Anthracyclines as effective anticancer drugs

Abstract

Anthracyclines have received significant attention due to their effectiveness and extensive use as anticancer agents. At present, the clinical use of these drugs is offset by drug resistance in tumours and cardiotoxicity. Therefore, a relentless search for the 'better anthracycline' has been ongoing since the inception of these drugs > 30 years ago. This review focuses on the most recent pharmacology and medicinal chemistry developments on the design and use of anthracyclines. Based on their crystal structures as well as molecular modelling, a more detailed mechanism of topoisomerase poisoning by these new anthracyclines has emerged. Chemical modifications of anthracyclines have been found to possibly change the target selectivity among various topoisomerases and, thus, vary their anticancer activity. Additionally, recent sugar modifications of anthracyclines have also been found to overcome P-glycoprotein-mediated drug resistance in cancer therapy. The continued improvement of anthracycline clinical applications so far and the clinical trials of the 'third generation' of anthracyclines (such as sabarubicin) are also discussed. To finally find the 'better' anthracycline, further areas of research still need to be explored such as: the elucidation of the topoisomerase and P-glycoprotein crystal structures, molecular modelling based on crystal structure in order to design the next generation of better anthracycline drugs, the continued modifications of the anthracycline sugar moieties, and the further improvement of anthracycline drug delivery methods.

Synthesis and biological properties of oxazolinodaunorubicin—a new derivative of daunorubicin with a modified daunosamine moiety

“…The antitumor effects of the new derivative (3) and the reference daunorubicin (1) 2 × length]/2} (assuming a specific density close to unity). The criteria for minimal activity (ILS and TGI) according to the NCI are 25% for leukemia (i.p.)…”

“…To improve their biological properties, many attempts to modify their structure were reported in the literature. Various substituents were introduced at different sites of the anthracycline molecule [1][2][3], but only a few of the thus obtained compounds found clinical application [4,5]. However, the main problems, i.e.…”

“…These properties of (3) were also compared with those of formamidinodaunorubicin (2), synthesized and investigated previously [7][8][9][10]. Moreover, the results of in vivo tests on different murine tumor models, including P388 and L1210 leukemia, C38 colon carcinoma, and 16/C mammary adenocarcinoma, are presented.…”

Inhibitory effect of puerarin on proliferation of retinoblastoma cells: An <i>in-vitro</i> study

“…Out of the millions of naturally occurring compounds, only a few have been developed for use as cancer therapies [9]. These include vinca alkaloids [10], paclitaxel, docetaxel [11], etoposide, teniposide [12], and camptothecin and camptothecin derivatives, topothecan, irinothecan [13], and anthracycline [14].…”

Synthesis of the Sugar Moieties

“…We can still hope to discover the proverbial "better doxorubicin", as a yet unknown secondary metabolite [6], but it seems that active combinatorial synthetic or biotechnological approaches, aimed at new compounds capable of specific target ligand interactions, offer more chances for success [7]. Anthracyclines, discovered as dye-like metabolites of Streptomyces species in the early 1960s [8], gained wide acceptance as clinically useful DNA intercalators and topoisomerase inhibitors [9][10][11][12] but their side effects, including myelosupression and cardiotoxicity, were recognized as dose-limiting and potentially life-threatening. This, together with the occurrence of multidrug resistance (MDR) evoked by application of anthracycline antibiotics, Fig.…”