Structure-activity studies with cytotoxic anthrapyrazoles

  • Authors:
    • Asher Begleiter
    • Denny Lin
    • Kimberly K. Larson
    • Jennifer Lang
    • Xing Wu
    • Teresa Cabral
    • Hallie Taylor
    • Lynn J. Guziec
    • Paul D. Kerr
    • Brian B. Hasinoff
    • Frank S. Guziec Jr
  • View Affiliations

  • Published online on: June 1, 2006     https://doi.org/10.3892/or.15.6.1575
  • Pages: 1575-1580
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Abstract

Anthrapyrazoles have been investigated as cancer chemotherapeutic agents. The mechanism of action of these compounds is thought to involve inhibition of DNA topoisomerase II. A structure-activity study was carried out to determine the in vitro cytotoxic activity of nine novel anthrapyrazoles against human breast carcinoma, head and neck squamous cell carcinoma and leukemia cells, and against Chinese hamster ovary cells. The activity of these anthrapyrazole analogues was compared with that of two clinically tested anthrapyrazoles, losoxantrone and piroxantrone. Inhibition of topoisomerase II as a mechanism of action for the analogues was also investigated. The cytotoxic activity of the analogues was determined in vitro by MTT cell growth inhibition assay and inhibition of catalytic topoisomerase II activity by each compound was measured using a fluorometric DNA decatenation assay. All of the anthrapyrazole analogues inhibited the growth of the four cell lines with IC50 values that ranged from 0.1 to 45.2 μM. Losoxantrone was the most potent of the anthrapyrazole analogues studied. A tertiary amine in the basic side chain at N-2 increased the cytotoxic activity compared with a secondary amine in this side chain for many of the analogues, but not if there was a basic side chain at the C-5 position. A chlorine substituent on the basic side chain at N-2 did not have a consistent effect on activity. Moving the position of a chlorine substituent from C-5 to C-7 or introducing a basic side chain at C-5 did not have a consistent effect on cytotoxic activity. Anthrapyrazole analogues showed a broad range of activity for inhibiting topoisomerase II decatenation activity. Losoxantrone and piroxantrone were the most potent inhibitors of topoisomerase II activity. There was no significant correlation between the cytotoxic activity of the anthrapyrazole analogues and their ability to inhibit decatenation by topoisomerase II.

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June 2006
Volume 15 Issue 6

Print ISSN: 1021-335X
Online ISSN:1791-2431

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Spandidos Publications style
Begleiter A, Lin D, Larson KK, Lang J, Wu X, Cabral T, Taylor H, Guziec LJ, Kerr PD, Hasinoff BB, Hasinoff BB, et al: Structure-activity studies with cytotoxic anthrapyrazoles. Oncol Rep 15: 1575-1580, 2006
APA
Begleiter, A., Lin, D., Larson, K.K., Lang, J., Wu, X., Cabral, T. ... Guziec Jr, F.S. (2006). Structure-activity studies with cytotoxic anthrapyrazoles. Oncology Reports, 15, 1575-1580. https://doi.org/10.3892/or.15.6.1575
MLA
Begleiter, A., Lin, D., Larson, K. K., Lang, J., Wu, X., Cabral, T., Taylor, H., Guziec, L. J., Kerr, P. D., Hasinoff, B. B., Guziec Jr, F. S."Structure-activity studies with cytotoxic anthrapyrazoles". Oncology Reports 15.6 (2006): 1575-1580.
Chicago
Begleiter, A., Lin, D., Larson, K. K., Lang, J., Wu, X., Cabral, T., Taylor, H., Guziec, L. J., Kerr, P. D., Hasinoff, B. B., Guziec Jr, F. S."Structure-activity studies with cytotoxic anthrapyrazoles". Oncology Reports 15, no. 6 (2006): 1575-1580. https://doi.org/10.3892/or.15.6.1575