Novel anthracycline analogs

Metabolic conversion of methoxymorpholinyl doxorubicin: from a DNA strand breaker to a DNA cross-linker

“…The preferential intracellular uptake of MMDX over that of doxorubicin has also been demonstrated by the direct measurement of intracellular drug concentrations (Grandi et al, 1990). MMDX is relatively more lipophilic than doxorubicin (Ripamonti et al, 1992 (Streeter et al.…”

“…Methoxymorpholinyl doxorubicin (MMDX) or FCE 23762 is a morpholinyl analogue possessing a methoxymorpholinyl group at the 3' position of the sugar moiety (Figure 1). MMDX is at least 80 times more potent than doxorubicin against P388 leukaemia in vivo, but only 3-to 4-fold more potent than doxorubicin in vitro (Grandi et al, 1990). This compound also maintains in vitro and in vivo cytotoxic activity against P388 leukaemia resistant to doxorubicin (Ripamonti et al, 1992).…”

In vivo anti-tumour activity of FCE 23762, a methoxymorpholinyl derivative of doxorubicin active on doxorubicin-resistant tumour cells

“…In both cases, activity on MDR cells is obtained because drugs have been made able to reach cytotoxic intracellular levels. Anthracyclines are an important class of clinically effective anti-tumour drugs, and much effort has been devoted to collecting structure-activity data in relation to their effect on MDR cells (Grandi et al, 1990b).…”

“…Among these, one of the most promising appears to be the class of morpholino anthracyclines, which were found to possess high effectiveness in vivo, as well as in vitro, on DX-resistant tumours (Watanabe et al, 1988;Grandi et al, 1990b).…”

“…Preliminary results on its cytotoxic activity, intracellular accumulation on LoVo and LoVo/DX human colon adenocarcinoma cells and anti-tumour activity have already been presented (Grandi et al, 1990b (Grandi et al, 1990a Melphalan (L-PAM) (Sigma Chemical Co., St Louis, IL, USA) was weighed and dissolved in 1 N HCI (20 mg ml-'), and further dissolved in H20; cis-platinum (cDDP) (Farmitalia C.Erba, Milan, Italy) was weighed and dissolved in water; 1,3 bis (2-chloroethyl)-l-nitrosourea (BCNU; Simes SpA, Vicenza, Italy) was weighed and dissolved in ethanol and H20.…”