Design, synthesis, and biological evaluation of a series of fluoroquinoanthroxazines with contrasting dual mechanisms of action against topoisomerase II and G-quadruplexes.
Topoisomerase inhibitors are important and clinically effective drugs, while G-quadruplex-interactive compounds that disrupt telomere maintenance mechanisms have yet to be proven useful in the clinic. If G-quadruplex-interactive compounds are to be clinically useful, it will most likely be in combination with more established cytotoxic agents. We have previously reported on a family of topoisomerase II inhibitors that also interact with G-quadruplexes. On the basis of previously established structure-activity relationships (SARs) for compounds that are able to inhibit topoisomerase II or interact with G-quadruplex to varying degrees, we have now designed and synthesized four new fluoroquinoanthroxazines (FQAs) that have different profiles of mixed topoisomerase II poisoning effects and G-quadruplex interactions. The biological profiles of the four new compounds were determined with respect to G-quadruplex interaction (polymerase stop and photocleavage assays) and topoisomerase II interaction (DNA cleavage and kDNA decatenation assays), alongside cytotoxicity tests with matched pairs of topoisomerase II-resistant and topoisomerase II-sensitive cells and with telomerase (+) and ALT (+) cell lines (ALT = alternative lengthening of telomeres). From this study, we have identified two FQAs with sharply contrasting profiles of potent G-quadruplex interaction with a weak topoisomerase II poisoning effect, and vice versa, for further evaluation to determine the optimum combination of these activities in subsequent in vivo studies.
Kim
Mu-Yong
MY
College of Pharmacy, The University of Arizona, 1703 E. Mabel, Tucson, Arizona 85721, USA.
Duan
Wenhu
W
Gleason-Guzman
Mary
M
Hurley
Laurence H
LH
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D004247:DNA / Q000737:chemistry / Q000187:drug effects*; D004250:DNA Topoisomerases, Type II / Q000172:deficiency / Q000378:metabolism; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D024841:Fluoroquinolones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D010078:Oxazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D016615:Telomere; D059005:Topoisomerase II Inhibitors; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D024841:Fluoroquinolones; D010078:Oxazines; D011759:Pyrrolidines; D059005:Topoisomerase II Inhibitors; D004247:DNA; D004250:DNA Topoisomerases, Type II