326914-13-0Relevant articles and documents
Metalloporphyrin-Catalyzed Oxidation of Sunitinib and Pazopanib, Two Anticancer Tyrosine Kinase Inhibitors: Evidence for New Potentially Toxic Metabolites
Paludetto, Marie-No?lle,Bijani, Christian,Puisset, Florent,Bernardes-Génisson, Vania,Arellano, Cécile,Robert, Anne
, p. 7849 - 7860 (2018)
Oxidation of two tyrosine kinase inhibitors (TKIs) sunitinib and pazopanib, using a chemical catalytic system able to mimic the cytochrome P450 type oxidation, allowed us to prepare putative reactive/toxic metabolites of these anticancer drugs. Among these metabolites, aromatic aldehyde derivatives were unambiguously characterized. Such biomimetic oxidation of TKI-type drugs was essential to facilitate the identification of low amounts of aldehydes generated from these TKIs when incubated with human liver microsomes (HLM), which are classical models of human hepatic metabolism. These TKI derivative aldehydes quickly react in vitro with amines. A similar reaction is expected to occur in vivo and may be at the origin of the potentially severe hepatotoxicity of these TKIs.
Substituted oxindol-3-ylidenes as AMP-activated protein kinase (AMPK) inhibitors
Backos, Donald S.,Casalvieri, Kimberly A.,Jordan, Craig T.,Matheson, Christopher J.,Minhajuddin, Mohammed,Reigan, Philip
, (2020/04/22)
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.
Malic acid lin's preparation method
-
Paragraph 0029; 0034; 0036; 0041; 0043, (2019/06/12)
The present invention relates to a sunitinib malate preparation method, wherein particularly 2,4-dimethyl-5-aldehyde-1H-pyrrole-3-carboxylic acid is adopted as a starting raw material, carboxyl activation with carbonyl diimidazole is performed, the obtained material and N, N-diethylethylenediamine are subjected to condensation under catalysis of 1-hydroxybenzotriazole to obtain an intermediate 1, the intermediate 1 and 5-fluoro-2-oxindole react to obtain sunitinib, and the sunitinib and malic acid are directly subjected to salifying without separation so as to obtain the target product. The method of the present invention has characteristics of easy operation, high yield and high product purity, and is suitable for industrial production.
