Design, Synthesis, and Functional Evaluation of Leukocyte Function Associated Antigen-1 Antagonists in Early and Late Stages of Cancer Development

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• 作者：Eider San Sebasti谩n ; Tahl Zimmerman ; Aizpea Zubia ; Yosu Vara ; Elyette Martin ; Finton Sirockin ; Annick Dejaegere ; Roland H. Stote ; Xabier Lopez ; David Pantoja-Uceda ; Mar铆a Valc谩rcel ; Lorea Mendoza ; Fernando Vidal-Vanaclocha ; Fernando P. Coss铆o ; Francisco J. Blanco
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：February 14, 2013
• 年：2013
• 卷：56
• 期：3
• 页码：735-747
• 全文大小：558K
• 年卷期：v.56,no.3(February 14, 2013)
• ISSN：1520-4804

文摘

The integrin leukocyte function associated antigen 1 (LFA-1) binds the intercellular adhesion molecule 1 (ICAM-1) by its 伪_L-chain inserted domain (I-domain). This interaction plays a key role in cancer and other diseases. We report the structure-based design, small-scale synthesis, and biological activity evaluation of a novel family of LFA-1 antagonists. The design led to the synthesis of a family of highly substituted homochiral pyrrolidines with antiproliferative and antimetastatic activity in a murine model of colon carcinoma, as well as potent antiadhesive properties in several cancer cell lines in the low micromolar range. NMR analysis of their binding to the isolated I-domain shows that they bind to the I-domain allosteric site (IDAS), the binding site of other allosteric LFA-1 inhibitors. These results provide evidence of the potential therapeutic value of a new set of LFA-1 inhibitors, whose further development is facilitated by a synthetic strategy that is versatile and fully stereocontrolled.