In the search for new more selective anticancer drugs new derivatives of doxorubicin, containing in the position C-3' of daunosamine moiety formamidino group with morpholine (DXM) or hexamethylenoimine (DXH) rings, have been synthesized. These analogs were compared with their parent doxorubicin (DX) for cytotoxic activity, cellular uptake, DNA damaging properties and lipid peroxidation potential. All experiments were carried out on leukemia L1210 cell line.

The values of DNA single strand breaks, measured by alkaline elution technique are 375.0 ± 41.0 for (DX), 573.0 ± 0.1 for (DXM) and for (DXH) 120.0 ± 10.0 rad-equivalents, DNA-protein crosslinks, quantified by KCl-SDS precipitation are 3.0 ± 0.43, 27.0 ± 0.23 and 77.0 ± 0.16 (crosslinking indices), accordingly. The amounts of anthracyclines uptaken by the cells are 76.0 ± 9.0, 247.0 ± 37.0 and 83.0 ± 6.0 (pmole/10⁶cells), as well as lipid peroxidation are 7.10 ± 0,14, 10.60 ± 0,47 and 8.76 ± 0.67 (MDA nmoles/10⁶cells), respectively (both estimated by spectrofluorimetric measurements). MDA = maleic dialdehyde.

Obtained results show that biological properties of above mentioned analogs are substantially different from those of the parent doxorubicin. The replacement of the amino group at C-3' position of daunosamine moiety in (DX) by amidino substituent, containing morpholine ring (DXM) resulted in the enhancement of genotoxicity, cellular uptake and slight loss of cytotoxic activity (IC₅₀ = 24.0 pM), whereas for (DX) IC₅₀ = 18.0 pM. Analog (DXH) exhibited low cytotoxicity (IC₅₀ = 91.0 pM) which was attributed to low ability of this drug to produce DNA damage. Both derivatives were more active in the production of lipid peroxidation then their parent drug.

It has to be pointed out that introduction of the formamidino group with morpholine ring into daunosamine moiety resulted in significant enhancement of cellular uptake of anthracyclines, which leads to assumption that (DXM) may be able to overcome the barrier of drug resistance, developed in tumor cells treated with anthracyclines.

• Legal notice:
  

  Copyright (c) Pielaszek Research, all rights reserved.
  The above materials, including auxiliary resources, are subject to Publisher's copyright and the Author(s) intellectual rights. Without limiting Author(s) rights under respective Copyright Transfer Agreement, no part of the above documents may be reproduced without the express written permission of Pielaszek Research, the Publisher. Express permission from the Author(s) is required to use the above materials for academic purposes, such as lectures or scientific presentations.
  In every case, proper references including Author(s) name(s) and URL of this webpage: https://science24.com/paper/8272 must be provided.

1. Cytotoxic and proapoptotic in vitro activity of two novel flavone complexes of ruthenium(II)
2. The effect of introduction of a formamidino group to the molecule of doxorubicin on its biological properties
3. Influence of Transformation of the Amino Group in Anthracyclines into -N=CH-N< or -N=CH-O- Group on Their Biological Properties