Dual-Targeting Antiproliferation Hybrids Derived from 1-Deoxynojirimycin and Kaempferol Induce MCF-7 Cell Apoptosis through the Mitochondria-Mediated Pathway

Abstract

1-Deoxynojirimycin, an α-glucosidase inhibitor, possesses various biological activities such as antitumor, antidiabetic, and antiviral effects. However, the application of 1-deoxynojirimycin is restricted by its poor lipophilicity and low bioavailability. In this study, three 1-deoxynojirimycin derivatives (8−10) comprising 1-deoxynojirimycin and kaempferol were designed and synthesized to modify their pharmacokinetics and improve their antitumor efficacy. Among them, compound 10, a conjugate of 1-deoxynojirimycin and kaempferol linked through an undecane chain, exhibited excellent lipophilicity, antiproliferative effects, and α-glucosidase inhibitory activity. Compared with 1-deoxynojirimycin, kaempferol, and their combination, compound 10 downregulated cyclooxygenase-2 (COX-2) expression, arrested the cell cycle at the S phase, induced cellular apoptosis, and inhibited the migration of MCF-7 cells. Moreover, further investigation indicated that compound 10 induced MCF-7 cell apoptosis through a mitochondrial-mediated pathway via the loss of mitochondrial membrane potential. This led to increasing intracellular levels of reactive oxygen species (ROS) and Ca 2+ , the downregulation of Bcl-2 expression, and the upregulation of Bax levels.

Ptxplatin: a multifunctional Pt(iv) antitumor prodrug

“…As is known, the intracellular accumulation of ROS leads to the release of excessive Ca 2+ from the ER, 42 and Ca 2+ overload causes ER dysfunction. 43 Therefore, Fluo-4 AM, a Ca 2+ indicator dye, was used to estimate the change of the Ca 2+ level after 5 -treated MCF-7 for 24 h. As shown in Fig.…”

Perplexing Polyphenolics: The Isolations, Syntheses, Reappraisals, and Bioactivities of Flavonoids, Isoflavonoids, and Neoflavonoids from 2016 to 2022

“…It was selectively demethylated using aluminum bromide, giving compound 383, which was treated with three linear dibromoalkanes, affording 384 to 386 ( Figure 23 ). Subsequently, treating them with 1-deoxynojirimycin in the presence of potassium carbonate furnished the final derivatives 387 to 389 [ 101 ].…”

“…It was also implicated in disrupting DNA synthesis and regulating cell cycle progression. Furthermore, compound 389 could induce MMP collapse and increase intracellular ROS levels, implying that it induced apoptosis through the mitochondrial pathway [ 101 ].…”

A systematic review of anti-cancer roles and mechanisms of kaempferol as a natural compound

“…Moreover, according to a recent study, a conjugate form of 1-deoxynojirimycin and kaempferol linked by an undecane chain revealed significant lipophilicity, anti-proliferative, and anti-α-glucosidase activities. The new derivative showed downregulation of the expression of COX-2, inhibited migration, decreased intracellular ROS and calcium cation levels, decreased Bcl-2 expression, and increased Bax expression in MCF-7 cells [ 56 ].…”