Abstract
New unsymmetrical bisacridines (UAs) demonstrated high activity not only against a set of tumor cell lines but also against human tumor xenografts in nude mice. Representative UA compounds, named C-2028, C-2045 and C-2053, were characterized in respect to their physicochemical properties and the following studies aimed to elucidate the role of metabolic transformations in UAs action. We demonstrated with phase I and phase II enzymes in vitro and in tumors cells that: (i) metabolic products generated by cytochrome P450 (P450), flavin monooxygenase (FMO) and UDP-glucuronosyltransferase (UGT) isoenzymes in noncellular systems retained the compound’s dimeric structures, (ii) the main transformation pathway is the nitro group reduction with P450 isoenzymes and the metabolism to N-oxide derivative with FMO1, (iii), the selected UGT1 isoenzymes participated in the glucuronidation of one compound, C-2045, the hydroxy derivative. Metabolism in tumor cells, HCT-116 and HT-29, of normal and higher UGT1A10 expression, respectively, also resulted in the glucuronidation of only C-2045 and the specific distribution of all compounds between the cell medium and cell extract was demonstrated. Moreover, P4503A4 activity was inhibited by C-2045 and C-2053, whereas C-2028 affected UGT1A and UGT2B action. The above conclusions indicate the optimal strategy for the balance among antitumor therapeutic efficacy and drug resistance in the future antitumor therapy.
Highlights
Malignant tumors are the second most common cause of death after cardiovascular diseases
The three unsymmetrical bisacridines (UAs) synthesized in our laboratory [29,30,31], named C-2028, C-2045 and
Considering the relations between electrochemical and enzymatic transformations of acridine derivatives investigated earlier [42,43], we performed the electrochemical conversion of the studied compounds C-2028, C-2045 and C-2053 in the potential range −2.5–0 V according to the new method developed in our group [44]
Summary
Malignant tumors are the second most common cause of death after cardiovascular diseases. Modern methods of cancer treatment and diagnosis have reduced patient mortality, some tumors, e.g., pancreatic, lung and colon cancers, are extremely resistant to chemotherapy [1,2]. Identification of the compounds that could offer significantly improved therapeutic efficacy against these diseases, especially those that are extremely complicated and insidious in nature, remains of great importance. Our group previously developed antitumor agents that reached an advanced stage of drug development. Was highly active against breast cancer in patients refractory to taxane treatment in phase. 9-Alkylamino-1-nitroacridines were developed as antitumor therapeutic agents (Nitracrine® , Gdańsk, Poland) [12] and a new derivative of this group, compound C-1748, is under preclinical evaluation against prostate cancer [13,14,15].
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