Design, synthesis and activity evaluation of Hedgehog inhibitor Itraconazole derivatives in A549 cells
Abstract
Hedgehog signal channel, a channel that plays a role in the occurrence and development of a variety of cancers. We introduce the composition and mechanism of Hedgehog signal channel, and the anti-tumor mechanism. A series of derivatives were designed and synthesized with the Hedgehog signal channel inhibitor Itraconazole in clinical phase II as the precursor. Compared with the other inhibitors, Itraconazole has a weaker inhibitory effect on Hedgehog, and there are few studies on improving the anti proliferation ability of Itraconazole on cells. Therefore, using Itraconazole as the lead, we obtained a series of derivatives that can effectively inhibit Hedgehog channels. Compared with Itraconazole, compounds 12g and 12n had stronger inhibitory effects in A549 cells.
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Structural modification of itraconazole may enhance its anticancer potency against non-small cell lung cancer.
“While clinical studies have evaluated ITZ as a repurposed agent, this preclinical work suggests that structural modification of ITZ may yield more potent hedgehog pathway inhibitors with enhanced activity against NSCLC.”
From Itraconazole as a repurposed anti-cancer agent: focusing on synthesis, mechanisms of action and therapeutic insights (2026) · cites this paper as [54]
Mechanistic assays demonstrated that compounds 18g and 18n inhibit colony formation, induce apoptosis, increase reactive oxygen species, and cause mitochondrial dysfunction in non-small cell lung cancer cells.
“Mechanistic assays demonstrated inhibition of colony formation, induction of apoptosis, increased reactive oxygen species, and mitochondrial dysfunction, suggesting that structural modification of ITZ may enhance its anticancer potency against NSCLC (Fig. 5).54”
From Itraconazole as a repurposed anti-cancer agent: focusing on synthesis, mechanisms of action and therapeutic insights (2026) · cites this paper as [54]
Novel itraconazole derivatives compounds 18g and 18n exhibited stronger anti-proliferative and Hedgehog pathway inhibitory effects than itraconazole and showed greater activity in A549 non-small cell lung cancer cells than in HepG2 liver cancer cells.
“Among them, compounds 18g and 18n exhibited stronger anti-proliferative and Hh pathway inhibitory effects than ITZ and showed greater activity in A549 cells than in HepG2 liver cancer cells.”
From Itraconazole as a repurposed anti-cancer agent: focusing on synthesis, mechanisms of action and therapeutic insights (2026) · cites this paper as [54]
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- Authors
- Cai, J., Chen, X., You, H., Li, X., & Ji, M.
- Affiliations
- Southeast University (CN)
- Corresponding author
- Cai, Jin
- Venue
- Bioorganic & Medicinal Chemistry Letters
- Publisher
- Elsevier BV
- Published
- 2022-11
- Volume
- 76
- Pages
- 129011
- ISSN
- 0960-894X (ISSN-L)
- OpenAlex
- W4298009328
- Cited by
- 4
- References
- 26
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 1 · 2023: 1
- FWCI
- 0.24
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Bioorganic & Medicinal Chemistry Letters (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Natural Science Foundation of Jiangsu Province (BK20161438)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Hedgehog Signaling Pathway Studies
- Physical Sciences › Chemistry › Organic Chemistry › Synthesis and biological activity
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Natural product bioactivities and synthesis
- Keywords
- Hedgehog signaling, A549 cells, lung cancer, antiproliferative activity, lead optimization, anticancer drug design
- MeSH terms
- A549 Cells, Antineoplastic Agents, Humans, Signal Transduction, Itraconazole, Hedgehog Proteins
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