ABSTRACT
Aurora and polo-like kinases control the G2/M phase in cell mitosis, which are both considered as crucial targets for cancer cell proliferations. Here, naphthalene-based Aurora/PLK coinhibitors as leading compounds were designed through in silico approach, and a total of 36 derivatives were synthesized. One candidate (AAPK-25) was selected under in vitro cell based high throughput screening with an IC50 value = 0.4 µM to human colon cancer cell HCT-116. A kinome scan assay showed that AAPK-25 was remarkably selective to both Aurora and PLK families. The relevant genome pathways were also depicted by microarray based gene expression analysis. Furthermore, validated from a set of in vitro and in vivo studies, AAPK-25 significantly inhibited the development of the colon cancer growth and prolonged the median survival time at the end of the administration (p < 0.05). To sum up, AAPK-25 has a great potential to be developed for a chemotherapeutic agent in clinical use.
Subject(s)
Antineoplastic Agents/pharmacology , Drug Discovery , Protein Kinase Inhibitors/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Aurora Kinase A/antagonists & inhibitors , Aurora Kinase A/metabolism , Cell Cycle Proteins/antagonists & inhibitors , Cell Cycle Proteins/metabolism , Cell Proliferation/drug effects , Cell Survival/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Female , Humans , Mice , Mice, Inbred BALB C , Mice, Nude , Molecular Structure , Neoplasms, Experimental/drug therapy , Neoplasms, Experimental/metabolism , Neoplasms, Experimental/pathology , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Protein Serine-Threonine Kinases/antagonists & inhibitors , Protein Serine-Threonine Kinases/metabolism , Proto-Oncogene Proteins/antagonists & inhibitors , Proto-Oncogene Proteins/metabolism , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Tumor Cells, Cultured , Tumor Suppressor Proteins , Polo-Like Kinase 1ABSTRACT
Hybridization of coordination polymers allows for combining two or more distinct structures into one material. Here, we explore the core/shell-type materials of Prussian blue analogues (PBAs) by heteroepitaxial growth and demonstrate how one phase structurally dominates the other. The volumetric ratio between the shell and core crystals determine the final structure of the hybrids. The outermost dominated the Na+ ion insertion/extraction, illustrating how the hybridization can adjust the function of PBAs.
ABSTRACT
Despite a continuously growing interest in the integration of coordination polymer (CP) colloids toward functional materials, collective properties of the CP colloids have rarely been addressed mainly due to the difficulty in assembling pure CP colloids into superstructures with impressive mechanical strength. We demonstrated that CP nanoplates could stack together spontaneously upon drying the slurry of the nanoplates. The stacked CP nanoplates could work like polymeric adhesives. Versatile articles could be glued when the CP nanoplates were sandwiched between two substrates. In addition, the CP nanoplates themselves could form well-defined bulk structures without using any additional adhesives. The anisotropic shape together with the lamellar stacking way of the CP nanoplates were found to be the key points in leading to the adhesion and cohesion effect. The reasonable adhesion strength of the CP nanoglues can allow the exploration of further applications of integrated CP colloids in the future.
ABSTRACT
A series of novel 5-hydrosulfonyl-1H-benzo[d]imidazol-2(3H)-one derivatives bearing natural product substructures has been successfully synthesized and their antitumor activity studied. These newly synthesized derivatives were characterized by ¹H-NMR, (13)C-NMR and high resolution mass spectral data, then screened as antitumor agents against the A549, HCC1937, and MDA-MB-468 human tumor cell lines using MTT cell proliferation assays. The results show that some of these compounds can effectively inhibit the growth of these cancerous cells, with compound 5b being the best one (IC50 = 2.6 µM). Flow cytometry data revealed that compound 5b induced apoptosis of HCC1937 cells with increased solution concentration. The structure and activity relationships (SAR) of these compounds is summarized.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Benzimidazoles/chemical synthesis , Benzimidazoles/pharmacology , Antineoplastic Agents/chemistry , Apoptosis , Benzimidazoles/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Molecular Docking Simulation , Molecular Structure , Structure-Activity RelationshipABSTRACT
An efficient approach for the synthesis of functionalized 4-substituted-2-amino-3-cyano-4H-chromenes moderate to high yields (up to 98%) has been achieved via a tandem K2CO3 catalyzed conjugate addition-cyclization reaction of malononitrile and a range of Knoevenagel adducts previously formed from oxindole, pyrazolone, nitromethane, N,N-dimethylbarbituric acid or indanedione. This methodology differs from the previous classical methods in its simplicity and ready availability of the catalyst.
