Abstract
In this work, a series of benzylsulfone coumarin derivatives 5a–5o were synthesized and characterized. Kinase inhibitory activity assay indicated that most of the compounds showed considerable activity against PI3K. Anti-tumor activity studies of the active compounds were also carried out in vitro on the Hela, HepG2, H1299, HCT-116, and MCF-7 tumor cell lines by MTS assay. The structure–activity relationships (SARs) of these compounds were analyzed in detail. Compound 5h exhibited the most potent activities against the mentioned cell lines with IC50 values ranging from 18.12 to 32.60 μM, followed by 5m with IC50 values of 29.30–42.14 μM. Furthermore, 5h and 5m clearly retarded the migration of Hela cells in vitro. Next, an in silico molecular docking study was conducted to evaluate the binding models of 5h and 5m towards PI3Kα and PI3Kβ. Collectively, the above findings suggested that compounds 5h and 5m might be promising PI3K inhibitors deserving further investigation for cancer treatment.
Highlights
The phosphoinositide 3-kinase (PI3K) pathway, one of the most frequently altered pathways in cancer, plays a momentous role in tumorigenesis and many other cellular processes [1,2,3,4]
PI3Kα and PI3Kβ are universally expressed in all cells and tissues, whereas gamma and delta isoforms are exclusively enriched in immune cells [12,13]
The target compounds 5a–5o were synthesized via a three-step synthetic route from substituted benzylchloride/bromide (1a–1j) as outlined in Scheme 1
Summary
The phosphoinositide 3-kinase (PI3K) pathway, one of the most frequently altered pathways in cancer, plays a momentous role in tumorigenesis and many other cellular processes [1,2,3,4]. As one key effector node, the intracellular lipid kinases PI3Ks have been studied thoroughly and validated as promising anticancer targets over the last 30 years [8,9]. Based on their structure and function, PI3K enzymes can be divided into three classes, of which class I has been the most studied, with the subdivisions of PI3Kα, PI3Kβ, PI3Kγ and PI3Kδ [10,11]. Small molecule inhibitors of PI3K, including pan- and isoform-specific, are currently being evaluated and have exhibited significant anti-tumor activities in laboratory and clinic, either monotherapy or in combination with cytotoxic agents [14,15,16]. Pan-PI3K inhibitors include but are not limited to buparlisib [17], pictilisib [18] and pilaralisib [19], targeting all isoforms
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