2-Cyclopropanecarboxamido- 6-carboxamide substituted benzothiazoles: Synthesis, in vitro and in vivo evaluation of their antiproliferative and anti-tumorigenic activity.

To expand our structure-activity relationship studies exploiting substituted benzothiazoles as potential antiproliferative and antitumor agents, we developed a new class of benzothiazole derivatives by coupling of 2-(cyclopropanecarboxamido)benzo[d]thiazole-6-carboxylic acid with a series of amines. All synthesized compounds bear a cyclopropanecarboxamido- moiety and a carboxamide functionality anchored to the positions C-2 and C-6 of the benzothiazole scaffold, respectively. Furthermore, the carboxamide was used as a handle for further derivatization using linkers with variability in length and conformation. The antiproliferative and antitumor activity of the compounds was assessed in various colorectal cancer and melanoma cell lines and several cancer cell lines generated from other tissues (hepatocyte carcinoma, prostate adenocarcinoma, breast adenocarcinoma, osteosarcoma, lung carcinoma, and adult acute monocytic leukemia). In all cell viability experiments, two analogs showed promising activity and, therefore, their effects were further investigated on the global gene expression of colorectal cell lines. In particular, treatment with the derivative 2-(cyclopropanecarboxamido)-N-[2-(phenylsulfonamido)ethylene]benzo[d]thiazole-6-carboxamide had the greatest influence on gene expression. Cancer-related biological processes were drastically affected, including nucleosome and chromatin assembly, cell cycle, p53 signal transduction and apoptosis. Both analogs were also evaluated in vivo in mice bearing a colon cancer xenograft model, demonstrating significant anticancer activity.