2-Aminothiophene scaffolds: Diverse biological and pharmacological attributes in medicinal chemistry

2. Biological and pharmacological properties of 2-ATs
2.1. Anticancer activity
In 2016, Véras of Aguiar et al. reported the antiproliferative activity of 2-AT derivatives against HeLa, PANC-1 and 3T3 cells, which were exposed to the compounds at concentrations of 5, 10, 25 or 50 µM for 24 or 48 hours [39]. Importantly, non-tumour fibroblast cells (3T3) were protected by treatment with the prepared 2-ATs, and a pronounced proliferative effect was observed, particularly at 48 h, suggesting greater neoplastic antiproliferative selectivity. Likewise, in the same period, the reference drug doxorubicin was more toxic than the selected 2-ATs, and displayed cell proliferation effect of less than 50%. Meanwhile, most of the thiophene derivatives showed cell proliferation effects that were superior to the non-treated control cells. The derivatives with 4-fluoro- (1) and 5-bromo-2-methoxy- (2) (Scheme 1) substituents at the benzaldehyde fragment exhibited greater efficiency in the antiproliferative evaluation. The prepared samples were less lethal to cancer cells and did not trigger the apoptotic cascade, as observed in the flow cytometry analysis of the HeLa and PANC-1 cell lines. However, they acted as cytostatic agents in the HeLa cell line by limiting cell growth and proliferation, as observed through alterations in the distribution of cells in different phases of the cell cycle. In addition, the diverse actions of these 2-ATs and their potential applications in cancer therapy are of great clinical interest.
Scheme 1.
In 2011, Romagnoli and colleagues synthesized and designed novel 2-AT scaffolds based on 2-amino-3-(3',4',5'-trimethoxybenzoyl)-thiophenes with an aryl/heteroaryl ethynedyl moiety at the C-5-position of the thiophene ring; these novel scaffolds functioned as antimitotic agents [40]. Studies of the antiproliferative effects of these compounds on several types of cells (murine leukaemia, murine mammary carcinoma, human cervical carcinoma and human T-lymphocyte) and examinations of the effects of the most active compounds on tubulin assembly and disruption of the cell cycle suggested that 2-amino-3-(3',4',5'-trimethoxybenzoyl)-5-(thiophen-3'-yl ethynyl) thiophene 3 (Scheme 2) was the most active new compound that inhibited cell growth, with IC₅₀ values ranging from 0.1–0.2 µM. The potency of compound 3 as an inhibitor of tubulin assembly was comparable to CA-4 (Chart 1).
Scheme 2.
Three years later, other 2-amino-3-alkoxycarbonyl/cyano-5-arylethylthiophene derivatives were investigated as a novel class of antitumour agents by Romagnoli et al. [41]. The 2-amino-3-cyano-[2-(2,5-dimethoxyphenyl)ethyl] thiophene 4 (Scheme 3) was the most promising derivative with antitumour activity against a wide panel of cell lines (T-cell lymphoma, T- leukaemia, B-cell lymphoma, osteosarcoma, mammary carcinoma, colon carcinoma, glioma and prostate) (IC₅₀= 17–130 nM). The antiproliferative activity of compound 4 was enhanced 3–230-fold in four cell lines compared to the reference drug SDZ LAP 977 (Chart 1). In addition, compound 4 was the most potent inhibitor of tubulin polymerization and colchicine binding among the selected compounds. Consistent with tubulin as its target, compound 4 induced cell cycle arrest in G2/M phase of the cell cycle and induced apoptosis through the intrinsic mitochondrial pathway by activating caspases. Moreover, compound 4 strongly reduced the expression of Bcl-2 and Mcl-1, an anti-apoptotic member of the Bcl-2 family, indicating that the mechanism of action of compound 4 was investigated well.