The role of structural factors in the kinetics of cellular uptake of pyrazoloacridines and pyrazolopyrimidoacridines

• Published in: Biochemical pharmacology Vol. 68; no. 9; pp. 1815 - 1823
• Main Authors: Tarasiuk, Jolanta, Majewska, Ewelina, Seksek, Olivier, Rogacka, Dorota, Antonini, Ippolito, Garnier-Suillerot, Arlette, Borowski, Edward
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01-11-2004
• Subjects: Acridine cytotoxic agents; Multidrug resistance; Non-cross resistant antitumour agents; P-glycoprotein; Pyrazoloacridines (PACs); Pyrazolopyrimidoacridines (PPACs); MRP1; P-gp; PACs; Multidrug resistance; Pyrazoloacridines (PACs); DOX; Acridine cytotoxic agents; PIRA; DR; P-glycoprotein; Non-cross resistant antitumour agents; Pyrazolopyrimidoacridines (PPACs); MDR; PPACs
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/j.bcp.2004.06.028

The appearance of multidrug resistance (MDR) of tumour cells to a wide array of antitumour drugs, structurally diverse and having different mechanisms of action, constitutes the major obstacle to the successful treatment of cancer. Our approach to search for non-cross resistant antitumour agents is based on the rational design of derivatives, which have a high kinetics of passive cellular uptake rendering their active efflux by MDR exporting pumps inefficient. Recently, two families of acridine cytotoxic agents were obtained, pyrazoloacridines (PACs) and pyrazolopyrimidoacridines (PPACs). The aim of this study was to examine molecular basis of the reported differences in retaining cytotoxic activity of these derivatives at cellular level against resistant erythroleukaemia K562/DOX (overexpressing P-glycoprotein) cell line. The study was performed using a spectrofluorometric method, which allows continuous monitoring of the uptake and efflux of fluorescent molecules by living cells. It was demonstrated that the presence of two additional rings, pyrazole and pyrimidine, fused to the acridine chromophore structure (PPAC) favoured more rapid cellular diffusion than the presence of only one additional pyrazole ring (PAC). The presence of hydrophobic subsituent OCH
3 markedly favoured the cellular uptake of pyrazoloacridines and pyrazolopyrimidoacridines while compounds having hydrophilic substituent OH exhibited very low kinetics of cellular uptake. In contrast, it was found that neither structure of the ring system nor the hydrophobic/hydrophilic character of examined substituents determined the rate of active efflux of these compounds by P-glycoprotein. Our data showed that a nearly linear relation exists between the resistance factor (RF) and ln
V
+ reflecting the impact of the cellular uptake rate (
V
+) on the ability of these compounds to overcome MDR.