915194-00-2Relevant articles and documents
Potent and fully noncompetitive peptidomimetic inhibitor of multidrug resistance P-glycoprotein
Arnaud, Ophélie,Koubeissi, Ali,Ettouati, Laurent,Terreux, Rapha?l,Alamé, Ghina,Grenot, Catherine,Dumontet, Charles,Di Pietro, Attilio,Paris, Jo?lle,Falson, Pierre
supporting information; experimental part, p. 6720 - 6729 (2010/11/16)
Nα-Boc-l-Asp(OBn)-l-Lys(Z)-OtBu (reversin 121, 1), an inhibitor of the P-gp ABC transporter, was used to conceive compounds inhibiting the drug efflux occurring through the Hoechst 33342 and daunorubicin transport sites of P-gp, respectively H and R sites. Replacement of the aspartyl residue by trans-4-hydroxy-l-proline (4(R)Hyp) gave compounds 11 and 15 characterized by half-maximal inhibitory concentrations (IC50) of 0.6 and 0.2 μM, which are 2-and 7-fold lower than that of the parent molecule. The difference in IC50 between 11 and 15 rests on the carbonyl group of the peptidyl bond, reduced in 15. Those compounds are rather specific of P-gp, having no or limited activity on MRP1 and BCRP. 15 displayed no marked cytotoxicity up to 10-fold its IC50. Importantly, 15 equally inhibited the Hoechst 33342 and daunorubicin effluxes through a typical noncompetitive inhibition mechanism, suggesting its binding to a site different from the H and R drug-transport sites.
Solution-phase automated synthesis of tripeptide derivatives
Kuroda,Hattori,Kitada,Sugawara
, p. 1138 - 1146 (2007/10/03)
An improved general method for automated synthesis of tripeptides was developed, in which methanesulfonic acid (MSA) was used in place of trifluoroacetic acid (TFA), thus making it possible to avoid, 1) corrosion of the apparatus by strong acid vapor, 2) formation of emulsions, and 3) use of the restricted solvent, dichloromethane. As an application of the automated synthesis apparatus, 216 fragment tripeptide derivatives were synthesized systematically using the MSA method, in excellent yield and with increased efficiency.
