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Influence of Transformation of the Amino Group in Anthracyclines into -N=CH-N< or -N=CH-O- Group on Their Biological Properties

Małgorzata Wąsowska-Łukawska 1Janusz Oszczapowicz 2Joanna Wietrzyk Adam Opolski Irena Oszczapowicz 1

1. Institute of Biotechnology and Antibiotics (IBA), Starościńska 5, Warszawa 02-516, Poland
2. Warsaw University, Faculty of Chemistry, Pasteura 1, Warszawa 02-093, Poland


The antitumor drugs of anthracycline group, e.g. daunorubicin are widely used in the treatment of variety of human neoplastic diseases. However, their clinical effectiveness is limited mainly by dose-dependent toxicity (particularly cardiotoxicity) and by the increase of resistance of cancer cells.

In the search for new derivatives of anthracyclines of lower toxicity and/or higher cytotoxic activity a series of new analogs in which the amino group bonded to the C-3' carbon atom of the daunosamine moiety was replaced by various -N=CH-N< (amidino) groups [1] or by the oxazoline ring (containing -N=CH-O- group) have been synthesized.

For derivatives of daunorubicin (I-V) their biological properties has been compared to those of the parent drug. It was found that new derivatives display both considerably lower toxicity (the LD50 values are 8-21 times higher) and significantly lower cardiotoxicity than those of the parent antibiotic. The cytotoxic activity in vitro of amidino derivatives (I-IV) is similar to that of the referential daunorubicin, but for oxazolino derivative (V) is even higher.

Moreover, opposite to daunorubicin, all of them appeared to be able to overcome the barrier of drug resistance of cancer cells. The values of ID50 for several sensitive human cancer cell lines and their resistant to anthracyclines sublines are almost identical, whereas these values for the parent drug are 8-650 times higher. The best results were obtained for the oxazolino derivative (V).

These advantageous results indicate that the transformation of the amino group in anthracyclines into amidino group or oxazoline ring appears to be very promising way to find new derivatives, which may be more useful in therapy than the parent daunorubicin on account of their lower toxicity, mainly cardiotoxicity, and an ability to overcome the barrier of drug resistance.

[1] M.Wąsowska, I. Oszczapowicz et al., Anticancer Res. 2005, 25, 2045-2048.


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Presentation: poster at 18th Conference on Physical Organic Chemistry, Posters, by Małgorzata Wąsowska-Łukawska
See On-line Journal of 18th Conference on Physical Organic Chemistry

Submitted: 2006-05-25 08:38
Revised:   2009-06-07 00:44