Introducing novel potent anticancer agents of1H-benzo[f]chromene scaffolds, targetingc-Srckinase enzyme with MDA-MB-231 cell line anti-invasion effect

Abstract

In our effort to develop novel and powerful agents with anti-proliferative activity, two new series of 1H-benzo[f]chromene derivatives, 4a–h and 6a–h, were synthesised using heterocyclocondensation methodologies under microwave irradiation condition. The structures of the target compounds were established on the basis of their spectral data, IR, 1H NMR, 13 C NMR, 13 C NMR-DEPT/APT, and MS data. The new compounds have been examined for their anti-proliferative activity against three cancer cell lines, MCF-7, HCT-116, and HepG-2. Vinblastine and Doxorubicin have been used as positive controls in the viability assay. The obtained results confirmed that most of the tested molecules revealed strong and selective cytotoxic activity against the three cancer cell lines. Moreover, these molecules exhibited weak cytotoxicity on the HFL-1 line, which suggested that they might be ideal anticancer candidates. The SAR study of the new benzochromene compounds verified that the substituents on the phenyl ring of 1H-benzo[f]chromene nucleus, accompanied with the presence of bromine atom or methoxy group at the 8-position, increases the ability of these molecules against the different cell lines. Due to their high anti-proliferative activity, compounds 4c and 6e were selected to be examined their proficiency to inhibit the invasiveness of the highly sensitive and invasive breast cancer cell line, MDA-MB-231. The anti-invasion behaviour of these molecules against the highly sensitive, non-oestrogen, and progesterone MDA-MB-231 cell line gave rise to their decreasing metastatic effect compared to the reference drug. Furthermore, this report explores the apoptotic mechanistic pathway of the cytotoxicity of the target compounds and reveals that most of these compounds enhance the Caspase 3/7 activity that could be considered as potential anticancer agents.

Design and Synthesis of Novel Heterocyclic-Based 4H-benzo[h]chromene Moieties: Targeting Antitumor Caspase 3/7 Activities and Cell Cycle Analysis

“…The in vitro antiproliferative performance of compounds 4 , 7 – 11 , and 12 – 16 towards breast cancer MCF-7, human colon cancer HCT-116, and liver cancer HepG-2 cell lines was explored, as shown in Figure 4 and Table 1. The judicious choice of the cell lines and standard drugs was instigated by the asserted anticancer behavior of a number of benzochromene and chromenopyrimidine molecules [13,14,15,16,17,18,19,20,21,22,23,24,25,26]. Their cytotoxic activities were evaluated via the 2-(4,5-dimethylthiazol-2-yl)-3,5-diphenyl-2 H -tetrazol-3-ium bromide (MTT) colorimetric assay [28,29], and the obtained IC 50 values were in comparison to the values of the reference cytotoxic drugs: Doxorubicin, Vinblastine, and Colchicine.…”

“…The β -enaminonitriles compound ( F ) (R = 2,4-OMe, 4-NO2, 3,4,5-OMe, 3,4-Cl) [23] has strong blood–brain barrier permeability profiles, determined in the parallel artificial membrane permeability assay (PAMPA), and experience low toxicity in the HepG-2 cells. The β -enaminonitrile compounds ( G ) exhibit antiproliferative and c-Src kinase inhibitory activities [24], and the β -enaminonitriles ( H ) [25] demonstrate cell cycle arrest at the S and G2/M phases, inducing apoptosis and c-Src kinase inhibitory, presented in Figure 2.…”

Synthesis, Cytotoxic Activity, Crystal Structure, DFT Studies and Molecular Docking of 3-Amino-1-(2,5-dichlorophenyl)-8-methoxy-1H-benzo[f]chromene-2-carbonitrile

“…For instance, some derivatives of 2-amino-4-aryl-4H-benzo[h]chromene-3-carbonitrile and 2-amino-4-aryl-6-methoxy-4H-benzo[h]chromene-3-carbonitrile act as potential tumor vascular-disrupting agents and induce cell cycle arrest at G2/M and apoptosis [11,12], thus they have emerged as a new class of cytotoxic agents [13][14][15][16][17][18][19][20][21]. In addition, a range of studies has revealed the potential anticancer effect of 1H-benzo[f]chromene derivatives [22][23][24][25][26][27]. Some 3-amino-1aryl-1H-benzo[f]chromene-2-carbonitrile derivatives exhibit c-Src kinase inhibitory and antiproliferative activities [22] and show a high potency for the inhibition of hAChE [23], while inducing cell cycle arrest and apoptosis in human cancer cells via dual inhibition of topoisomerase I and II [26,27].…”

“…In addition, a range of studies has revealed the potential anticancer effect of 1H-benzo[f]chromene derivatives [22][23][24][25][26][27]. Some 3-amino-1aryl-1H-benzo[f]chromene-2-carbonitrile derivatives exhibit c-Src kinase inhibitory and antiproliferative activities [22] and show a high potency for the inhibition of hAChE [23], while inducing cell cycle arrest and apoptosis in human cancer cells via dual inhibition of topoisomerase I and II [26,27]. In continuation of our previous work in benzochromenes chemistry [2][3][4]22,26,27] and the study of crystal structure for benzochromene derivatives [2,[28][29][30][31][32][33][34], we report the synthesis, NMR spectra, crystal structure, theoretical calculations (DFT), molecular modeling analyses, and cytotoxic activity of 3-amino-1-(2,5-dichlorophenyl)-8-1H-benzo[f]chromene-2-carbonitrile.…”

Synthesis, Biological Assessment, and Structure Activity Relationship Studies of New Flavanones Embodying Chromene Moieties

“…As a continuation of our preceding work in the area of the synthesis and biological screening of the bioactive molecules [19][20][21][22] based on extensive molecular modeling and in-silico studies, we carried out the synthesis of a novel series of chromene-incorporating flavanones, endeavoring to find new and alternative drug candidates to replace those in peril of facing resistance from microorganisms.…”