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Updated: Sep 27, 2025
Functionalized Spirocyclic Heterocycle Synthesis and Cytotoxicity Assay
Published on: February 9, 2021
Synthesis and structure-activity relationship study of a potent MHO7 analogue as potential anti-triple negative
Jian-Jia Liang1, Wu-Lin Yu1, Liang Yang1
1Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, School of Pharmaceutical Sciences, Wuhan University, Wuhan, 430071, PR China.
Abstract:
Triple-negative breast cancer (TNBC) is the most aggressive, high recurrence and metastatic breast cancer subtype. There are few safe and effective therapeutic drugs for treatment of TNBC. The marine natural product MHO7 has been determined to be a potential antitumor agent. However, its moderate activity and complex structure hampered its clinical application. In this study, a series of novel derivatives with modification on C24 of MHO7 were first synthesized. Some of the analogues were significantly more potent than MHO7 against all selected breast cancer cell lines. Among them, compound 4m had the best activity, and its IC50 value against TNBC was up to 0.51 μM. A whole-genome transcriptomic analysis shown that the mechanism of compound 4m against TNBC cells was similar with that of parent compound MHO7. Subsequent cellular mechanism studies showed that compound 4m could induce apoptosis of MDA-MB-231 cells through mitochondria pathway and cause G1 phase arrest. Moreover, 4m could disrupt the expressions of MAPK/Akt pathway-associated proteins (p-p38 and p-Akt) and remarkably increase the ratio of Bax to Bcl-2 and activate cleaved caspase 3/9/PARP. Importantly, 4m could influence the expression of Smad 7, and p-Smad 3 to inhibit TNBC cells metastasis. Stability assays in rat plasma and liver microsomes indicated that 4m still have room for further optimization. And the results of the online molinspiration software predicted that 4m has desirable physicochemical properties but some properties still have violation from the Lipinski rule of five. Overall, the modification on C24 of MHO7 was a promising way for developing novel anti-TNBC agents with considerable potential for optimization.
Insights
Novel MHO7 derivatives show enhanced potency against triple-negative breast cancer (TNBC). Compound 4m effectively inhibits TNBC cell growth and metastasis, offering a promising avenue for developing new anti-TNBC therapies.
Area of Science:
- Marine Natural Products Chemistry
- Medicinal Chemistry
- Cancer Biology
Background:
- Triple-negative breast cancer (TNBC) is aggressive with limited therapeutic options.
- Marine natural product MHO7 shows antitumor potential but has limitations.
- Structural modification of MHO7 is explored for improved efficacy.
Purpose of the Study:
- Synthesize novel MHO7 derivatives modified at the C24 position.
- Evaluate the antitumor activity of these derivatives against breast cancer cell lines, particularly TNBC.
- Investigate the mechanism of action for the most potent derivative.
Main Methods:
- Chemical synthesis of MHO7 analogues.
- In vitro cytotoxicity assays (IC50 determination).
- Whole-genome transcriptomic analysis.
- Apoptosis assays (mitochondrial pathway, caspase activation).
- Cell cycle analysis (G1 arrest).
- Western blotting for pathway-associated proteins (MAPK/Akt, Smad).
- Plasma and liver microsome stability assays.
- In silico prediction (Lipinski's rule of five).
Main Results:
- Several synthesized analogues exhibited significantly enhanced potency compared to MHO7.
- Compound 4m demonstrated the highest activity against TNBC with an IC50 of 0.51 μM.
- Compound 4m induced apoptosis via the mitochondrial pathway and caused G1 phase arrest.
- 4m modulated MAPK/Akt pathways, increased Bax/Bcl-2 ratio, activated caspases, and inhibited TNBC cell metastasis by affecting Smad signaling.
- Stability assays and Lipinski rule analysis indicated potential for further optimization.
Conclusions:
- Modification at the C24 position of MHO7 is a viable strategy for developing potent anti-TNBC agents.
- Compound 4m represents a promising lead candidate with a multi-targeted mechanism of action.
- Further optimization of 4m is warranted to improve its drug-like properties for clinical application.
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