Protoflavone-Chalcone Hybrids Exhibit Enhanced Antitumor Action through Modulating Redox Balance, Depolarizing the Mitochondrial Membrane, and Inhibiting ATR-Dependent Signaling

Abstract

Hybrid compounds combine fragments with complementary targets to achieve a common pharmacological goal. This approach represents an increasingly popular strategy for drug discovery. In this work, we aimed to design antitumor hybrid compounds based on an inhibitor of ataxia-telangiectasia and Rad3-related protein (ATR)-dependent signaling, protoapigenone, and a pro-oxidant ferrocene or chalcone fragment. Four new triazole-coupled hybrids were prepared. The compounds were cytotoxic against human breast cancer cell lines in vitro, showing IC50 values in the sub-micromolar range. The nature of interactions between relevant fragments of the hybrids was evaluated by the Chou–Talalay method. Experimental combination treatment with the fragments showed additive effects or slight/moderate synergism, while strong synergism was observed when the fragments were virtually combined into their hybrids, suggesting a relevant pharmacological benefit of the coupling. All hybrids were strong inhibitors of the ATR-mediated activation of Chk1, and they interfered with the redox balance of the cells leading to mitochondrial membrane depolarization. Additionally, they induced late apoptosis and primary necrosis in MDA-MB-231 and MCF-7 breast cancer cells, respectively. Our results demonstrate that coupling the ATR-dependent signaling inhibitor protoflavone with a pro-oxidant chalcone dramatically increases the antitumor activity compared with either fragment alone. Such compounds may offer an attractive novel strategy for the treatment of various cancers.

Phytochemistry reflects different evolutionary history in traditional classes versus specialized structural motifs

“…For example, late-stage modification of common flavonoid scaffolds can result in the production of non-aromatic protoflavonoids. These compounds rarely occur across the plant kingdom and have only recently been found in one species of Piper 49 , but this type of subtle structural modification that leaves most of the flavonoid scaffold intact dramatically enhances the cytotoxic properties compared to that of the parent flavonoid 50 , 51 .…”

Evidence for both phylogenetic conservatism and lability in the evolution of secondary chemistry in a tropical angiosperm radiation

“…These compounds rarely occur across the plant kingdom and have only recently been found in one species of Piper (Freitas et al, 2014). Importantly, this subtle structural modification that leaves most of the flavonoid scaffold intact has been demonstrated to dramatically enhance the cytotoxic properties compared to that of the parent flavonoid (Hunyadi et al, 2014;Latif et al, 2020).…”

Recent Advances in Bioactive Flavonoid Hybrids Linked by 1,2,3-Triazole Ring Obtained by Click Chemistry

“…Compounds 23a – 23d ( Figure 8 ), reported by Latif et al (2020), were screened for their cytotoxic activity against the estrogen receptor (ER)-positive breast cancer cell line MCF-7 and the triple-negative breast cancer (TNBC) MDA-MB-231 cell line [ 66 ]. Although the activity of ferrocenylchalcone 23a was lower than 10% at 20 µM for both cancer cells, 23b – 23d showed considerable cytotoxic activity for MCF-7 (2.51 < IC 50 < 15.07 µM) and MDA-MB-231 cells (4.40 < IC 50 < 11.11 µM), 23b being the most active for both cells, better than the positive control cisplatin.…”