期刊
CHEMISTRY-A EUROPEAN JOURNAL
卷 23, 期 58, 页码 14410-14415出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/chem.201703093
关键词
antitumor agents; click chemistry; integrins; multivalency; peptidomimetics
资金
- University of Milan
- European Commission (Marie Sklodowska-Curie ITN MAGICBULLET) [642004]
- Ministero dell'Universita e della Ricerca (PRIN) [20157WW5EH]
- Marie Curie Actions (MSCA) [642004] Funding Source: Marie Curie Actions (MSCA)
This work reports the synthesis of three multimeric RGD peptidomimetic-paclitaxel conjugates featuring a number of alpha(V)beta(3) integrin ligands ranging from 2 to 4. These constructs were assembled by conjugation of the integrin alpha(V)beta(3) ligand cyclo[DKP-RGD]-CH2NH2 with paclitaxel via a 2 '-carbamate with a self-immolative spacer, the lysosomally cleavable Val-Ala dipeptide linker, a multimeric scaffold, a triazole linkage, and finally a PEG spacer. Two monomeric conjugates were also synthesized as reference compounds. Remarkably, the new multimeric conjugates showed a binding affinity for the purified integrin alpha(V)beta(3) receptor that increased with the number of integrin ligands (reaching a minimum IC50 value of 1.2 nm for the trimeric), thus demonstrating that multivalency is an effective strategy to strengthen the ligand-target interactions.
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