# Schiff Bases: Interesting Scaffolds with Promising Antitumoral Properties
## 2 Schiff Bases as Antiproliferative Agents
### Mono-Schiff Bases
Among the tested compounds, the authors evidenced a selectivity toward the adopted cells lines, indicating that the highest inhibitory activity toward the MCF-7 and T47D cells was obtained under the imine **44** treatment (IC\({}_{50}\) values of 0.024 and 0.034 M, respectively). Moreover, they suggested that this different selectivity could depend on the difference forms of the phosphatidylinositol 3-kinases (PI3 Ks) present in the adopted cell models. This hypothesis was proven by the means of in silico and in vitro studies, indicating that the phosphoinositide 3-kinase \(\alpha\) (PI3K \(\alpha\)) is one of the targets of the compound **44**, which influences the fundamental PI3K/Akt signaling pathway [66] leading, ultimately, to cancer cell apoptosis. At the same time, compound **44** reduces the expression of the Vascular Endothelial Growth factor (VEGF) in MCF-7 cells, suggesting a role in inhibiting the angiogenesis process. However, no evidence about the effects on normal cell lines has been reported. [PERSON] et al. (2018) [67] described a series of Schiff bases and evaluated their antiproliferative activities against HepG2 (liver) and MCF-7 (breast) cell lines using the MTT assay. The majority of prepared Schiff bases displayed better antitumor activity than doxorubicin. Compounds **45** and **46** were the most interesting of the series. Compound **45** was the most active against HepG2 cell line compared to doxorubicin (IC\({}_{50}\) = 66.3 uM versus 80.9 uM), while compound **46** showed high activity against MCF-7 (IC\({}_{50}\) = 60.8 uM versus 65.6 uM of doxorubicin). They were also demonstrated to induce apoptosis in HepG2 and MCF-7, increasing the caspase-3 levels. [PERSON] et al. (2018) [68] reported a series of Schiff bases bearing a pyranoquinolino moiety. They were evaluated for topoisomerase II\(\beta\) (TOP2B) inhibitory activity [69; 70] and cytotoxicity against breast cancer cell line (MCF-7). The compounds **47**-**49** displayed a significant TOP2B cytotoxicity compared to the reference doxorubicin (IC\({}_{50}\) = 0.042, 0.83, and 0.6 uM versus IC\({}_{50}\) = 1.17 uM of doxorubicin). Several Schiff bases derived from 2-aminobenzzothiazole were reported by [PERSON] et al. (2018) [71], who performed in vitro MTT assay on HeLa cell lines to validate the cytotoxic activity against cervical cancer cells. Compound **50** showed high activity with an IC\({}_{50}\) value of 2.517 ug/mL (cisplatin: IC\({}_{50}\) = 17.2 ug/mL). [PERSON] et al. (2019) [72] studied a series of Schiff bases and evaluated their cytotoxicity against cancer cell lines (HeLa and MCF-7) and a normal cell line (BHK-21) by means of the MTT assay. Compounds **51** and **53** showed a slight cytotoxic activity against HeLa (IC\({}_{50}\) = 56.7 and 20.8 uM, respectively, versus 5.13 uM of carboplatin) and BHK-21 cells (IC\({}_{50}\) = 32.2 and 60.2 uM, respectively). The mechanism of action for the active compound L5 was deepened, studying the pro-apoptotic mechanism by fluorescence microscopy, cell cycle analysis, caspase-9 and -3 activity, reactive oxygen species (ROS) production, and DNA binding. Compound **52** exhibited disintegrated cell membranes and condensed cellular protein, probably due to the lipids' and proteins' oxidation, suggesting that it could be a potent drug against cancer. Several Schiff bases of tetrahydrorocurcumin have been recently reported by [PERSON] et al. (2019) [PERSON] et al. (2019) [PERSON] et al. (2019) as potential anticancer agents. The in vitro anticancer activity was evaluated against three human cancer cell lines: human epithelial lung carcinoma (A549) and cervical cancer (HeLa) and human breast adenocarcinoma (MCF-7) cells. Most compounds exhibited moderate to good anticancer activity against all three tested cell lines and were significantly more active than tetrahydrorocurcumin. The most interesting was compound **53** (IC\({}_{50}\) = 11.9, 12.7, 4.8 uM, against the three cell lines considered, respectively). [PERSON] et al. (2020) [PERSON] et al.