Discovery of potent ureido tetrahydrocarbazole derivatives for cancer treatments through targeting tumor-associated macrophages

Tumor-associated macrophages (TAMs) are one of the prominent components of the tumor microenvironment (TME). The polarization peculiarity of TAMs drives them to infiltrate and active with states between M1 (anti-tumor) and M2 (pro-tumor) phenotypes in cancers. Exploiting small molecular drugs through targeting TAMs to repolarize them into an antitumor phenotype is considered as a novel strategy for cancer treatments in recent years. For discovering novel compounds that target TAMs, a series of ureido tetrahydrocarbazole derivatives were designed, synthesized and evaluated both in vitro and in vivo. Among them, compound 23a was found to dose-dependently repolarize TAMs from M2 to M1 both in vitro and in vivo. And more importantly, the in vivo experiments also revealed that compound 23a was capable of remarkably inhibiting tumor growth of the LLC mouse model. Moreover, the synergy of compound 23a with anti-PD-1 antibody had more superior antineoplastic effects than the exclusive use of either in vivo. [Display omitted] •A series of ureido tetrahydrocarbazole derivatives were designed and optimized.•Compound 23a was found to dose-dependently repolarize TAMs from M2 to M1 both in vitro and in vivo.•The synergy of 23a with PD-1 antibody demonstrated more superior antineoplastic effects in vivo.