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Design, synthesis, and functional evaluation of leukocyte function associated antigen-1 antagonists in early and late stages of cancer development

AuthorsSan Sebastián, E.; Zimmerman, T.; Zubia, A.; Vara, Y.; Martin, E.; Sirockin, F.; Dejaegere, A.; Stote, R.H.; Lopez, X.; Pantoja-Uceda, D.; Valcárcel, M.; Mendoza, L.; Vidal-Vanaclocha, F.; Cossío, F.P.; Blanco, F.J.
Issue Date2013
PublisherAmerican Chemical Society
CitationJournal of Medicinal Chemistry 56: 735- 747 (2013)
AbstractThe integrin leukocyte function associated antigen 1 (LFA-1) binds the intercellular adhesion molecule 1 (ICAM-1) by its αL-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. © 2013 American Chemical Society.
Identifiersdoi: 10.1021/jm3016848
issn: 0022-2623
Appears in Collections:(IQFR) Artículos
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