Synthesis of Nonsymmetrically Substituted 2,3-Dialkoxyphenazine Derivatives and Preliminary Examination of Their Cytotoxicity.

Fourteen new 2,3-dialkoxyphenazine derivatives with two different alkoxy groups bearing R and R alkyl chains, defined as -CHCH(CH) and -(CH)CH for = 1, 2, 4, 6, 8, and 10, were prepared regioselective synthesis. The applied synthetic protocol is based on the following reactions: the Buchwald-Hartwig coupling of a nonsymmetrically substituted 4,5-dialkoxy-2-nitroaniline with a 1-bromo-2-nitrobenzene derivative featuring additional -butyl, trifluoromethyl or two methoxy groups; the reduction of bis(2-nitrophenyl)amine; and a final step of tandem-like oxidation that leads to the preparation of a heterocyclic phenazine system. The regioselectivity of these steps and the molecular structure of the compounds under investigation were confirmed by nuclear magnetic resonance and additionally by single-crystal X-ray diffraction performed for some examples of and phenazine series. For 7-(-butyl)-3-isobutoxy-2-(octyloxy)phenazine (), 3-(hexyloxy)-2-isobutoxy-7-(trifluoromethyl)phenazine (), and 2,3-bis(hexyloxy)-7,8-dimethoxyphenazine (), viability and cytotoxicity assays were performed on the LoVo human colon adenocarcinoma cell line, with confirmed to exhibit cytotoxicity.