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.
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