyl)piperazine (3), 1-(4-fluorophenyl)piperazine (4), 1-(2-methoxyphenyl)piperazine (5)]. The structure of the synthesized compounds was characterized by

Topics: Antineoplastic Agents; Apoptosis; Carbonic Anhydrase I; Carbonic Anhydrase II; Carbonic Anhydrase Inhibitors; Cell Proliferation; Humans; Mannich Bases; Molecular Structure; Neoplasms; Piperazines; Structure-Activity Relationship; Tumor Cells, Cultured

Prenyl flavonoid icaritin (1) and β-anhydroicaritin (2) are two natural products with important biological and pharmacological effects. such as antiosteoporosis, estrogen regulation and antitumor properties.. The present study investigates the synthesis and cytotoxic activities on three Human cancer cell lines (Hela, HCC1954 and SK-OV-3) of icaritin and β-anhydroicaritin Mannich base derivatives in vitro models.. Preylated flavonoid icaritin (1) upon treatment with formic acid under microwave assistance gave another natural product β-anhydroicaritin (2) in good yield (89%). Based on Mannich reaction of 1 or 2 with various secondary amines and formaldehyde, two series eighteen new 6-aminomethylated flavonoids Mannich base derivatives 3-11 and 12-20 were synthesized. Their cytotoxic potential against three human cancer cell lines (Hela, HCC1954 and SK-OV-3) were evaluated by the standard MTT method with cis-Platin and Paclitaxel as positive control.. Our research showed that most of these flavonoid Mannich base derivatives displayed equal or higher (lower IC50 values) cytotoxic activities than the positive control cis-Platin. Some compounds possess the IC50 value below 10µM. Compounds 6-(diisopropylamino)methyl- and 6-morpholinylmethyl substituted β-anhydroicaritin (15 and 19) showed selective cytotoxicity against HCC1954 cells (IC50 12.688 µM) and Hela cells (IC50 6.543 µM) respectively.. Our finding most of icaritin and β-anhydroicaritin Mannich base derivatives possessing moderate to potent cytotoxicity against these three cancer cells (Hela, HCC1954 and SK-OV-3). Compound 15 and 19 showed selective cytotoxicity against HCC1954 cells and Hela cells respectively, they are potential and selective anticancer agent and worthy of further development.

Topics: Antineoplastic Agents; Benzopyrans; Cell Line, Tumor; Cell Survival; Drug Screening Assays, Antitumor; Flavonoids; Humans; Mannich Bases; Neoplasms

Chalcones and Mannich bases are a group of compounds known for their cytotoxicities. In this study restricted chalcone analogue, compound 2-(4-hydroxybenzylidene)-2,3-dihydroinden-1-one MT1, was used as a starting compound to synthesize new mono Mannich bases since Mannich bases may induce more cytotoxicity than chalcone analogue that they are derived from by producing additional alkylating center for cellular thiols. In this study, cyclic and acyclic amines were used to synthesize Mannich bases. All compounds were tested against Ca9-22 (gingival carcinoma), HSC-2, HSC-3 and HSC-4 (oral squamous cell carcinoma) as tumour cell lines and HGF (gingival fibroblasts), HPC (pulp cells) and HPLF (periodontal ligament fibroblasts) human normal oral cells as non tumour cell lines. Cytotoxicity, selectivity index (SI) values and potency selectivity expression (PSE) values expressed as a percentage were determined for the compounds. According to data obtained, the compound MT8 with the highest PSE value bearing N-methylpiperazine moiety seems to be a good candidate to develop new cytotoxic compounds and is suited for further investigation.

Topics: Antineoplastic Agents; Cell Line; Cell Line, Tumor; Cell Survival; Humans; Hydroxybenzoates; Indenes; Mannich Bases; Molecular Structure; Neoplasms

Six zinc(II) complexes have been synthesized from two designed Mannich-base ligands which consist of three dinuclear complex [Zn2(L(1))2X2] (1-3) and three mononuclear complex [ZnH(L(2))X2] (4-6), respectively, where X = Cl(-) (1,4), Br(-) (2,5), I(-) (3,6), as reported earlier by us (Sanyal et al., Inorg Chem 53:85-96, 2014). The catecholase activity of the complexes has been investigated under completely aerobic conditions in DMF-water medium (9:1) at pH 8.5 against the model substrate 3,5-di-tert-butylcatechol (3,5-DTBC). Saturation kinetic studies show that the order of conversion of substrate to product (quinone) follows the trend 5 > 4 > 2 > 1 while 3 and 6 are inactive. The generation of phenoxyl radicals, confirmed by UV-vis and EPR spectral studies, is supposed to be responsible for the oxidation of 3,5-DTBC. The in vitro evaluation of 1-6 comprises the study of their DNA-cleaving ability using plasmid DNA and the assessment of their cytotoxic activity against Jurkat (T cell lymphoma) cell line by MTT assay. The mechanisms of toxicity appeared to be predominantly by reactive oxygen species (ROS). The comparative analysis helps to arrive at the following facts under experimental conditions: (1) mononuclear species prevail over the dinuclear ones, unlike the behavior in phosphatase activity as reported in Inorganic Chemistry; (2) the halide substituents at the active site control the overall activity in the order: (a) In catecholase activity, Cl(-) < Br(-) (dinuclear) and Cl(-) > Br(-) (mononuclear) and (b) in biological activity, Cl(-) > Br(-) > I(-) regardless of nuclearity.

Topics: Antineoplastic Agents; Biomimetic Materials; Catechol Oxidase; Coordination Complexes; DNA Cleavage; Humans; Jurkat Cells; Ligands; Mannich Bases; Neoplasms; Reactive Oxygen Species; Zinc

The Mannich base containing ciprofloxacin and kojic acid structural units was prepared and evaluated in antitumor activity. The enhancement in antitumor activity was observed both from the Mannich base (IC(50): 103.3±5.0 µM for HepG2, 87.9±8.0 µM for HCT-116 cell) and its copper complex (IC(50): 11.5±1.8 µM for HepG2, 44.4±2.5 µM for HCT-116 cell) compared to the ciprofloxacin and kojic acid. The mechanistic studies via RT-PCR, cell cycle analysis, mitochondrial membrane potential measurement, inhibition of topoisomerase and molecular docking indicated that there is a different molecular mechanism between the Mannich base and its copper complex. The cytotoxicity of the Mannich base was involved in apoptosis, cell cycle arrest, depolarization of mitochondrial membrane and weaker topoisomerase II inhibition, but the copper complex exerted its cytotoxicity mainly through dual topoisomerase inhibition, especially stabilizing the intermediate of cleavage DNA-topoisomerase complex.

Topics: Apoptosis; Cell Cycle; Cell Proliferation; Ciprofloxacin; Copper; Drug Screening Assays, Antitumor; HCT116 Cells; Humans; Mannich Bases; Neoplasms; Pyrones