Synthesis and in-vitro biological activity of macrocyclic urea Chk1 inhibitors |
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Authors: | Li Gaoquan Tao Zhi-Fu Tong Yunsong Przytulinska Magdalena K Kovar Peter Merta Philip Chen Zehan Zhang Haiying Sowin Thomas Rosenberg Saul H Lin Nan-Horng |
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Institution: | Cancer Research, Global Pharmaceutical Research & Development, Abbott Laboratories, Abbott Park, IL 60064, USA. gaoquanli@wisc.edu |
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Abstract: | A variety of macrocyclic urea compounds were prepared as potent Chk1 inhibitors by modifying the C5 position of the benzene ring of the macrocyclic urea with ether moieties, aliphatic carbon chains, amide and halides. Enzymatic activity less than 20nM was observed in 29 of 40 compounds. Compounds 14, 46d, and 48j provided the best overall results in the cellular assays as they abrogated doxorubicin-induced cell cycle arrest (IC(50)=3.31, 3.08, and 3.13microM) and enhanced doxorubicin cytotoxicity (IC(50)=0.54, 1.27, and 0.96microM) while displaying no single agent activity, respectively. |
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