Discovery of Chromeno[4,3-<i>c</i>]pyrazol-4(2<i>H</i>)-one Containing Carbonyl or Oxime Derivatives as Potential, Selective Inhibitors PI3Kα

Abstract

A series of novel chromeno[4,3-c]pyrazol-4(2H)-one containing carbonyl or oxime derivatives (4a-n, 5a-n) have been synthesized and evaluated their biological activities as phosphatidyl inositol 3-kinase (PI3K) inhibitors. Out of them, compound 5l showed the most potent antiproliferative activities against HCT-116 with IC 50 of 0.10 µM in vitro, and exhibited the most potent activity for PI3Kα with the value of 0.012 µM. Docking simulation of 5l into PI3Kα active site were performed to determine the probable binding model, and it indicated that compound 5l could be optimized as a potential inhibitor of PI3Kα in the further study. Key words chromeno[4,3-c]pyrazol-4(2H)-one derivative; inhibitor; antiproliferativeThree distinct classes of lipid phosphatidyl inositol 3-kinases (PI3Ks), as a family, play a key role in cellular processes by regulating functions such as cell metabolism, proliferation, differentiation, motility, and intracellular trafficking.

The Good, the Bad, and the Ugly: “HiPen”, a New Dataset for Validating (S)QM/MM Free Energy Simulations

“…Molecule 8 (ZINC ID 00107778, 4,6-dichloro-2 H -chromene-3-carbaldehyde oxime) is another oxime species similar to molecule 2 . As mentioned above, oxime species have been used recently as promising anti-cancer agents, and thus the computational community should ensure our methods can properly model such compounds [82,84,85,86].…”

Oximes: Novel Therapeutics with Anticancer and Anti-Inflammatory Potential

“…Similarly, several chromeno [4,3- c ]pyrazol-4(2 H )-one oxime derivatives have been shown to target PI3Ks, including PI3Kα, which is inhibited by compound 26 . This compound also exhibited the most potent antiproliferative activity against human colorectal carcinoma HCT-116 cells [ 39 ].…”

“…Oximes have been used in the design of various kinase inhibitors, including phosphatidyl inositol 3-kinase (PI3K) inhibitors [ 39 ], phosphorylase kinase (PhK) [ 40 ], and JNK [ 38 , 41 ] (see Table 1 and Table 2 ). For example, indirubin oximes are of interest because of their high affinity binding to the ATP-binding site of protein kinases involved in tumorigenesis, e.g., cyclin-dependent kinases (CDK), glycogen synthase kinase (GSK) 3β, vascular endothelial growth factor receptor 2 (VEGFR-2), c-Src, and casein kinase 2 (CK2) [ 42 , 43 , 44 , 45 , 46 , 47 , 48 ].…”

Synthetic Routes to Coumarin(Benzopyrone)-Fused Five-Membered Aromatic Heterocycles Built on the α-Pyrone Moiety. Part II: Five-Membered Aromatic Rings with Multi Heteroatoms

“…The preparation of chromen[4,3- c ]pyrazol-4-ones 9 from the reaction of 3-formyl-4-chlorocoumarin ( 5 ) with the appropriate aryl or alkyl hydrazine hydrochloride in the presence of base was intensively investigated ( Scheme 3 ) [ 10 , 18 , 19 , 25 , 26 , 27 , 28 , 29 , 30 ]. Compound 9a was employed as starting material to enrich the derivatives of chromen[4,3- c ]pyrazol-4-ones 10–12 through the reaction with benzyl bromides [ 26 ], alkyl sulfonyl chlorides [ 28 ], or N -piperazine sulfonyl chlorides [ 30 ] ( Scheme 4 ).…”