Discovery of Novel Isoquinoline Analogues as Dual Tubulin Polymerization/V-ATPase Inhibitors with Immunogenic Cell Death Induction.

Cancer immunotherapy has revolutionized clinical advances in a variety of cancers. Due to the low immunogenicity of the tumor, only a few patients can benefit from it. Specific microtubule inhibitors can effectively induce immunogenic cell death and improve immunogenicity of the tumor. A series of isoquinoline derivatives based on the natural products podophyllotoxin and diphyllin were designed and synthesized. Among them, showed robust antiproliferation activity against four human cancer cell lines, and it was verified that exerted antiproliferative activity by inhibiting tubulin and V-ATPase. Further studies indicated that is able to induce immunogenic cell death in addition to apoptosis. Meanwhile, inhibited tumor growth in an RM-1 homograft model with enhanced T lymphocyte infiltration. These results suggest that may be a promising lead compound for the development of a new generation of microtubule drugs.