Synthesis and Antitumor Evaluation of Symmetrical 1,5-Diamidoanthraquinone Derivatives as Compared to Their Disubstituted Homologues

Abstract

In a continuation of our work on anthraquinones that widely occur in the plant kingdom and that may have biological activities, we have developed and synthesized a series of small-molecule tricyclic anthraquinone structural motifs which represents an attractive target for the rational design of new anticancer agents. [1][2][3][4][5][6][7][8] Antineoplastic drugs generally have a narrow therapeutic index and are delivered at doses close to toxicity. Despite extensive and long-standing clinical utilization, the mechanisms responsible for the antiproliferative and cytotoxic effects of anthracycline antibiotic doxorubicin are still uncertain and have been the subject of considerable controversy. 9) Several naturally occurring compounds having substituted anthraquinone moieties are widely used in cancer chemotherapy and constitute some of the most powerful cytostatics. [10][11][12] In previous papers, [1][2][3][4][5][6]13,14) we reported a series of anthraquinone derivatives (Chart 1) that showed in vitro anticancer activity, together with some of human telomerase evaluation. The structure-activity relationships indicated amido substitution may lead to a different mechanism of cytotoxicity. 5) Although an explanation for the mechanism has not yet emerged, the cytotoxic activity in cultured tumor cell lines is well understood. We still envisioned a new approach to the anthraquinone, taking advantage of the amido side arms at different positions and pharmacophore moiety to the pharmacophore that, if it is not active in the anticancer, can develop activity to produce a synergistic effect. The primary aim for developing anticancer drugs has been for their cytotoxic and cytostatic properties and for their binding capacity to a recombinant fragment of the multi-drug-resistance transporter.12) These hypotheses suggest that the threering aromatic moiety gives DNA-intercalating ability to cross-linkable side arms of substituents, and the anthraquinone analog is considered as a possible antitumor lead pharmacophore. We established a novel strategy to obtain new derivatives of anthraquinone and screened against the in vitro cytotoxicity in C6, Hepa G2 and 2.2.15 cell lines; the results are presented in Table 1.We recently described the human telomerase inhibition and cytotoxicity properties of a series of regioisomeric difunctionalized anthraquinones at the 1,4-, 1,5-and 1,8-positions, respectively. [3][4][5][6]14) Their in vitro cytotoxicity was reported and compared with those of their isomers, and it was proposed that their activity may be due to their ability to bind to and stabilize G-quadruplex structures. 8,15) The positional attachment and character of the diacyloxy-, dithio-, diamino-, and diamido side chains have been shown to profoundly influence their mode of DNA binding and cytotoxicity. For example, 1,4-diamidoanthraquinones have been shown to bind to duplex DNA by classical intercalation, 16) whereas their cytotoxicity and human telomerase inhibition, 5,14) in which the different functionalized side chains may si...

Synthesis and Human Telomerase Inhibition of a Series of Regioisomeric Disubstituted Amidoanthraquinones

“…23,25,28,29) By comparing these results with our compounds, 20,27,30,31) it is clear that the chemical and biological activities of anthraquinones are greatly affected by various substituents of the planar ring system. 17,22,25,29,[32][33][34][35][36] Neidle et al 23,25,28,29) have also indicated that some of disubstituted anthraquinones inhibit telomerase which provide us rational design for the further investigation of SARs and comparison with their series of disubstituted homologues.…”

“…17,22,25,29,[32][33][34][35][36] Neidle et al 23,25,28,29) have also indicated that some of disubstituted anthraquinones inhibit telomerase which provide us rational design for the further investigation of SARs and comparison with their series of disubstituted homologues. Previously we described a method of synthesizing 1,5-diamidoanthraquinones (2-17) and comparing to their cytotoxicity, 31) these compounds considered as aglycon analogues of anthracycline antibiotics in which the side chains substitutes for small-molecule planar tricyclic anthraquinone structural motifs. In this investigation, we continue to focus our attention on the role of our newly synthesized 2,6-diamidoanthraquinones.…”

“…The backbone of these compounds also resemble the anticancer agents mitoxantrone and ametantrone, and were prepared by a two-stage reaction which similar to our previous paper. 30,31) We first evaluate the effects of these disubstituted amidoanthraquinones on telomerase activity using PCR-based telomerase assay, and TRAP (telomeric repeat amplification protocol) assay. Here, a modified telomerase assay (TRAP-G4) is used to evaluate the effects of anthraquinones on G-quadruplex-induced telomerase activity.…”

“…The following 1,5-diamidoanthraquinones (2-27) were prepared by previously described procedures. 31) All other compounds were commercial materials.…”