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Synthesis and Screening of Pro-apoptotic and Angio-inhibitory Activity of Novel Benzisoxazole Derivatives both In
Sathish Byrappa1, Kavitha Rachaiah2, Sumana Y Kotian1
1Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore 570 006, India.
Background:
Triple Negative Breast Cancer (TNBC) tends to be more aggressive than other types of breast cancer. Resistance to chemotherapy is a major obstacle hence there is a significant need for new antineoplastic drugs with multi-target potency. Numerous Benzoisoxazole moieties have been found to possess a broad spectrum of pharmacological activities. In the present study, we have synthesized 9 novel derivatives of Benzisoxazole 7(a-i) and screened them for their biological potential.
Methods:
Chemical synthesis, Mass spectrometry (HRMS), cell proliferation and cytotoxicity assay, wound healing assay, flow cytometry and nuclear staining. Angio-inhibitory activity assessed by corneal micropocket assay and in vivo peritoneal angiogenesis assay.
Results:
The Benzisoxazole derivatives 7(a-i) were synthesized and screened for their biological potency by both in vitro and in vivo experimental models. Among the series, compound 3-(1-((3-(3(Benzyloxy)-4-methoxyphenyl)- 4,5-dihydroisoxazole-5-yl)methyl)piperidine-4-yl)6-fluorobenzo[d] isoxazole (7e) was found to be most promising, with an average IC50 value of 50.36 ± 1.7 µM in MTT assay and showed 81.3% cell death. The compound 7e also showed 60-70% inhibition on a recombinant Metastasis-Associated protein (MTA1) induced proliferation and cell migration in MDAMB-231 cells, which is known to play a major role in angiogenesis. The anti-tumour studies inferred the regression of tumour activity. This was due to inhibition of neovascularization and evoking apoptosis process as assessed by corneal vascularization, peritoneal angiogenesis and apoptotic hallmarks in 7e treated cells.
Conclusion:
These findings not only show the biological efficacy of compound 7e but it is also an effective beginning to explore the mechanism of metastasis and cancer therapy strategy targeting MTA1. The observed biological activity makes compound 7e an attractive drug candidate.
Insights
Researchers synthesized novel Benzisoxazole derivatives to combat aggressive Triple Negative Breast Cancer (TNBC). Compound 7e demonstrated significant anti-cancer activity by inhibiting proliferation, migration, and angiogenesis, making it a promising drug candidate.
Area of Science:
- Medicinal Chemistry
- Pharmacology
- Oncology
Background:
- Triple Negative Breast Cancer (TNBC) is an aggressive form of breast cancer with limited treatment options.
- Chemotherapy resistance is a significant challenge in TNBC treatment, necessitating novel antineoplastic drugs.
- Benzisoxazole derivatives are known for their diverse pharmacological activities, offering potential for new therapeutic agents.
Purpose of the Study:
- To synthesize and evaluate novel Benzisoxazole derivatives for their anti-cancer potential.
- To identify potent compounds against Triple Negative Breast Cancer (TNBC).
- To investigate the anti-angiogenic and anti-metastatic properties of the synthesized derivatives.
Main Methods:
- Synthesis of nine novel Benzisoxazole derivatives (7a-i).
- In vitro assays: cell proliferation, cytotoxicity (MTT assay), wound healing, flow cytometry, and nuclear staining.
- In vivo assays: corneal micropocket assay and peritoneal angiogenesis assay to assess anti-angiogenic activity.
Main Results:
- Compound 7e exhibited significant cytotoxicity with an average IC50 of 50.36 ± 1.7 µM and induced 81.3% cell death.
- Compound 7e inhibited Metastasis-Associated protein 1 (MTA1)-induced proliferation and migration in MDAMB-231 cells by 60-70%.
- In vivo studies showed tumor regression attributed to the inhibition of neovascularization and induction of apoptosis.
Conclusions:
- Compound 7e displays significant biological efficacy against TNBC, demonstrating anti-proliferative, anti-migratory, and anti-angiogenic properties.
- The findings support targeting Metastasis-Associated protein 1 (MTA1) as a therapeutic strategy for TNBC.
- Compound 7e is a promising drug candidate for further development in cancer therapy.
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