Studies Towards the Synthesis of Methionine Aminopeptidase Inhibitors: Diversification Utilizing a ROMP-Derived Coupling Reagent

详细信息    查看全文

• 作者：Punitha Vedantham ; Mianji Zhang ; Parul J. Gor ; Min Huang ; Gunda I. Georg ; Gerald H. Lushington ; Lester A. Mitscher ; Qi-Zhuang Ye ; Paul R. Hanson
• 刊名：Journal of Combinatorial Chemistry
• 出版年：2008
• 出版时间：March 2008
• 年：2008
• 卷：10
• 期：2
• 页码：195 - 203
• 全文大小：315K
• 年卷期：v.10,no.2(March 2008)
• ISSN：1520-4774

文摘

Efforts to synthesize potential methionine aminopeptidase inhibitors is described. Preliminary SAR and docking studies served as a guide to design the compound libraries. “Chromatography-free” synthesis of various heterocyclic amides was realized by using a high-load, soluble coupling reagent derived via ring-opening metathesis polymerization (ROMP). Subsequent microwave-assisted Suzuki reactions with ortho-substituted arylboronic acids, followed by chromatographic purification afforded a 55-member library in high yields and purities. While the biological testing was not satisfactory, concurrent X-ray crystallography studies revealed key structural features essential for inhibition of methionine aminopeptidase, which directed fruitful results reported in the accompanying manuscript. In addition, in silico Lipinksi profiles and ADME properties of the library are also reported.