Kinase Inhibitors of Marine Origin

Kinase Inhibitors of Marine Origi

Dimethyltin Dichloride Catalyzed Regioselective Alkylation of <i>cis</i>-1,2-Diols at Room Temperature

Here, we have developed a mild and general method for the regioselective installation of benzyl, allyl, <i>para</i>-methoxybenzyl and naphthyl groups on <i>cis</i>-1,2-diols. The optimized method operates at room temperature using dimethyltin dichloride as catalyst and silver oxide as an additive. The present method works well with both sugars (such as mono- and disaccharides) and nonsugars (such as inositols, propan-1,2-diol, 1,2-cycloalkanediols and anhydroerythritol) and also provides comparatively better functional group compatibility

Iron-catalyzed Cross-Coupling of Electron-Deficient Heterocycles and Quinone with Organoboron Species via Innate C–H Functionalization: Application in Total Synthesis of Pyrazine Alkaloid Botryllazine A

Here, we report an iron-catalyzed cross<b>-</b>coupling reaction of electron-deficient heterocycles and quinone with organoboron species via innate C–H functionalization. Iron­(II) acetylacetonate along with oxidant (K₂S₂O₈) and phase-transfer catalyst (TBAB) under open flask conditions efficiently catalyzed the cross<b>-</b>coupling of pyrazine with arylboronic acids and gave monoarylated products in good to excellent yields. Optimized conditions also worked for other heterocylces such as quinoxalines, pyridines, quinoline, and isoquinoline as well as quinones. In addition, we demonstrated as a first example its application for the synthesis of anticancer marine pyrazine alkaloid botryllazine A

Metal-Free, Phosphonium Salt-Mediated Sulfoximination of Azine <i>N</i>‑Oxides: Approach for the Synthesis of <i>N</i>‑Azine Sulfoximines

Herein, we report a simple and metal-free method for the synthesis of <i>N</i>-azine sulfoximines by the nucleophilic substitution of azine <i>N</i>-oxides with <i>NH</i>-sulfoximines. The present method works at room temperature with wide functional group compatibility and gives several unprecedented <i>N</i>-azine sulfoximines. The reaction conditions were also found suitable with enantiopure substrates and furnished products without any racemization. It also finds an application in the sulfoximination of azine-based functional molecules such as 2,2′-bipyridine, 1,10-phenanthroline, and quinine

Amino Catalytic Oxidative Thioesterification Approach to α‑Ketothioesters

An efficient metal-free method for the synthesis of α-ketothioesters is described for the first time. This reaction features the ability of pyrrolidine to fine-tune the reaction between 2-oxoaldehyde and thiols through iminium to the desired product in moderate to good yields. As an advantage, no external oxidants or metal catalysts are required in our method. Reactions performed under modified conditions lead to an apparent balance in reactivity of secondary amine and thiols toward 2-oxoaldehydes

Fusion of Structure and Ligand Based Methods for Identification of Novel CDK2 Inhibitors

Cyclin dependent kinases play a central role in cell cycle regulation which makes them a promising target with multifarious therapeutic potential. CDK2 regulates various events of the eukaryotic cell division cycle, and the pharmacological evidence indicates that overexpression of CDK2 causes abnormal cell-cycle regulation, which is directly associated with hyperproliferation of cancer cells. Therefore, CDK2 is regarded as a potential target molecule for anticancer medication. Thus, to decline CDK2 activity by potential lead compounds has proved to be an effective treatment for cancer. The availability of a large number of X-ray crystal structures and known inhibitors of CDK2 provides a gateway to perform efficient computational studies on this target. With the aim to identify new chemical entities from commercial libraries, with increased inhibitory potency for CDK2, ligand and structure based computational drug designing approaches were applied. A druglike library of 50,000 compounds from ChemDiv and ChemBridge databases was screened against CDK2, and 110 compounds were identified using the parallel application of these models. On <i>in vitro</i> evaluation of 40 compounds, seven compounds were found to have more than 50% inhibition at 10 μM. MD studies of the hits revealed the stability of these inhibitors and pivotal role of Glu81 and Leu83 for binding with CDK2. The overall study resulted in the identification of four new chemical entities possessing CDK2 inhibitory activity

I₂/Aqueous TBHP-Catalyzed Coupling of Amides with Methylarenes/Aldehydes/Alcohols: Metal-Free Synthesis of Imides

We present a metal-free method for the synthesis of imides by the direct coupling of NH-amides with methylarenes under iodine/aqueous TBHP conditions. The optimized conditions worked very well with benzaldehydes and benzyl alcohol and furnished the corresponding imides in good to excellent yields. A series of control and radical scavenger experiments were also performed, which suggested the involvement of radical pathways. The labeling experiment in the presence of ¹⁸O-labeled H₂O suggested water as a source of oxygen in the imides

Metal-Free Approach for the Synthesis of <i>N</i>‑Aryl Sulfoximines via Aryne Intermediate

A metal-free and operationally simple <i>N</i>-arylation of <i>NH</i>-sulfoximines with aryne precursors is reported. Transition metal-free reaction conditions and shorter reaction times are the highlights of the present method. The mild optimized condition was also found to be suitable with enantiopure substrates

Metal-free Cross-Dehydrogenative Coupling of <i>HN</i>-azoles with α‑C(sp³)‑H Amides via C–H Activation and Its Mechanistic and Application Studies

A metal-free one step coupling reaction between various <i>N</i>-azole rings and diverse α-C­(sp³)-H containing amides has been developed under oxidative reaction conditions. Commercially available tetrabutyl ammonium iodide (TBAI) in the presence of terbutylhydroperoxide (TBHP), under neat reaction condition, efficiently catalyzed the coupling. Various azole types, such as 1<i>H</i>-benzotriazoles, 1<i>H</i>-1,2,3-triazoles, 1<i>H</i>-1,2,4-triazoles, 1<i>H</i>-tetrazoles, 1<i>H</i>-pyrazoles, and 1<i>H</i>-benzimidazoles, and α-C­(sp³)-H containing amides, such as <i>N</i>,<i>N</i>-dimethylacetamide, <i>N</i>,<i>N</i>-dimethylbenzamide, <i>N</i>-methylacetamide, <i>N</i>,<i>N</i>-diethylacetamide, <i>N</i>-methylpyrrolidine, and pyrrolidine-2-one, were successfully employed for the coupling. A series of designed and controlled experiments were also performed in order to study the involvement of the different intermediates. Based on the evidence, a plausible mechanism is also proposed. These novel, simple, rapid, attractive, and straightforward transformations open the way of the construction of novel highly functionalized <i>N</i>-azoles via direct covalent N–H bond transformations onto N–C bonds. This approach allows to the synthesis of complex molecules requiring number of steps using classical synthetic ways. In addition, the range of α-C­(sp³)-H containing amide substrates is virtually unlimited highlighting the potential value of this simple system for the construction of complex heterocyclic molecules, such as fused azoles derivatives

Metal-free Cross-Dehydrogenative Coupling of <i>HN</i>-azoles with α‑C(sp³)‑H Amides via C–H Activation and Its Mechanistic and Application Studies

A metal-free one step coupling reaction between various <i>N</i>-azole rings and diverse α-C­(sp³)-H containing amides has been developed under oxidative reaction conditions. Commercially available tetrabutyl ammonium iodide (TBAI) in the presence of terbutylhydroperoxide (TBHP), under neat reaction condition, efficiently catalyzed the coupling. Various azole types, such as 1<i>H</i>-benzotriazoles, 1<i>H</i>-1,2,3-triazoles, 1<i>H</i>-1,2,4-triazoles, 1<i>H</i>-tetrazoles, 1<i>H</i>-pyrazoles, and 1<i>H</i>-benzimidazoles, and α-C­(sp³)-H containing amides, such as <i>N</i>,<i>N</i>-dimethylacetamide, <i>N</i>,<i>N</i>-dimethylbenzamide, <i>N</i>-methylacetamide, <i>N</i>,<i>N</i>-diethylacetamide, <i>N</i>-methylpyrrolidine, and pyrrolidine-2-one, were successfully employed for the coupling. A series of designed and controlled experiments were also performed in order to study the involvement of the different intermediates. Based on the evidence, a plausible mechanism is also proposed. These novel, simple, rapid, attractive, and straightforward transformations open the way of the construction of novel highly functionalized <i>N</i>-azoles via direct covalent N–H bond transformations onto N–C bonds. This approach allows to the synthesis of complex molecules requiring number of steps using classical synthetic ways. In addition, the range of α-C­(sp³)-H containing amide substrates is virtually unlimited highlighting the potential value of this simple system for the construction of complex heterocyclic molecules, such as fused azoles derivatives