936712-91-3Relevant academic research and scientific papers
Design, synthesis, and functional evaluation of leukocyte function associated antigen-1 antagonists in early and late stages of cancer development
San Sebastián, Eider,Zimmerman, Tahl,Zubia, Aizpea,Vara, Yosu,Martin, Elyette,Sirockin, Finton,Dejaegere, Annick,Stote, Roland H.,Lopez, Xabier,Pantoja-Uceda, David,Valcárcel, María,Mendoza, Lorea,Vidal-Vanaclocha, Fernando,Cossío, Fernando P.,Blanco, Francisco J.
, p. 735 - 747 (2013/03/28)
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.
