2024-03-28T12:42:13Zhttp://digital.csic.es/dspace-oai/requestoai:digital.csic.es:10261/1693092022-03-11T12:46:17Zcom_10261_34com_10261_5col_10261_287
2018-08-31T10:48:43Z
urn:hdl:10261/169309
Design, synthesis, and functional evaluation of leukocyte function associated antigen-1 antagonists in early and late stages of cancer development
San 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, Fernando P.
Blanco, F.J.
The 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.
2018-08-31T10:48:43Z
2018-08-31T10:48:43Z
2013
2018-08-31T10:48:43Z
artículo
Journal of Medicinal Chemistry 56: 735- 747 (2013)
http://hdl.handle.net/10261/169309
10.1021/jm3016848
eng
Sí
closedAccess
American Chemical Society