Intervenolin analogs with a phenyl substituent at the 2- or 3-position were synthesized. The compounds (3–11) showed weak or no inhibitory activity toward the growth of MKN-74 gastric adenocarcinoma cells, even in the presence or absence of the corresponding Hs738 stromal cells, whereas 2-substituted analogs exhibited selective anti-Helicobacter pylori activity. Introduction of a pendant side chain on the nitrogen alleviated their acute toxicity in mice. The 2-phenyl-substituted analogs are reasonable structural templates for structure–activity relationship studies toward the development of anti-H. pylori agents that do not affect human cells.
MK, HA and TW are grateful to the Japan Agency for Medical Research and development (AMED) (the Project for Cancer Research And Therapeutic Evolution (P-CREATE)) for financial support. We thank Dr Ryuichi Sawa, Ms Yumiko Kubota, Dr Kiyoko Iijima and Ms Yuko Takahashi (BIKAKEN) for spectroscopic analysis.
Supplementary Information accompanies the paper on The Journal of Antibiotics website (http://www.nature.com/ja)