Synthesis of N -(4-chlorophenyl) substituted pyrano[2,3-c]pyrazoles enabling PKBβ/AKT2 inhibitory and in vitro anti-glioma activity

Abstract

A series of N -(4-chlorophenyl) substituted pyrano[2,3-c]pyrazoles was synthesised and screened for their potential to inhibit kinases and exhibit anticancer activity against primary patient-derived glioblastoma 2D cells and 3D neurospheres. A collection of 10 compounds was evaluated against glioma cell lines, with compound 4j exhibiting promising glioma growth inhibitory properties. Compound 4j was screened against 139 purified kinases and exhibited low micromolar activity against kinase AKT2/PKBβ. AKT signalling is one of the main oncogenic pathways in glioma and is often targeted for novel therapeutics. Indeed, AKT2 levels correlated with glioma malignancy and poorer patient survival. Compound 4j inhibited the 3D neurosphere formation in primary patient-derived glioma stem cells and exhibited potent EC 50 against glioblastoma cell lines. Although exhibiting potency against glioma cells, 4j exhibited significantly less cytotoxicity against non-cancerous cells even at fourfold–fivefold the concentration. Herein we establish a novel biochemical kinase inhibitory function for N -(4-chlorophenyl) substituted pyrano[2,3-c]pyrazoles and further report their anti-glioma activity in vitro for the first time. KEY MESSAGE Anti-glioma pyrano[2,3-c]pyrazole 4j inhibited the 3D neurosphere formation in primary patient-derived glioma stem cells. 4j also displayed PKBβ/AKT2 inhibitory activity. 4j is nontoxic towards non-cancerous cells.

Dual inhibition of HSF1 and DYRK2 impedes cancer progression

“…Expression analysis from single-cell RNA sequencing datasets: This analysis was carried out as stated previously [ 23 ]. To understand expression across various cell states of diverse cancers, we queried DYRK2 and HSF1 levels in previously published single-cell RNA sequencing datasets of cancer [ 24–27 ] available on the Single Cell portal of Broad Institute, MIT and Harvard, U.S.A. ( https://singlecell.broadinstitute.org/single_cell ).…”

Recent Synthesis of Mono‐ & Bis‐Pyranopyrazole Derivatives

“…[131] N-(4-chlorophenyl) substituted pyrano[2,3-c]pyrazoles (9) were synthe-sized and showed potential for anticancer activity and inhibit kinases against glioma cell lines. With unsubstituted compound (9) exhibited strong glioma growth inhibitory properties [58] (Scheme 4).…”

“…The synthesis of pyranopyrazole and its derivatives commonly involves two-, three-, and four-component reactions (Figure 4). [3,58] The starting materials of the four-component reaction have been modified by many researchers. Sajjadi et al (2023), for instance, reported on the synthesis of dihydropyrano[2,3c]pyrazoles via Knoevenagel-Michael multiple reactions by using green catalyst Fe 3 O 4 @gC 3 N 4 for the reaction of aldehydes, phenylhydrazine, ethyl acetoacetate and malononitrile under 1 h reflux to achieve 97 % yield of product (Route 1).…”

Indole clubbed 2,4‐thiazolidinedione linked 1,2,3‐triazole as a potent antimalarial and antibacterial agent against drug‐resistant strain and molecular modeling studies

“…Considering the current need for a new chemical entity for the microbial resistance strains and in continuation of our finding, we have designed and synthesized 2,4-thiazolidinedione clubbed indole-1,2,3-triazole derivatives. [26][27][28][29][30][31][32][33][34][35] The synthesized compounds were evaluated for their in vitro antibacterial, antifungal, and antimalarial activities. The best in vitro outcome was also confirmed to have considerable binding affinities toward the target proteins.…”