Synthesis and evaluation of novel heterocyclic ferrocenyl chalcone hybrids as possible anticancer and antioxidant agents

Abstract

Breast cancer is currently the most diagnosed cancer in women, with 287,850 new cases estimated in 2022, as reported by the American Cancer Society. Therefore, finding an effective treatment for this disease is imperative. Triple-negative breast cancer (TNBC) is a cancer subtype that does not over-express the female hormones, estrogen (ER), progesterone (PR), and the epidermal growth factor (HER-2). TNBC minimizes the treatment options given the lack of targeted therapy agents, resulting in a worse prognosis and a higher tendency to relapse. Approximately 10-15 % of breast carcinomas are TNBC, therefore, there is an urgency to find effective therapeutic agents. Photodynamic therapy (PDT) is a minimally invasive and selective therapy that uses light to excite a photosensitizer (PS), which in the presence of oxygen, can cause cell death. Many photosensitizers have been studied, but phthalocyanines are among the most promising. Because the innermost part of a tumor is hypoxic, drugs that target the outer vasculature are needed for a more effective response. Ferrocenyl chalcones with diverse heterocycles have shown significant anti-cancer activity, and although the mechanism of action is unclear, anti-angiogenic and vascular disruption have been linked to their activity. Therefore, phthalocyanine-ferrocenyl chalcone conjugates were proposed as ideal photosensitizers with dual activity potential for cancer treatment.<br /> <br /> Chalcones are α,β-unsaturated systems found in nature. These compounds have shown a wide array of biological activities, making them popular synthetic targets. Chalcones consist of two aromatic substituents connected by an enone bridge; this arrangement allows for many derivatives. Given the biological relevance of these compounds, novel ferrocene-heterocycle containing chalcones were synthesized and characterized based on a hybrid drug design approach. These heterocycles included thiophene, pyrimidine, thiazolyl, and indole groups. Fourteen heterocyclic-ferrocenyl chalcones were synthesized and characterized. Herein, we also report their cytotoxicity against the breast cancer cell line MDA-MB-231 (TNBC cell line). System 3 ferrocenyl chalcones displayed superior anticancer properties compared to their system 1 analogs. System 3 chalcones bearing five-membered heterocyclic substituents (pyrazole, pyrrole, and pyrimidine) were the most active towards this particular cancer cell line with IC₅₀ values of 6-12 μM. Antioxidant activity was also evaluated, where, contrary to anticancer capabilities, system 1 ferrocenyl chalcones were superior to their system 3 analogs. Antioxidant activity is comparable to ascorbic acid observed for thiophene-bearing ferrocenyl chalcone with EC₅₀ = 31. Further functionalization of synthesized ferrocenyl chalcones was attempted to obtain a precursor for conjugation with phthalocyanine photosensitizer. Although proposed precursors were not obtained, substantial synthetic and molecular insight was gathered on the synthesis of relatively unstudied heterocyclic ferrocenyl chalcones.