190654-78-5

Upstream product

• 108-42-9 3-chloro-aniline 
• 203436-45-7 2,6-dichloro-9-isopropyl-9H-purine 
• 75-26-3 isopropyl bromide 
• 190654-76-3 2-chloro-6-(3-chlorophenylamino)-purine 
• 75-30-9 2-iodo-propane 
• 534-17-8 caesium carbonate 
• 5451-40-1 2,6 dichloropurine 

Downstream Products

• 220792-00-7 (+/-)-Purvalanol A 
• 212779-48-1 NG-52 

Relevant academic research and scientific papers

Design, synthesis and biological evaluation of novel histone deacetylase1/2 (HDAC1/2) and cyclin-dependent Kinase2 (CDK2) dual inhibitors against malignant cancer

In the current study, we have designed and synthesized a series of novel histone deacetylase1/2 (HDAC1/2) and cyclin-dependent kinase2 (CDK2) dual inhibitors by integrating purine-based pharmacophore into the recognition cap group of CS055. The representative compound 14d with excellent antiproliferative activities towards five solid cancer cells, showed potent inhibitory activities against HDAC1, HDAC2 and CDK2 with IC50 values of 70.7 nM, 23.1 nM and 0.80 μM, respectively. Besides, compound 14d could effectively block the cell cycle in the G2/M phase and induce apoptosis, which might be related to increasing intracellular ROS levels. Importantly, compound 14d exhibited desirable pharmacokinetic (PK) properties with the intraperitoneal bioavailability of 50.8percent in ICR mice, and potent in vivo antitumor activity in the HCT116 xenograft model. Therefore, compound 14d could be considered as a promising lead compound for the development of multitargeting anticancer agents.

DUAL CLK/CDK1 INHIBITORS FOR CANCER TREATMENT

This disclosure generally relates to dual CLK2/CDK1 inhibitors or more potent and specific CLK inhibitors to target CLK2 and CDKl kinases in the treatment of germ-line mutations of the spliceosome leading to the development of cancers and other human dise

A triple exon-skipping luciferase reporter assay identifies a new CLK inhibitor pharmacophore

The splicing of pre-mRNA is a critical process in normal cells and is deregulated in cancer. Compounds that modulate this process have recently been shown to target a specific vulnerability in tumors. We have developed a novel cell-based assay that specifically activates luciferase in cells exposed to SF3B1 targeted compounds, such as sudemycin D6. This assay was used to screen a combined collection of approved drugs and bioactive compounds. This screening approach identified several active hits, the most potent of which were CGP-74514A and aminopurvalanol A, both have been reported to be cyclin-dependent kinases (CDKs) inhibitors. We found that these compounds, and their analogs, show significant cdc2-like kinase (CLK) inhibition and clear structure-activity relationships (SAR) at CLKs. We prepared a set of analogs and were able to ‘dial out’ the CDK activity and simultaneously developed CLK inhibitors with low nanomolar activity. Thus, we have demonstrated the utility of our exon-skipping assay and identified new molecules that exhibit potency and selectivity for CLK, as well as some structurally related dual CLK/CDK inhibitors.

Oxidative amination of cuprated pyrimidine and purine derivatives

Using regioselective cuprations (via magnesiations), various primary, secondary and tertiary aminated pyrimidine and purine derivatives were prepared by the oxidative coupling of lithium amidocuprates using chloranil. DNA and RNA units such as aminated uracil or thymine, and adenine, as well as a CDK inhibitor, purvalanol A, were all obtained under mild conditions and satisfactory yields.

Synthesis and biological properties of C-2, C-8, N-9 substituted 6-(3-chloroanilino)-purine derivatives as cyclin-dependent kinase inhibitors. Part II

In this study, C-2, C-8, N-9 substituted 6-(3-chloroanilino)purine derivatives were synthesized and their inhibitory effects on cyclin-dependent kinases (CDK2, 4) as well as their cytotoxicities were evaluated. The effects of substituents at the C-2, C-8, and N-9 positions of the substituted purine were investigated. Among the compounds tested, [6-(3-chloroanilino)-2-(2-hydroxymethyl-4-hydroxypyrrolidyl)- 9-isopropylpurine] (4h) was the most active inhibitor of CDK2 with IC50 of 0.3μM i.e. a two-fold increased inhibitory activity as compared to roscovitine. Results from structure-activity relationship studies should allow the design of more potent and selective CDK2 inhibitors, which may provide an effective therapy for cancer or other CDK-dependent diseases.