Synthesis and evaluation of modified chalcone based p53 stabilizing agents

Abstract

Tumor suppressor protein p53 induces cell cycle arrest and apoptotic cell death in response to various cellular stresses thereby preventing cancer development. Activation and stabilization of p53 through small organic molecules is, therefore, an attractive approach for the treatment of cancers retaining wild-type p53. In this context, a series of nineteen chalcones with various substitution patterns of functional groups including chloro, fluoro, methoxy, nitro, benzyloxy, 4-methyl benzyloxy was prepared using Claisen-Schmidt condensation. The compounds were characterized using NMR, HRMS, IR and melting points. Evaluation of synthesized compounds against human colorectal (HCT116) and breast (CAL-51) cancer cell lines revealed potent antiproliferative activities. Nine compounds displayed GI values in the low micromolar to submicromolar range; for example (E)-1-phenyl-3-(3,4,5-trimethoxyphenyl)prop-2-en-1-one (SSE14108) showed GI of 0.473±0.043µM against HCT116 cells. Further analysis of these compounds revealed that (E)-3-(4-chlorophenyl)-1-phenylprop-2-en-1-one (SSE14105) and (E)-3-(4-methoxyphenyl)-1-phenylprop-2-en-1-one (SSE14106) caused rapid (4 and 8-h post-treatment) accumulation of p53 in HCT116 cells similar to its induction by positive control, Nutlin-3. Such activities were absent in 3-(4-methoxyphenyl)propiophenone (SSE14106H2) demonstrating the importance of conjugated ketone for antiproliferative and p53 stabilizing activity of the chalcones. We further evaluated p53 levels in the presence of cycloheximide (CHX) and the results showed that the p53 stabilization was regulated at post-translational level through blockage of its degradation. These chalcones can, therefore, act as fragment leads for further structure optimization to obtain more potent p53 stabilizing agents with enhanced anti-proliferative activities.

Antiproliferative activity and p53 upregulation effects of chalcones on human breast cancer cells

“…Formazan crystals were solubilised in dimethylsulfoxide (DMSO, Sigma Aldrich V R , St. Louis, MO), and absorbance rates were measured at 562 nm in ThermoPlate V R TP Reader. Chalcones 1,6,8,9,11,17,19, and 20 had the highest antiproliferative activity and were assayed against both cell lines at seven concentrations, ranging from 1.25 to 80 lM for IC 50 values determination.…”

“…Mai et al described chalcone was effective against ERpositive breast cancer cells (MCF-7 line) targeting 20 apoptotic markers 16 . Iftikhar et al reported that chalcone bearing chlorine at position 2 was effective against breast cancer cells (CAL-51 line) and induced accumulation of p53 protein 17 . Silva and coauthors described unsubstituted chalcone increased p53 protein activity in osteosarcoma cells (U2OS line) through the induction of heat shock protein DNAJB1 18 .…”

Identification and characterization of SSE15206, a microtubule depolymerizing agent that overcomes multidrug resistance

“…Similarly, N-benzoylated pyrazolines 34 inhibited microtubule polymerization at nano-molar concentrations. We have recently synthesized and characterized the antiproliferative potential of novel compounds based on modified chalcones 35 . In continuation of our work we have prepared a small library of chalcone derivatives, pyrazolinethioamides, and have evaluated their antiproliferative potential.…”

Targeting triple negative breast cancer heterogeneity with chalcones: a molecular insight

“…Table 1 summarises published studies on chalcone derivatives that were tested on different cell lines resembling the different subclasses of TNBCs [7,29]. The effects of chalcones were explored on basal-like 1 [39][40][41][42], basal-like 2 [43], Mesenchymal [43][44][45][46][47][48], luminal androgen receptor [49] and unclassified [43,50,51] TNBCs cells. Besides, gene expression studies have identified potential promising molecular targets related to TNBC.…”