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

Area of Science:

• Medicinal Chemistry
• Pharmacology
• Oncology

Background:

• Rapamycin is an mTOR inhibitor with immunosuppressive, anticancer, and lifespan-extending properties.
• Clinical mTOR-targeting anticancer drugs like temsirolimus and everolimus are semi-synthetic derivatives of rapamycin modified at the C-43 position.
• Previous research focused on C-43 modified rapalogs, necessitating exploration of other modification sites.

Purpose of the Study:

• To design and synthesize novel rapamycin triazole hybrids by modifying the C-28 position.
• To evaluate the in vitro anticancer activity of these novel compounds.
• To investigate the mechanism of action of the most potent derivative, including its effect on the mTORC1 signaling pathway.

Main Methods:

• Synthesis of 13 novel rapamycin triazole hybrids (6a-g, 7a-f) using Huisgen's reaction at the C-28 position.
• Anticancer assays were performed on various cell lines.
• Mechanism of action studies included apoptosis induction, cell cycle arrest analysis, and Western blotting to assess mTORC1 pathway inhibition (mTOR, 4EBP1, p70S6K1 phosphorylation).

Main Results:

• Compounds with phenyl and 4-methylphenyl groups at C-28 exhibited enhanced anticancer activity.
• Derivatives with methoxyl, amine, and halogen groups showed reduced activity.
• Compound 6c demonstrated superior inhibition compared to rapamycin across most tested cell lines and significantly induced apoptosis and cell cycle arrest in A549 cells.
• Compound 6c effectively inhibited mTORC1 signaling by reducing the phosphorylation of mTOR, 4EBP1, and p70S6K1 in A549 cells.

Conclusions:

• Novel rapamycin triazole hybrids modified at the C-28 position were successfully synthesized.
• Compound 6c is a highly potent anticancer agent with significant mTORC1 inhibitory activity.
• Compound 6c holds potential for development as a new therapeutic agent for specific cancer types.