Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 56, Issue 3, Pages 735-747Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm3016848
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Funding
- Ministerio de Ciencia y Competitividad (MINECO) [CTQ2011-28680, CTQ2010-16959, CSD2007-00006]
- UPV/EHU (UPI QOSYC 11/22) [IT-324-07]
- National Program for the Promotion of Human Resources within the National Plan of Scientific Research, Development and Innovations, Fondo Social Europeo MCyT
- University of Strasbourg
- Centre National de la Recherche Scientifique (CNRS)
- INSERM
- Ligue Nationale Contre le Cancer
- EGIDE
- Ministere des Affaires Etrangeres, France
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The integrin leukocyte function associated antigen 1 (LFA-1) binds the intercellular adhesion molecule 1 (ICAM-1) by its alpha(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.
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