Cholecystokinin-1 receptor antagonists: 5-hydroxy-5-aryl-pyrrol-2-ones as anticancer agents
Eric LattmannSteven Thomas RussellCarl H. SchwalbeA. ShorttP. N. BalaramE. TheochariMuhammad AlharbiRamesh NarayananPornthip Lattmann
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Hydroxy-pyrrolones, which were potent CCK1R antagonists, showed nanomolarAbstract The title reaction provides a mild alternative method for the synthesis of N‐substituted carbamates or amides.
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The sequence of a cholecystokinin (CCK) related peptide was modified to obtain analogues, which interact selectively either with CCK-B, or with delta-opioid receptors. Two kinds of peptides were designed, namely, the cyclic peptides of the H-Tyr-cyclo (D-Pen-Gly-Trp-L/D-3-transmercaptoproline)-Asp-Phe-NH2 sequence (compounds 1a and 1b, respectively), and the linear peptides of the H-Tyr-D-Val-Gly-Trp-L/D-3-trans-methylmercaptoproline-Asp-Phe- NH2 sequence (compounds 2a and 2b, respectively). The only difference between the chemical structures of the linear analogues compared to the cyclic ones is that one covalent bond has been eliminated and a sulfur atom is replaced by a methyl group. Molecular modeling showed that, among low-energy conformers of cyclic compounds 1, there are three-dimensional structures compatible to the model for delta-receptor-bound conformer, suggested earlier [G. V. Nikiforovich, V.J. Hruby, O. Prakash, and C.A. Gehrig (1991) Biopolymers, vol. 31, pp. 941-955]. Results of binding assays fully supported the rationale for the design of compounds 1 and 2. The cyclic analogue 1a has Ki values of 4.5 and > 5000 nM at delta- and mu-opioid receptors, respectively; and IC50 values of 1.6 and > 10,000 nM for CCK-A and CCK-B receptors, respectively. The results of this study demonstrate a possibility to redirect a peptide sequence that interacts with one type of receptors (CCK-B receptors) toward interaction with another type (delta-opioid receptors) belonging to a different physiological system. This redirection could be performed by changing the conformational properties of the peptide with very minimal changes in its chemical structure.
Conformational isomerism
Cyclic peptide
Sequence (biology)
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Abstract For Abstract see ChemInform Abstract in Full Text.
Coupling reaction
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Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
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Thio-
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Abstract α‐Arylacetamides as well as α‐arylketones are exclusively arylated at the meta‐position, irrespective of the substituents at the arene.
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