Abstract
The present work aims to design and synthesize novel series of spiro pyrazole-3,3’-oxindoles analogues and investigate their bioactivity as antioxidant and antimicrobial agents, as well as antiproliferative potency against selected human cancerous cell lines (i.e., breast, MCF-7; colon, HCT-116 and liver, HepG-2) relative to healthy noncancerous control skin fibroblast cells (BJ-1). The mechanism of their cytotoxic activity has been also examined by immunoassaying the levels of key anti- and proapoptotic protein markers. The analytical and spectral data of the all synthesized target congeners were compatible with their structures. Synthesized compounds showed diverse moderate to powerful antimicrobial and antioxidant activities. Results of MTT assay revealed that seven synthesized compounds (i.e., 11a, 11b, 12a, 12b, 13b, 13c and 13h) particularly exhibited significant cytotoxicity against the three cancerous cell lines under investigation. Ranges of IC50 values obtained were 5.7–21.3 and 5.8–37.4 µg/mL against HCT-116 and MCF-7, respectively; which is 3.8 and 6.5-fold (based on the least IC50 values) more significant relative to the reference chemotherapeutic drug doxorubicin. In HepG-2 cells, the analogue 13h exhibited the highest cytotoxicity with IC50 value of 19.2µg/mL relative to doxorubicin (IC50 = 21.6µg/mL). The observed cytotoxicity was specific to cancerous cells, as evidenced by the minimal toxicity in the noncancerous control skin-fibroblast cells. ELISA results indicated that the observed antiproliferative effect against examined cancer cell lines is mediated via engaging the activation of apoptosis as illustrated by the significant increase in proapoptotic protein markers (p53, bax and caspase-3) and reduction in the antiapoptotic marker bcl-2. Taken together, results of the present study emphasize the potential of spiro pyrazole-oxindole analogues as valuable candidate anticancer agents against human cancer cells.
Highlights
Cancer is a primary global burden disease that is classified as the second-leading cause of death after cardiovascular diseases [1,2]
The results indicate that the ability of the tested compounds to reduce a solution of violet DPPH
The results indicated that compounds 11a, 11b, 12a and 12b significantly reduced the expression levels of the antiapoptotic protein B-cell lymphoma-2 (Bcl-2) by ~ 50%, 63%, 52% and 51%, respectively, towards MCF-7 cells compared to the control (Table 5)
Summary
Cancer is a primary global burden disease that is classified as the second-leading cause of death after cardiovascular diseases [1,2]. Designing and discovering effective and selective antitumor agents remains the primary objective in organic medical chemistry known as targeted therapeutic strategies [3]. One of these strategies is apoptosis a.k.a. programmed cell death that is considered an essential mechanism by the body to eliminate unwanted cells [4,5]. Induction of apoptosis is considered as one of the most successful strategies to target cancer [4,5,6,7]
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