RESUMO
Six novel ciprofloxacin-1,2,3-triazole hybrids (6a-f) were synthesized via click reaction, by reacting of methyl 1-cyclopropyl-6-fluoro-4-oxo-7-(4-(3-oxobutanoyl)piperazin-1-yl)-1,4-dihydroquinoline-3-carboxylate (5) with various aryl azides (9a-f). The new compounds were characterized using High-Resolution Mass Spectrometry (HRMS), 1H NMR, 13C NMR, and elemental analysis. Compounds (6a-f) screened for their in vitro anticancer activity against three cell lines, namely, non-small cell lung cancer (A549), glioblastoma (U-87 MG), and breast cancer (MCF7). Hybrids 6a and 6b exhibited remarkable anti-proliferative activity against all three cell-lines. IC50 values of 6b for all cancer cell lines were significantly lower comparing to the standard reference compound IC50. The IC50 of 6b for the normal cell (HDF) line was significantly higher than the reported for cisplatin [IC50 = 170.7 ± 8.1 µM/ml (HDF), (p ≤ 0.001)], indicating less toxicity towards normal cells and thereby has a better therapeutic index, with a selectivity index of 142.3 for U87 cell line. Compounds 6e, 6d, and 6f displayed significant cytotoxic activity against only U-87 and MCF-7 cancer cell lines, compared to normal cells (HDF). Compound 6f [IC50 = 7.9 ± 2.3 µM/ml (U-87) and 10.6 ± 3 µM/ml (MCF-7)] was more potent than cisplatin [IC50 = 28.3 ± 5.3 µM/ml (U-87) and 26.9 ± 4.7 µM/ml (MCF-7)] in displaying anti-proliferative effect against U-87 and MCF-7 cells, with less cytotoxic to normal cells [IC50 = 141.7 ± 4.1] than cisplatin [IC50 = 40.9 ± 5.4]. Moreover, they were tested for their antioxidant activity in DPPH and ABTS assays and antibacterial activity.
RESUMO
Background and Objectives: breast cancer remains the most common health burden affecting females worldwide. Despite developments in breast cancer diagnostic approaches and treatment strategies, the clinical management of metastatic breast cancer remains challenging. Thus, there is a need to identify new biomarkers and novel drug targets for breast cancer diagnosis and therapy. Recently, aberrant glypican-3 (GPC3) expression in cancers has gained considerable interest in cancer research. The studies, however, have yielded contradictory results about GPC3 expression in breast cancer. Therefore, the current study aims to analyse GPC3 expression across a large panel of different breast cancer subtypes. Materials and Methods: GPC3 expression was immunohistochemically evaluated in 230 breast cancer patients along with eight normal tissues and its associations to clinical and demographic characteristics, as well as immunohistochemical biomarkers for breast cancer. Moreover, a public database consisting of breast cancer patients' survival data and GPC3 gene expression information was used to assess the prognostic value of GPC3 in the survival of breast cancer patients. Results: GPC3 expression was only characterised in 7.5% of different histological breast cancer subtypes. None of the normal breast tissues displayed GPC3 expression. Interestingly, all cases of Paget's disease, as well as 42.9% of intraductal and 16.7% of mucinous carcinomas were found to have GPC3 expression, where it was able to significantly discriminate Paget's disease and intraductal carcinoma from other breast cancer subtypes. Importantly, GPC3 expression was found more often in tumours that tested positive for the expression of hormone receptors and human epidermal growth factor receptor 2 (HER2), indicating more favourable histological subtypes of breast cancer. Consequently, longer relapse-free survival (RFS) was significantly correlated with higher GPC3 mRNA expression. Conclusions: Our study proposes that GPC3 is a promising breast cancer subtype-specific biomarker. Moreover, GPC3 may have the potential to be a molecular target for the development of new therapeutics for specific subtypes of breast cancer.
