65435-04-3

Usage

Uses

Used in Pharmaceutical Industry:
5-CHLOROACETYLOXINDOLE is used as a key intermediate for the synthesis of [(dihydrooxoindolylidene)methyl]pyrrolepropanoic acid and pyrido[2,3-d]pyrimidine. These compounds are known as tyrosine kinase inhibitors, which play a significant role in the development of targeted therapies for various diseases, including cancer.
As a precursor in the synthesis of tyrosine kinase inhibitors, 5-CHLOROACETYLOXINDOLE contributes to the development of novel drugs that can potentially inhibit the activity of tyrosine kinases, which are often overexpressed or mutated in cancer cells. By targeting these enzymes, these inhibitors can help regulate cell signaling pathways and prevent uncontrolled cell growth, ultimately leading to the suppression of tumor development and progression.

InChI:InChI=1/C10H8ClNO2/c11-5-9(13)6-1-2-8-7(3-6)4-10(14)12-8/h1-3H,4-5H2,(H,12,14)

Upstream product

• 59-48-3 2-oxoindole 
• 79-04-9 chloroacetyl chloride 
• 118289-70-6 5-(chloroacetyl)-N-ethyloxindole 

Downstream Products

• 102386-52-7 5-[2-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]acetyl]oxindol hydrochloride 
• 1129403-60-6 C₁₇H₁₂N₂OS*ClH 

Relevant academic research and scientific papers

CONJUGATES OF AMPK INHIBITORS AND PROTAC DEGRADERS AND RELATED USES

The present disclosure relates to compounds of Formula (I): T-L-D, stereoisomers thereof, prodrugs thereof, and pharmaceutically acceptable salts thereof, wherein T is an AMPK inhibiting moiety; L is a linking moiety; and D is a PROTAC degrading moiety. The present disclosure also relates to uses of the compounds, e.g., to inhibit AMP-Activated protein kinase (AMPK), degrading AMPK protein, and/or treat cancer in a subject.

Yb(OTf)3catalyzed [1,3]-rearrangement of 3-alkenyl oxindoles

A Yb(OTf)3catalyzed [1,3]-rearrangement of 3-alkenyl oxindoles was achieved, affording a variety of multifunctional 3-ylideneoxindoles with good yields andZ/Eselectivities (64%-89% yield, 78?:?22->99?:?1Z/E). Importantly, an operationally simple, one-pot sequential catalytic synthesis of 3-ylideneoxindoles was also developed. Additionally, a cross [1,3]-rearrangement experiment and nonracemic transformation were also carried out, which indicated a concerted rearrangement mechanism of this methodology.

AMP-ACTIVATED PROTEIN KINASE INHIBITORS AND METHODS OF MAKING AND USING THE SAME

The present disclosure relates to compounds of Formula (I): (I); stereoisomers thereof, prodrugs thereof, and pharmaceutically acceptable salts thereof. The present disclosure also relates to uses of the compounds, e.g., to inhibit AMP-Activated protein kinase (AMPK) and treat cancer in a subject.

Impurity in ziprasidone hydrochloride and preparation method thereof

The invention provides an impurity in ziprasidone hydrochloride. The impurity has a structure as shown in formula 1. The impurity with a specific structure is obtained on the basis that chlorine impurities are doped in the ziprasidone hydrochloride preparation process, or impurities are brought in and transferred into a final product in the dechlorination step in the acylation reaction process, and the corresponding impurity preparation steps are provided, so that corresponding technical support is provided for preparation of ziprasidone hydrochloride. The synthesis method provided by the invention is simple in process, strong in controllability and mild in condition, can be used for quality standard establishment and quality control links in ziprasidone hydrochloride process research and development, production and the like, and provides technical support for the medication safety of ziprasidone hydrochloride. The method can be used for quality research such as qualitative and quantitative analysis of impurities in ziprasidone hydrochloride synthesis, so that improvement of the quality of ziprasidone hydrochloride is facilitated, and important guiding significance is provided for reducing the medication risk of ziprasidone hydrochloride.

Substituted oxindol-3-ylidenes as AMP-activated protein kinase (AMPK) inhibitors

AMP-activated protein kinase (AMPK) is a central metabolic regulator that promotes cancer growth and survival under hypoxia and plays a role in the maintenance of cancer stem cells. A major challenge to interrogating the potential of targeting AMPK in cancer is the lack of potent and selective small molecule inhibitors. Compound C has been widely used as an AMPK inhibitor, but it lacks potency and has a poor selectivity profile. The multi-kinase inhibitor, sunitinib, has demonstrated potent nanomolar inhibition of AMPK activity and has scope for modification. Here, we have designed and synthesized several series of oxindoles to determine the structural requirements for AMPK inhibition and to improve selectivity. We identified two potent, novel oxindole-based AMPK inhibitors that were designed to interact with the DFG motif in the ATP-binding site of AMPK, this key feature evades interaction with the common recptor tyrosine kinase targets of sunitinib. Cellular engagement of AMPK by these oxindoles was confirmed by the inhibition of phosphorylation of acetyl-CoA carboxylase (ACC), a known substrate of AMPK, in myeloid leukemia cells. Interestingly, although AMPK is highly expressed and activated in K562 cells these oxindole-based AMPK inhibitors did not impact cell viability or result in significant cytotoxicity. Our studies serve as a platform for the further development of oxindole-based AMPK inhibitors with therapeutic potential.

Novel Human Aminopeptidase N Inhibitors: Discovery and Optimization of Subsite Binding Interactions

Aminopeptidase N (APN/CD13) is a zinc-dependent M1 aminopeptidase that contributes to cancer progression by promoting angiogenesis, metastasis, and tumor invasion. We have previously identified hydroxamic acid-containing analogues that are potent inhibitors of the APN homologue from the malarial parasite Plasmodium falciparum M1 aminopeptidase (PfA-M1). Herein, we describe the rationale that underpins the repurposing of PfA-M1 inhibitors as novel APN inhibitors. A series of novel hydroxamic acid analogues were developed using a structure-based design approach and evaluated their inhibition activities against APN. N-(2-(Hydroxyamino)-2-oxo-1-(3′,4′,5′-trifluoro-[1,1′-biphenyl]-4-yl)ethyl)-4-(methylsulfonamido)benzamide (6ad) proved to be an extremely potent inhibitor of APN activity in vitro, selective against other zinc-dependent enzymes such as matrix metalloproteases, and possessed limited cytotoxicity against Ad293 cells and favorable physicochemical and metabolic stability properties. The combined results indicate that compound 6ad may be a useful lead for the development of anticancer agents.

Design, synthesis, structure-activity relationships study and X-ray crystallography of 3-substituted-indolin-2-one-5-carboxamide derivatives as PAK4 inhibitors

We have previously described the identification of indolin-2-one-5-carboxamides as potent PAK4 inhibitors. This study expands the structure-activity relationships on our original series by presenting several modifications in the lead compounds, 2 and 3. A series of novel derivatives was designed, synthesized, and evaluated in biochemical and cellular assay. Most of this series displayed nanomolar biochemical activity and potent antiproliferative activity against A549 and HCT116 cells. The representative compound 10a exhibited excellent enzyme inhibition (PAK4 IC50 = 25 nM) and cellular potency (A549 IC50 = 0.58 μM, HCT116 IC50 = 0.095 μM). An X-ray structure of compound 10a bound to PAK4 was obtained. Crystallographic analysis confirmed predictions from molecular modeling and helped refine SAR results. In addition, Compound 10a displayed focused multi-targeted kinase inhibition, good calculated drug-likeness properties. Further profiling of compound 10a revealed it showed weak inhibitory activity against various isoforms of human cytochrome P450.

HETEROCYCLIC COMPOUNDS, PROCESS FOR PREPARATION OF THE SAME AND USE THEREOF

The present invention provides a heterocyclic compound represented by the formula (I), its stereoisomers, or a pharmaceutically acceptable salt thereof, pharmaceutical compositions thereof, and their use in preparing a medicament for the prevention and/or treatment of central nervous system disease.

Discovery of indolin-2-one derivatives as potent PAK4 inhibitors: Structure-activity relationship analysis, biological evaluation and molecular docking study

Utilizing a pharmacophore hybridization approach, a novel series of substituted indolin-2-one derivatives were designed, synthesized and evaluated for their in vitro biological activities against p21-activated kinase 4. Compounds 11b, 12d and 12g exhibited the most potent inhibitory activity against PAK4 (IC50?=?22?nM, 16?nM and 27?nM, respectively). Among them, compound 12g showed the highest antiproliferative activity against A549 cells (IC50?=?0.83?μM). Apoptosis analysis in A549 cells suggested that compound 12g delayed cell cycle progression by arresting cells in the G2/M phase of the cell cycle, retarding cell growth. Further investigation demonstrated that compound 12g strongly inhibited migration and invasion of A549 cells. Western blot analysis indicated that compound 12g potently inhibited the PAK4/LIMK1/cofilin signalling pathways. Finally, the binding mode between compound 12g with PAK4 was proposed by molecular docking. A preliminary ADME profile of the compound 12g was also drawn on the basis of QikProp predictions.

PLASMINOGEN ACTIVATOR-1 INHIBITORS AND METHODS OF USE THEREOF

The invention relates to plasminogen activator- 1 (PAI-1) inhibitor compounds and uses thereof in the treatment of any disease or disorder associated with elevated PAI-1. The invention includes, but is not limited to, the use of such compounds to prevent or reduce thrombosis and fibrosis, to promote thrombolysis, and to modulate lipid metabolism and treat diseases or disorders associated with elevated PAI-1, cholesterol, or lipid levels.