34404-33-6Relevant articles and documents
Novel NK1R‐Targeted68Ga‐/177Lu‐Radioconjugates with Potential Application against Glioblastoma Multiforme: Preliminary Exploration of Structure–Activity Relationships
Matalińska, Joanna,Kosińska, Katarzyna,Halik, Pawe? K.,Ko?miński, Przemys?aw,Lipiński, Piotr F. J.,Gniazdowska, Ewa,Misicka, Aleksandra
, (2022/01/24)
Locoregionally administered, NK1 receptor (NK1R) targeted radionuclide therapy is a promising strategy for the treatment of glioblastoma multiforme. So far, the radiopharmaceuticals used in this approach have been based on the endogenous agonist of NK1R, Substance P or on its close analogues. Herein, we used a well‐known, small molecular NK1R antagonist, L732,138, as the basis for the radiopharmaceutical vector. First, 14 analogues of this compound were evaluated to check whether extending the parent structure with linkers of different lengths would not deteriorate the NK1R binding. The tested analogues had affinity similar to or better than the parent compound, and none of the linkers had a negative impact on the binding. Next, five DOTA conjugates were synthesized and used for labelling with68Ga and177Lu. The obtained radioconjugates turned out to be fairly lipophilic but showed rather limited stability in human plasma. Evaluation of the receptor affinity of the (radio)conjugates showed that neither the chelator nor the metal negatively impacts the NK1R binding. The177Lu‐radioconjugates exhibited the binding characteristics towards NK1R similar or better than that of the177Lu‐labelled derivative of Substance P, which is in current clinical use. The experimental results presented herein, along with their structural rationalization provided by modelling, give insight for the further molecular design of small molecular NK1R‐targeting vectors.
Stereochemical requirements for β-hairpin formation: Model studies with four-residue peptides and depsipeptides
Haque, Tasir S.,Little, Jennifer C.,Gellman, Samuel H.
, p. 6975 - 6985 (2007/10/03)
Spectroscopic and crystallographic data are present for a series of tetrapeptides and analogous depsipeptides that can form a minimal β-hairpin (two intramolecular hydrogen bonds). These model compounds have been used to test the hypothesis that 'mirror image' β-turns promote β-hairpin formation. This hypothesis was inspired by a statistical survey of β-hairpins in globular proteins (Sibanda, B.L.; Thornton, J.M. Nature 1985, 316, 170), which showed that mirror image β-turns (type I' and type II'), although rare in general, are very commonly associated with β-hairpins containing a two-residue loop between the strand segments. Each of our four-residue molecules contains proline at the second position, to promote a central β-turn. The β-turn is induced to be either 'common' or 'mirror-image', relative to the outer residues, by choice of residue configuration (L vs D). In methylene chloride, end-capped tetrapeptide Ac-L-Val-D-Pro-D-Ala-L-Leu-NMe2 folds largely into the β-hairpin conformation, while the diastereomer Ac-L-Val-L-Pro-L-Ala-L-Leu-NMe2 displays little or no β-hairpin folding. For each diastereomer, the hydrogen-bonded driving force for β-hairpin folding is identical, and the dramatic difference in folding behavior therefore reflects a variation in the intrinsic conformational properties of the diastereomeric backbones. Similar behavior is seen for the diastereomeric peptide pair Ac-L-Val-D-Pro-Gly-L-Leu-NMe2 vs Ac-L-Val-L-Pro-Gly-L-Leu-NMe2, and for the analogous depsipeptides with a lactic acid or glycolic acid residue at the third position. Thus, our results show not only that mirror-image Pro-X turns strongly promote β-hairpin folding, but also that common β-turns strongly discourage formation of a β-hairpin with a two-residue loop.
Collagenase-sensitive peptidyl-nitrogen mustards as potential antitumor agents.
Marquisee,Kauer
, p. 1188,1191 (2007/10/08)
Attempts to design an agent which would release cytotoxic nitrogen mustards within collagenase-producing tumors led to the synthesis of Cbz-L-Pro-L-Leu-Gly-L-Pro-Gly-NHC6H4N(CH2CH2Cl)2 (10). 10 was cleaved in vitro by bacterial and tumor-associated collagenase as expected at the peptide bond joining L-leucine and glycine to give Gly-L-Pro-Gly-NHC6H4N(CH2CH2Cl)2 which was over six times more toxic, on a molar basis, than 10. In vivo tests of 10 against well-advanced Sarcoma-180 gave disappointing results. The lack of specific antitumor activity may be accounted for by the presence of competing cleavage reactions by collagenases in certain normal tissues.
