Preparation and antischistosomal and antitumor activity of hycanthone and some of its congeners. Evidence for the mode of action of hycanthone.
The synthesis of a series of esters of hycanthone (HC) and 7-hydroxyhycanthone, their antitumor activity, and their antischistosomal effects on HC-sensitive and HC-resistant schistosomes are reported. Binding studies using tritium-labeled HC and hycanthone N-methylcarbamate (HNMC) with calf thymus DNA provided evidence that HNMC but not HC alkylated the DNA. Tritiated HNMC also bound to the DNA of intact HeLa cells exposed to the drug while very little tritiated HC bound to DNA under the same conditions. The mechanism proposed previously to account for the antischistosomal action of HC, namely, drug esterification followed by alkylation of DNA, applies also to the antitumor action of the drug as shown in Scheme I.
Archer
S
S
Cogswell Laboratory, Department of Chemistry, Rensselaer Polytechnic Institute, Troy, New York 12180-3590.
Pica-Mattoccia
L
L
Cioli
D
D
Seyed-Mozaffari
A
A
Zayed
A H
AH
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis*; D006826:Hycanthone / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000627:therapeutic use*; D007202:Indicators and Reagents; D007941:Leukemia P388 / Q000188:drug therapy*; D007942:Leukemia, Experimental / Q000188:drug therapy*; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D012550:Schistosoma mansoni / Q000187:drug effects* / Q000254:growth & development; D012556:Schistosomicides / Q000138:chemical synthesis*; D013329:Structure-Activity Relationship; D013892:Thioxanthenes / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D007202:Indicators and Reagents; D012556:Schistosomicides; D013892:Thioxanthenes; D006826:Hycanthone