Novel spiroindoline quinazolinedione derivatives as anticancer agents and potential FLT3 kinase inhibitors.

Despite considerable recent progress in therapeutic strategies, cancer still remains one of the leading causes of death. Molecularly targeted therapies, in particular those focused on blocking receptor tyrosine kinases have produced promising outcomes in recent years. In this study, a new series of spiro[indoline-3,2'-quinazoline]-2,4'(3'H)-dione derivatives (5a-5l) were synthesized and evaluated as potential kinase inhibitors with anticancereffects. The anti-proliferative activity was measured by MTT assay, while the cell cycle was studied using flow cytometry. Moreover, kinase inhibition profiles of the most promising compounds were assessed against a panel of 25 oncogenic kinases. Compounds 5f,5g,5i, and 5jshowed anti-proliferative effect against EBC-1, A549, and HT-29 solid tumor models in addition to leukemia cell line K562. In particular, compound 5f, bearing 4-methylphenyl pendant on the isatin ring displayed considerable potency with IC50 values of 2.4 to 13.4 µM against cancer cells. The most potent derivatives also altered the distribution of cells in different phases of cell cycle and increased the sub-G1 phase cells in K562 cells. Moreover, kinase inhibition assays identified FLT3 kinase was as the primary targetof these derivatives. Compound 5f at 25 µM concentration showed inhibitory activities of 55% and 62% against wild-type FLT3 and its mutant, D835Y, respectively. Finally, the docking and simulation studies revealed the important interactions of compound 5f with wild type and mutant FLT3. The results of this study showed that some novel spiroindoline quinazolinedione compounds could be potential candidates for further development as novel targeted anticancer agents.

Anticonvulsant activity, molecular modeling and synthesis of spirooxindole-4H-pyran derivatives using a novel reusable organocatalyst.

Fifteen derivatives of spirooxindole-4H-pyran (A1-A15) were subjected to evaluate through intravenous infusion of pentylenetetrazole (PTZ)-induced epilepsy mouse models. Four doses of the compounds (20, 40, 60 and 80 mg/kg) were tested in comparison with diazepam as positive control. The resulted revealed that compounds A3 and A12 were the most active compounds and indicated significant anticonvulsant activity in the PTZ test. The tested compounds were prepared via a multicomponent reaction using graphene oxide (GO) based on the 1-(2-aminoethyl) piperazine as a novel heterogeneous organocatalyst. The prepared catalyst (GO-A.P.) was characterized using some diverse microscopic and spectroscopic procedures as well. The results showed high catalytic activity of the catalyst in the synthesis of spirooxindole-4H-pyran derivatives. The GO-A.P. catalyst was reusable at least for 5 times with no significant decrease in its catalytic action. In silico assessment of physicochemical activity of all compounds also were done which represented appropriate properties. Finally, molecular docking study was performed to achieve their binding affinities as γ-aminobutyric acid-A (GABA-A) receptor agonists as a plausible mechanism of their anticonvulsant action. Binding free energy values of the compounds represented strongly matched with biological activity.

Self-interrupted synthesis of sterically hindered aliphatic polyamide dendrimers.

2,2-Bis(azidomethyl)propionic acid was prepared in four steps and 85% yield from the commercially available 2,2-bis(hydroxymethyl)propionic acid and used as the starting building block for the divergent, convergent, and double-stage convergent-divergent iterative methods for the synthesis of dendrimers and dendrons containing ethylenediamine (EDA), piperazine (PPZ), and methyl 2,2-bis(aminomethyl)propionate (COOMe) cores. These cores have the same multiplicity but different conformations. A diversity of synthetic methods were used for the synthesis of dendrimers and dendrons. Regardless of the method used, a self-interruption of the synthesis was observed at generation 4 for the dendrimer with an EDA core and at generation 5 for the one with a PPZ core, whereas for the COOMe core, self-interruption was observed at generation 6 dendron, which is equivalent to generation 5 dendrimer. Molecular modeling and molecular-dynamics simulations demonstrated that the observed self-interruption is determined by the backfolding of the azide groups at the periphery of the dendrimer. The latter conformation inhibits completely the heterogeneous hydrogenation of the azide groups catalyzed by 10% Pd/carbon as well as homogeneous hydrogenation by the Staudinger method. These self-terminated polyamide dendrimers are enzymatically and hydrolytically stable and also exhibit antimicrobial activity. Thus, these nanoscale constructs open avenues for biomedical applications.

Synthesis of α-aminonitriles with benzimidazolic and theophyllinic backbones using the Strecker reaction.

An example of the application of the Strecker reaction in the synthesis of a new class of α-aminonitriles with benzimidazole and theophylline backbones has been developed. For the synthesis of these compounds, first 4-hydroxybenzaldehyde was reacted with 1,3- and 1,5-dibromides/epibromohydrin to produce the corresponding bromo-substituted aldehydes. Then, benzimidazole/theophylline was reacted with the latter to generate the related benzimidazolic/theophyllinic aldehydes. Finally, the Strecker reactions of the synthetic benzimidazolic and theophyllinic aldehydes with different amines afforded the target products.

Study of the anticancer effect of new quinazolinone hydrazine derivatives as receptor tyrosine kinase inhibitors.

The advent of novel receptor tyrosine kinase inhibitors has provided an important therapeutic tool for cancer patients. In this study, a series of quinazolinone hydrazide triazole derivatives were designed and synthesized as novel MET (c-MET) receptor tyrosine kinase inhibitors. The antiproliferative effect of the synthesized compounds was examined against EBC-1, A549, HT-29 and U-87MG cells by MTT assay. MET kinase inhibitory effect was tested by a Homogenous Time Resolved Fluorescence (HTRF) assay. The antiproliferative effect of compounds in a three-dimensional spheroid culture was studied by acid phosphatase (APH) assay, while apoptosis induction was examined by Hoechst 33258 staining. We found that compound CM9 bearing p-bromo benzyl pendant inhibited MET kinase activity at the concentrations of 10-50 µM (% Inhibition = 37.1-66.3%). Compound CM9 showed antiproliferative effect against cancer cells, in particular lung cancer cells with MET amplification (EBC-1) with an IC50 value of 8.6 µM. Moreover, this derivative inhibited cell growth in spheroid cultures in a dose-dependent manner and induced apoptosis in cancer cells. Assessment of inhibitory effect of CM9 against a panel of 18 different protein kinases demonstrated that this compound also inhibits ALK, AXL, FGFR1, FLT1 (VEGFR1) and FLT4 (VEGFR3) more than 50% at 25 µM. Finally, molecular docking and dynamics simulation corroborated the experimental findings and showed critical structural features for the interactions between CM9 and target kinases. The findings of this study present quinazolinone hydrazide triazole derivatives as kinase inhibitors with considerable anticancer effects.