One-pot three-component synthesis of novel spirooxindoles with potential cytotoxic activity against triple-negative breast cancer MDA-MB-231 cells

Abstract

Triple-negative breast cancer (TNBC) is a highly aggressive malignancy with limited treatment options due to its heterogeneity and the lack of well-defined molecular targets. In our endeavour towards the development of novel anti-TNBC agents, herein we report a one-pot three-component synthesis of novel spirooxindoles 6a–p, and evaluation of their potential anti-proliferative activity towards TNBC MDA-MB-231 cells. Spirooxindoles 6a, 6e and 6i emerged as the most potent analogues with IC50 = 6.70, 6.40 and 6.70 µM, respectively. Compounds 6a and 6e induced apoptosis in MDA-MB-231 cells, as evidenced by the up-regulation of the Bax and down-regulation of the Bcl-2, besides boosting caspase-3 levels. Additionally, 6e displayed significant increase in the percent of annexin V-FITC positive apoptotic cells from 1.34 to 44%. Furthermore, spirooxindoles 6e and 6i displayed good inhibitory activity against EGFR (IC50 = 120 and 150 nM, respectively). Collectively, these data demonstrated that 6e might be a potential lead compound for the development of effective anti-TNBC agents.

Euphosantianane A–D: Antiproliferative Premyrsinane Diterpenoids from the Endemic Egyptian Plant Euphorbia Sanctae-Catharinae

“…After a 24 h incubation period with 5% CO 2 at 37 °C, stock test compounds ( 1 – 13 ) dissolved in dimethyl sulfoxide (DMSO) were added at concentrations of 100, 50, 25, 12.5, and 6.25 µM in culture medium (final DMSO concentration in medium = 0.1%, by volume). After 48 h of incubation, MTT solution in PBS (5 mg/mL) was added to each well, after which the incubation was resumed for a further 90 min [ 37 , 38 ]. The formation of intracellular formazan crystals (mitochondrial reduction product of MTT) was confirmed by a phase contrast microscopic examination.…”

Marine-Inspired Bis-indoles Possessing Antiproliferative Activity against Breast Cancer; Design, Synthesis, and Biological Evaluation

“…Inspired by the aforementioned discoveries and in connection with our research work concerning the development of effective anti-breast cancer agents [15][16][17][18], we were endeavored to design novel indole derivatives that promisingly possess antiproliferative activity. Perceiving the significance of these facts and based on our growing research interest in marine natural products, we were persuaded to tackle this study to design and synthesize marine-inspired bis-indole derivatives that have potential in vitro antitumor activity against breast cancer.…”

Antitumor properties of certain spirooxindoles towards hepatocellular carcinoma endowed with antioxidant activity

“…Then, cells were sub-cultured with trypsine/EDTA solution, counted with haemocytometer and plated onto 96-well plates (5000 cells/well) and left overnight so as to form a semiconfluent monolayer. A modified method was employed utilising the (3-[4,5-dimethylthiazol-2-yl] À 2,5-diphenyltetrazolium bromide (MTT) dye, as reported earlier [25][26][27] . IC 50 values were calculated using non-linear regression curve fitting of the dose response plots on GraphPad Prism V.6.0 software.…”

“…Strychnofoline, spirotryprostatin A and spirotryprostatin B ( Figure 1) are other examples for natural spirooxindoles possessing anticancer activities 20,21 . Isolation and identification of such bioactive spirooxindole alkaloids have inspired the researchers and paved the way to design and synthesise various spirooxindole-based small molecules with promising biological activities such as antioxidant 22 and anticancer [23][24][25] activities.…”

“…Recently, we have reported a one-pot three-component synthesis of novel spirooxindole derivatives 6a-p as efficient anti-proliferative agents towards the aggressive triple-negative breast cancer MDA-MB-231 cell line 25 . In the current study, the reported promising anti-proliferative impact of spirooxindoles 6a-p spurred us to extend our investigations around their different potential biological activities, where they were evaluated for their potential antioxidant activity via assessing their DPPH radical scavenging capacities and Ferric reducing antioxidant power (FRAP).…”