Antitumor triptycene bisquinones: a novel synthetic class of dual inhibitors of DNA topoisomerase I and II activities.
Synthetic triptycene analogs (TT code number) mimic the antitumor effects of daunorubicin in the nanomolar range in vitro, but have the advantage of blocking nucleoside transport and retaining their efficacy in multidrug-resistant (MDR) tumor cells. Since TT bisquinones induce poly(ADP-ribose) polymerase-1 cleavage at 6 h and internucleosomal DNA fragmentation at 24 h, which are, respectively, early and late markers of apoptosis, these lead antitumor drugs were tested for their ability to trigger the DNA topoisomerase (Topo) inhibitions responsible for the initial and massive high-molecular-weight cleavage of DNA required for tumor cells to commit apoptosis. Interestingly, antitumor TTs have the unusual ability to inhibit, in a concentration-dependent manner, the relaxation of supercoiled plasmid DNA catalyzed by both purified human Topo I and II enzymes. However, if there is a relationship between the ability of TT analogs to inhibit Topo activities and their quinone functionality and cytotoxicity, it is far from perfect, suggesting that other molecular targets may be involved in the mechanism of action of these antitumor drugs. Moreover, one of the most cytotoxic TT bisquinone, 6-bromo-7-methoxy- or 7-bromo-6-methoxy-2-N-methylamino-1 H,4 H,5 H,8H-9,10-dihydro-9,10-[1',2']benzenoanthracene-1,4,5,8-tetraone (TT24), inhibits Topo II activity more effectively than amsacrine (m-AMSA) and matches the Topo I inhibitory effect of camptothecin (CPT). The dual inhibitory activity of TT24 is substantiated by the findings that TT24 mimics the action of m-AMSA in the Topo II assay, where the Topo I inhibitor CPT is ineffective, and also mimics the action of CPT in the Topo I assay, where the Topo II inhibitor etoposide is ineffective. Because of their ability to target nucleoside transport and topoisomerase activities, synthetic TT bisquinones might represent a novel class of bifunctional drugs valuable to develop new means of polychemotherapy and circumvent MDR.
Wang
Buna
B
Anti-Cancer Drug Laboratory, Division of Biology, Ackert Hall, Kansas State University, Manhattan 66506-4901, USA.
Perchellet
Elisabeth M
EM
Wang
Yang
Y
Tamura
Masafumi
M
Hua
Duy H
DH
Perchellet
Jean-Pierre H
JP
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D011809:Quinones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D059003:Topoisomerase Inhibitors; D014407:Tumor Cells, Cultured / Q000187:drug effects*; D000095622:Benzoisochromanequinones
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D011809:Quinones; D059003:Topoisomerase Inhibitors; C447411:triptycene bisquinone; D000095622:Benzoisochromanequinones