Majusculamide-o, a simplified marine natural product analog, exhibits potent and specific cancer cell cytotoxicity

Metastatic solid tumors (e.g., ovary, pancreas, liver, lung, and brain) contribute to a high mortality rate in cancer patients with few therapeutically effective anticancer drugs available for their treatment, highlighting the need to develop agents that target solid tumors. Natural products (NPs) derived from cyanobacteria possess potent anticancer activity, yet most are hard to synthesize and modify to improve therapeutic efficacy. Here, we have efficiently synthesized a simplified analog of the marine NP majusculamide D, majusculamide o (maj-o, 1), that has remarkable potency and selective cytotoxicity towards various metastatic cancer cells. We found that maj-o (1) treatment presents potent cytotoxicity in various cancer cell lines of the ovary (OVCAR3), pancreas (PANC1), brain (U251N), and lung (H125) in a dose-dependent manner, with the least cytotoxic effect towards non-metastatic or primary tumors of the liver (HEPG2) and ovary (OVCAR8). 1 significantly alters gene expression signatures with more treatment time and affects pathways associated with PI3K-Akt signaling and the Hippo pathway. Our finding suggests that maj-o has great potential to serve as a lead compound for the development of novel antineoplastics for solid tumors.