Acid-base catalysis of N-[(morpholine)methylene]daunorubicin.

The stability of N-[(morpholine)methylene]-daunorubicin hydrochloride (MMD) was investigated in the pH range 0.44-13.54, at 313, 308, 303 and 298 K.

Effect of structural modifications of anthracyclines on the ability to overcome drug resistance of cancer cells.

In the search for new derivatives of anthracycline antibiotics with the ability to overcome the drug resistance barrier, a series of new analogs of these antibiotics, containing the amidino group at C-3' position of the daunosamine moiety, have been synthesized. The new compounds were tested for their cytotoxic activity in vitro against the sensitive LoVo, MES-SA and HL-60 human cancer cell lines as well as their resistant sublines: LoVo/Dx, MES-SA/Dx5 and HL-60/MX2, respectively. The majority of these derivatives appeared to be able, completely or partially, to overcome the drug resistance barrier of cancer cells.

Cytotoxicity, cellular uptake and DNA damage by daunorubicin and its new analogues with modified daunosamine moiety.

Daunorubicin (DRB) and its two analogues containing a trisubstituted amidino group at the C-3' position of the daunosamine moiety have been compared regarding their cytotoxic activity, cellular uptake, subcellular localization and DNA damaging properties. An analogue containing in the amidino group a morpholine moiety (DRBM) as well as an analogue with a hexamethyleneimine moiety (DRBH), tested against cultured L1210 cells, exhibited lower cytotoxicity then DRB. The decrease of cytotoxic activity was not related to cellular uptake and subcellular localization of drugs.

Influence of the structure of new anthracycline antibiotics on their biological properties.

In the search for new derivatives of anthracycline antibiotics with advantageous biological properties, particularly with lower toxicity and/or higher activity, a series of new analogs of antibiotics applied in therapy such as daunorubicin, doxorubicin, as well as epidoxorubicin and, for comparison, analogs of epidaunorubicin, have been synthesized. Our results show that the new derivatives have antiproliferative activities similar to or higher than the parent antibiotics. The toxicities of these analogs were significantly lower, with LD50 values from 1.

Inhibition of RNA synthesis in vitro and cell growth by anthracycline antibiotics.

New derivatives of doxorubicin and daunorubicin with amidine group bonded to daunosamine at C-3' atom and bearing the morpholine ring attached to the amidine group have been recently synthesized. Their cytotoxic activities and effects on RNA synthesis in vitro were assayed. The drug concentrations inhibiting mouse leukaemia L1210 cell growth to 50% were about two- and three fold higher for the derivatives compared to doxorubicin and daunorubicin respectively.