Impact of Stepwise NH2‑Methylation of Triapine on the Physicochemical Properties, Anticancer Activity, and Resistance Circumvention

• Published in: Journal of medicinal chemistry Vol. 59; no. 14; pp. 6739 - 6752
• Main Authors: Kowol, Christian R, Miklos, Walter, Pfaff, Sarah, Hager, Sonja, Kallus, Sebastian, Pelivan, Karla, Kubanik, Mario, Enyedy, Éva A, Berger, Walter, Heffeter, Petra, Keppler, Bernhard K
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 28.07.2016; Amer Chemical Soc
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Cell Proliferation - drug effects; Cell Survival - drug effects; Chemistry, Medicinal; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Life Sciences & Biomedicine; Methylation; Molecular Structure; Pharmacology & Pharmacy; Pyridines - chemical synthesis; Pyridines - chemistry; Pyridines - pharmacology; Science & Technology; Structure-Activity Relationship; Thiosemicarbazones - chemical synthesis; Thiosemicarbazones - chemistry; Thiosemicarbazones - pharmacology; Tumor Cells, Cultured; IN-VITRO; COPPER-COMPLEXES; RIBONUCLEOTIDE REDUCTASE INHIBITOR; IRON CHELATORS; DI-2-PYRIDYLKETONE THIOSEMICARBAZONES; REDOX ACTIVITY; 3-AMINOPYRIDINE-2-CARBOXALDEHYDE THIOSEMICARBAZONE 3-AP; SELECTIVE ANTITUMOR-ACTIVITY; PHASE-I; CANCER
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.6b00342

One of the most promising classes of iron chelators are α-N-heterocyclic thiosemicarbazones with Triapine as the most prominent representative. In several clinical trials Triapine showed anticancer activity against hematological diseases, however, studies on solid tumors failed due to widely unknown reasons. Some years ago, it was recognized that “terminal dimethylation” of thiosemicarbazones can lead to a more than 100-fold increased activity, probably due to interactions with cellular copper depots. To better understand the structural requirements for the switch to nanomolar cytotoxicity, we systematically synthesized all eight possible N-methylated derivatives of Triapine and investigated their potential against Triapine-sensitive as well as -resistant cell lines. While only the “completely” methylated compound exerted nanomolar activity, the data revealed that all compounds with at least one N-dimethylation were not affected by acquired Triapine resistance. In addition, these compounds were highly synergistic with copper treatment accompanied by induction of reactive oxygen species and massive necrotic cell death.