Samenvatting
Five enantiomeric pairs of palladium complexes of 1,2,4-triazole-derived chiral N-heterocyclic carbene ligands were investigated to probe the influence of chirality on the compound's anticancer activity. Although no chirality-related influence was observed for any of the enantiomeric pair, strong anticancer activity was seen for a particular pair, (1S,2S,5R)-1c and (1R,2R,5S)-1c, which was significantly more active than the benchmark drug cisplatin for human breast cancer cells, MCF-7 (ca. 24-27-fold), and human cervical cancer cells, HeLa (ca. three- to fourfold). Broadening its scope of application, (1R,2R,5S)-1c also exhibited antiproliferative activity against lung cancer (A549), skin cancer (B16F10), and multidrug-resistant mammary tumor (EMT6/AR1) cell lines. Interestingly, (1R,2R,5S)-1c displayed 8- and 16-fold stronger antiproliferative activity toward B16F10 and MCF-7 relative to their respective noncancerous counterparts, L929 (fibroblast skin cells) and MCF10A (epithelial breast cells), thereby upholding the potential of these complexes for further development as anticancer agents. (1R,2R,5S)-1c inhibited tumor-cell proliferation by blocking the cells at the G2 phase. (1R,2R,5S)-1c caused DNA damage in MCF-7 cells, leading to mitochondrial reactive oxygen species production and subsequently cell death. We also present evidence indicating that (1R,2R,5S)-1c induced p53-dependent programmed cell death in MCF-7 cells.
| Originele taal-2 | Engels |
|---|---|
| Pagina's (van-tot) | 4632-4646 |
| Aantal pagina's | 15 |
| Tijdschrift | ACS Omega |
| Volume | 2 |
| Nummer van het tijdschrift | 8 |
| DOI's | |
| Status | Gepubliceerd - aug. 2017 |
| Extern gepubliceerd | Ja |
Bibliografische nota
Publisher Copyright:© 2017 American Chemical Society.
Financiering
The authors acknowledge Department of Science and Technology (File No.: EMR/2014/000254), New Delhi, and DAE-SRC fellowship from Board of Research in Nuclear Sciences, Government of India, for financial support of this research. They gratefully acknowledge the Single Crystal X-ray Diffraction Facility, Department of Chemistry, IIT Bombay, India, for the crystallographic characterization data and FACS facility and Centre for Research in Nanotechnology and Science (CRNTS), IIT Bombay, for the flow cytometry data. A.K., A.P.P., and M.K.G. acknowledge CSIR, New Delhi, for research fellowship. Most of the work is covered in Indian patent Application No.: 201721000741 (filed on Jan 7, 2017).
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