Designed Chalcone-Dihydropyrimidinone hybrid compounds were synthesized expeditiously. The hybridization was performed through the Copper-catalyzed Alkyne-Azide Cycloaddition (CuAAC) from the propargyloxy chalcones and azido-dihydropyrimidinones. The hybrid products were prepared in five steps with a 30–48% overall yield. Most of the compounds showed selective cytotoxicity and lower IC₅₀ values (<10 µM) against MCF-7 (breast adenocarcinoma) cancer. Cytotoxicity was also observed against OVCAR-3 (ovary, adenocarcinoma), NCI/ADR-RES (ovary, multidrug-resistant adenocarcinoma), and U-251 (brain, glioblastoma) cell lines. The potency of the most active hybrids 9d, 9g, and 9h was greater than the individual parental compounds, suggesting the effectiveness of molecular hybridization on the cytotoxicity. Compounds 9d, 9g, and especially 9h showed high selectivity for breast cancer cells (MCF-7) regarding human keratinocytes (HaCaT). Molecular docking calculations for the 9d, 9g, and 9h hybrids in the active site of estrogen supported the hypothesis that the compounds act as ER-α antagonists, disrupting the cell proliferation process of MCF-7, corroborating the potency and selectivity observed for this tumoral cell line.

Despite the breakthrough in the development of anticancer therapies, plant‐derived chemotherapeutics continue to be the basis of treatment for most types of cancers. Fridericia platyphylla is a shrub found in Brazilian cerrado biome which has cytotoxic, anti‐inflammatory, and analgesic properties. The aim of this study was to investigate the antiproliferative potential of the crude hydroethanolic extract, subfraction (containing 59.3% of unusual dimeric flavonoids Brachydin E and 40.7% Brachydin F), as well as Brachydin E and Brachydin F isolated from F. platyphylla roots. The cytotoxic activity was evaluated in glioblastoma, lung, prostate, and colorectal human tumor cell lines. The crude hydroethanolic extract did not present cytotoxic activity, but its subfraction presented lower IC50 values for glioblastoma (U‐251) and prostate adenocarcinoma (PC‐3) cell lines. Brachydins E and F significantly reduced cell viability, proliferation, and clonogenic potential of PC‐3, inducing them to the process of regulated cell death. In silico studies have indicated nuclear receptors as targets for Brachydins E and F, and molecular docking has pointed out their binding into glucocorticoid receptor (GR) ligand pocket. Targeting GR pathway has been described as a therapeutic strategy, especially for prostate cancer. These results suggest that Brachydin E and Brachydin F are promising compounds to be further explored for their antitumor effects.

Multidrug resistance (MDR) is the main obstacle in anticancer therapy. The use of drug combinations to circumvent tumor resistance is a well-established principle in the clinic. Among the therapeutic targets, glycoprotein-P (P-gp), an energy-dependent transmembrane efflux pump responsible for modulating MDR, is highlighted. Many pharmacological studies report the ability of calcium channel blockers to reverse tumor resistance to chemotherapy drugs. Isolated for the first time from parsley, the phenylpropanoid apiole is described as a potent calcium channel inhibitor. Taking this into account, herein, the ability of apiole to potentiate the action of well-established chemotherapeutics in the clinic, as well as the compound’s relationship with the reversal of the resistance phenomenon by blocking P-gp, is reported. The association of apiole with both chemotherapeutic drugs doxorubicin and vincristine resulted in synergistic effect, in a concentration-dependent manner, as evaluated by the concentration reduction index. Molecular docking analysis demonstrated the affinity between apiole and the active site of P-gp, corroborating the inhibitory effect. Moreover, apiole demonstrated druglikeness, according to ADME analysis. In conclusion, apiole possibly blocks the active P-gp site, with strong binding energy, which, in turn, inhibits doxorubicin and vincristine efflux, increasing the antiproliferative response of these chemotherapeutic agents.

Dimeric flavonoids, also called biflavonoids, are bioactive compounds that exhibit various activities described in the literature, including antibacterial, antifungal, antiviral, anti-inflammatory, analgesic, antioxidant, vasorelaxant, and anticancer properties. This work focuses on the anticancer action of naturally occurring dimeric flavonoids against prostate and breast cancer, as well as on the mechanisms of action involved in their activity and presents the most current information on this subject in the literature. In the present review, we summarize the latest findings on the antiproliferative activity of 33 dimeric flavonoid-based compounds selected from recently published studies. The tests conducted were in silico and in vitro and demonstrated the cytotoxic activity potential of biflavonoids against prostate and breast tumor cells. Biflavonoids were capable of interfering with the migration and replication of cancer cells and their mechanism of action is related to cell death pathways, especially apoptosis, necrosis, and ferroptosis. These compounds decreased mitochondrial membrane potential and significantly increased intracellular levels of reactive oxygen species (ROS). Additionally, they significantly upregulated the expression of p21, Bax, and cleaved caspase-3, while downregulating Bcl-2 and caspase-3 levels, indicating their cell death mechanism of action is through the Bcl-2/Bax/cleaved caspase-3 pathway and cell cycle arrest. The biflavonoids here related have shown promising anticancer activity and are considered potential drug candidates for prostate and breast cancer treatment.