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

[ Vol. 16 , Issue. 4 ]

Author(s):

Lin Zhang and Lei Zhang*   Pages 469 - 478 ( 10 )

Abstract:


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.

Methods: Various substituted groups were introduced into the zinc binging group, linker, and cap regions of SCA by various chemical synthetic methods.

Results: 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.

Keywords:

Cancer, histone deacetylase 2, inhibitor, santacruzamate A, SAR, selectivity.

Affiliation:

Department of Medicinal Chemistry, School of Pharmacy, Weifang Medical University, Weifang, Department of Medicinal Chemistry, School of Pharmacy, Weifang Medical University, Weifang



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