Synthesis and anticancer activity of novel rapamycin C‐28 containing triazole moiety compounds

Abstract

Rapamycin is an mTOR allosteric inhibitor with multiple functions such as immunosuppressive, anticancer, and lifespan prolonging activities. Its C-43 semisynthetic derivatives temsirolimus and everolimus have been used as mTOR targeting anticancer drugs in the clinic. Following our previous research on antitumor rapalogs modified on the C-43 position, 13 novel rapamycin triazole hybrids (6a-g, 7a-f) were designed and synthesized on the C-28 position of rapamycin via Huisgen's reaction.Anticancer assays indicated that the targeted derivatives containing phenyl and 4-methylphenyl groups showed an obvious raise in anticancer activity. On the contrary, the compounds with methoxyl, amine, and halogen groups on the benzene ring displayed lower anticancer activity. Compound 6c, as the most active compound, showed a stronger inhibition effect as compared with rapamycin for almost all of the tested cell lines (p < 0.01), except PC-3. Meanwhile, the effect of 6c on inducing apoptosis and cell cycle arrest in A549 cells was more powerful than that of rapamycin.In addition, 6c inhibited the phosphorylation of mTOR and its downstream key kinases 4EBP1 and p70S6K1 in A549 cells, indicating that 6c also effectively inhibits the mTORC1 signaling pathway as rapamycin. On the basis of these findings, 6c may have the potential to be developed as a new mTOR inhibitor against specific cancers. K E Y W O R D Santicaner activity, rapamycin, semi-synthesis, triazole

Click Chemistry in Natural Product Modification

“…Thus, N4 may have the potential to serve as a new mTOR inhibitor. C28 rapamycin-triazole N5 (IC 50 = 12.8–14.8 μ M) could also exert more potent inhibitory against A549, 769-P, ECA-109, and Caski cancer cells than rapamycin (IC 50 = 12.3–24.5 μ M) ( Huang Q. et al, 2018 ). Mechanistic studies indicated that N5 could inhibit the mTOR signaling by downregulating mTOR phosphorylation and its downstream key proteins such as P70S6K1 and 4EBP1.…”

In Vitro Study of Cytotoxic Mechanisms of Alkylphospholipids and Alkyltriazoles in Acute Lymphoblastic Leukemia Models

“…Studies have reported 1,2,3-triazole derivatives with bactericidal [ 19 ] and anticancer [ 20 ] activity. These derivatives can induce cell cycle arrest and apoptosis of cancer cells [ 13 , 21 ].…”