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Bisacylphosphane oxides as photo-latent cytotoxic agents and potential photo-latent anticancer drugs.

ABSTRACT: Bisacylphosphane oxides (BAPOs) are established as photoinitiators for industrial applications. Light irradiation leads to their photolysis, producing radicals. Radical species induce oxidative stress in cells and may cause cell death. Hence, BAPOs may be suitable as photolatent cytotoxic agents, but such applications have not been investigated yet. Herein, we describe for the first time a potential use of BAPOs as drugs for photolatent therapy. We show that treatment of the breast cancer cell lines MCF-7 and MDA-MB-231 and of breast epithelial cells MCF-10A with BAPOs and UV irradiation induces apoptosis. Cells just subjected to BAPOs or UV irradiation alone are not affected. The induction of apoptosis depend on the BAPO and the irradiation dose. We proved that radicals are the active species since cells are rescued by an antioxidant. Finally, an optimized BAPO-derivative was designed which enters the cells more efficiently and thus leads to stronger effects at lower doses.

SUBMITTER: Beil A

PROVIDER: S-EPMC6461680 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Bisacylphosphane oxides as photo-latent cytotoxic agents and potential photo-latent anticancer drugs.

Beil Andreas A Steudel Friederike A FA Bräuchle Christoph C Grützmacher Hansjörg H Möckl Leonhard L

Scientific reports 20190412 1

Bisacylphosphane oxides (BAPOs) are established as photoinitiators for industrial applications. Light irradiation leads to their photolysis, producing radicals. Radical species induce oxidative stress in cells and may cause cell death. Hence, BAPOs may be suitable as photolatent cytotoxic agents, but such applications have not been investigated yet. Herein, we describe for the first time a potential use of BAPOs as drugs for photolatent therapy. We show that treatment of the breast cancer cell l ...[more]

PMID: 30979960

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Project description:The diverse pharmacological role of dihydropyrimidinone scaffold has made it to be an interesting drug target. Because of the high incidence and mortality rate of breast cancer, there is a dire need of discovering new pharmacotherapeutic agents in managing this disease. A series of twenty-two derivatives of 6-(chloromethyl)-4-(4-hydroxyphenyl)-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (3a-3k) and ethyl 6-(chloromethyl)-4-(2-hydroxyphenyl)-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (4a-4k) synthesized in a previous study were evaluated for their anticancer potential against breast cancer cell line. Molecular docking studies were performed to analyze the binding mode and interaction pattern of these compounds against nine breast cancer target proteins. The in vitro cell proliferation assay was performed against the breast cancer cell line MCF-7. The structure activity relationship of these compounds was further studied using QSARINS. Among nine proteins, the docking analysis revealed efficient binding of compounds 4f, 4e, 3e, 4g, and 4h against all target proteins. The in vitro cytotoxic assay revealed significant anticancer activity of compound 4f having IC50 of 2.15 μM. The compounds 4e, 3e, 4g, and 4h also showed anticancer activities with IC50 of 2.401, 2.41, 2.47 and 2.33 μM, respectively. The standard tamoxifen showed IC50 1.88 μM. The 2D qualitative structure-activity relationship (QSAR) analysis was also carried out to identify potential breast cancer targets through QSARINS. The final QSAR equation revealed good predictivity and statistical validation R 2 and Q 2 values for the model obtained from QSARINS was 0.98 and 0.97, respectively. The active compounds showed very good anticancer activities, and the binding analysis has revealed stable hydrogen bonding of these compounds with the target proteins. Moreover, the QSAR analysis has predicted useful information on the structural requirement of these compounds as anticancer agents with the importance of topological and autocorrelated descriptors in effecting the cancer activities.

Dataset Information

Bisacylphosphane oxides as photo-latent cytotoxic agents and potential photo-latent anticancer drugs.

Publications

Bisacylphosphane oxides as photo-latent cytotoxic agents and potential photo-latent anticancer drugs.

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