Santacruzamate: Compositions, Analogs and Methods of Use: A Patent Evaluation of WO 2014/018913 (A2).

Background Santacruzamate A (SCA) is a natural product isolated from a marine cyanobacterium. Activity test results revealed that SCA is a highly potent HDAC2 inhibitor with an IC50 value of 0.112 nM. The IC50 of SCA in inhibiting cancer cell proliferation is 28.3 μM and 1.3μM on HCT116 and HuT-78 cells, respectively. Objective To develop HDAC inhibitors with improved activity, SCA analogs were synthesized for the structure-activity relationship (SAR) studies. Method Various substituted groups were introduced into the zinc binging group, linker, and cap regions of SCA by various chemical synthetic methods. Result Compared with SCA, the derivatives of SCA did not exhibit improved HDAC2 inhibitory activity. Nevertheless, several molecules such as III-32, III-33, IV-4b, and IV-11 showed improved activity in inhibiting cell proliferation on HCT116 and HuT-78 cells. Conclusion Collectively, a potent HDAC2 inhibitor SCA was discovered as a lead compound for further development of selective HDAC inhibitors.