Syntheses, molecular targets and antitumor activities of novel triptycene bisquinones and 1,4-anthracenedione analogs.
Novel substituted triptycene bisquinones and 1, 4-anthracenediones were synthesized and screened for their anti-cancer activities. A number of analogs were synthesized utilizing various synthetic transformations and found to elicit interesting antitumor effects. Analogs included water-soluble pro-drugs and ammonium salts. These potent antitumor drugs are DNA topoisomerase inhibitors that induce DNA strand breaks, inhibit DNA, RNA and protein syntheses and reduce tumor cell proliferation in the nanomolar range in vitro. They induce cytochrome c release, caspase-9, -3 and -8 activities, poly(ADP)-ribose polymerase-1 (PARP) cleavage, and internucleosomal DNA fragmentation by a mechanism which involves caspase-2 activation but not Fas signaling. Moreover, these drugs remain effective in multidrug-resistant tumor cells and have the advantage of blocking nucleoside transport and inducing a rapid loss of mitochondrial transmembrane potential. Based on their effects in tumor cells and isolated mitochondria, it is hypothesized that these drugs might, directly and indirectly, target components of the permeability transition pore to induce mitochondrial permeability transition and the release of proapoptotic factors. This review provides a summary of synthetic efforts and mechanistic endeavor.
Hua
Duy H
DH
Department of Chemistry, Kansas State University, 111 Willard Hall, Manhattan, KS 66506-3701, USA. duy@ksu.edu
Lou
Kaiyan
K
Battina
Srinivas K
SK
Zhao
Huiping
H
Perchellet
Elisabeth M
EM
Wang
Yang
Y
Perchellet
Jean-Pierre H
JP
D000818:Animals; D000880:Anthraquinones / Q000138:chemical synthesis / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D006801:Humans; D051379:Mice; D033681:Mitochondrial Membrane Transport Proteins / Q000037:antagonists & inhibitors; D000083162:Mitochondrial Permeability Transition Pore; D011355:Prodrugs / Q000138:chemical synthesis / Q000494:pharmacology; D011809:Quinones / Q000138:chemical synthesis / Q000494:pharmacology; D059004:Topoisomerase I Inhibitors; D000095622:Benzoisochromanequinones
D000880:Anthraquinones; D000970:Antineoplastic Agents; D020169:Caspases; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D011355:Prodrugs; D011809:Quinones; D059004:Topoisomerase I Inhibitors; C447411:triptycene bisquinone; D000095622:Benzoisochromanequinones