Synthesis, Structure Analysis, and Antitumor Evaluation of 3,6-Dimethyl-1,2,4,5-tetrazine-1,4-dicarboxamide Derivatives

• Published in: ChemMedChem 2012-06, Vol.7 (6), p.973-976
• Main Authors: Rao, Guo-Wu, Guo, Yan-Mei, Hu, Wei-Xiao
• Format: Article
• Language: English
• Subjects: Amides - chemistry; Amides - therapeutic use; Amides - toxicity; Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - therapeutic use; Antineoplastic Agents - toxicity; antitumor agents; Apoptosis - drug effects; Cell Line, Tumor; Crystallography, X-Ray; Crystals; cytotoxicity; Derivatives; Diffraction; Female; Heterocyclic Compounds, 3-Ring - chemistry; Humans; Lung Neoplasms - drug therapy; Male; Mice; Mice, Nude; Molecular Conformation; Structure-Activity Relationship; tetrazines; Transplantation, Heterologous; X-ray diffraction
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.201200109

3,6‐Dimethyl‐1,2,4,5‐tetrazine‐1,4‐dicarboxamide derivatives were synthesized, and their structures were confirmed by single‐crystal X‐ray diffraction. This reaction yields the 1,4‐dicarboxamide derivatives rather than the 1,2‐dicarboxamide derivatives. Their in vitro antitumor activities were evaluated against SGC‐7901, HO‐8910, MCF‐7, and A‐549 cells. The results showed several compounds to be endowed with cytotoxicity in the low micromolar range. One compound (IC50=0.57 μM) was further evaluated in vivo against an A‐549 xenograft in BALB/cA nude mice; it effected 76.4 % inhibition of tumor weight through intraperitoneal (i.p.) administration of 40 mg kg−1 body weight. Moreover, its acute toxicity was evaluated, and the i.p. LD50 value was 325 mg kg−1 in mice. Tumor downsizing: A series of tetrazine derivatives were synthesized and characterized. Their antitumor activity in vitro showed several compounds to be endowed with cytotoxicity in the low micromolar range. The activity of one compound in vivo and its acute toxicity were further evaluated. The results revealed that it has relatively low toxicity and good efficacy.