4.4.8. 2,3-Dialkoxyphenazine Derivatives

Endo et al. reported the only antitumor activity of 2,3-disubstituted phenazines against sarcoma and carcinoma tumors in 1965 [84]. The presence of long fatty chains could provide a good effect to cross the lipid barrier [85]. Moris et al. synthesized 2,3-dialkoxyphenazine derivatives using an easy, efficient and straightforward condensation method. These compounds **208**–**211** (Figure 24) were firstly reported to show activity on MiaPaca pancreatic cell lines with IC50 of 0.06 μM, 21 μM, 75 μM and 7 μM, respectively. Interestingly, **208** and **209** interacted with DNA through hydrogen bonds remarkably, showing significant anticancer activity. Compared to Gemzar®, **208** and **211** were the most effective ones against pancreatic MiaPaca cell resistant lines. The experimental results showed that the carboxyl substituents on position 7 did not interact with each other through hydrogen bonds. Although possessing planar structures, these derivatives did not have similar mechanism of action as Gemcitabine. In vivo study on mice, **211** was as efficient as Gemzar® at a ten times lower concentration (1 mg/kg vs. 10 mg/kg) [21].

**Figure 24.** The chemical structures of compounds **208**–**211**.
