Conformationally restricted peptide isosteres. 2.1 Synthesis and in vitro potency of dipeptide renin inhibitors employing a 2-alkylsulfonyl-3-phenylcyclopropane carboxamide as a P3 amino acid replacement

Baker, William R.; Jae, Hwan Soo; Martin, Stephen R.; Condon, Stephen L.; Stein, Herman H.; Cohen, Jerome; Kleinert, Hollis D.

doi:10.1016/s0960-894x(00)80522-3

Cited by 19 publications

(8 citation statements)

References 7 publications

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“…To establish the efficacy of dipeptide replacements related to 2 , we developed methods for their enantioselective synthesis and then introduced them into a number of biologically active pseudopeptides, including inhibitors of renin, HIV-1 protease, and matrix metalloproteinases as well as enkephalin analogues. − Others have used such cyclopropane-derived mimics in non-peptide fibrinogen receptor antagonists . The predicted structural properties of these rigid replacements were verified in a significant study in which truncated analogues of 2 were incorporated in conformationally restricted inhibitors of HIV-1 protease.…”

Section: Introductionmentioning

confidence: 99%

Cyclopropane-Derived Peptidomimetics. Design, Synthesis, and Evaluation of Novel Ras Farnesyltransferase Inhibitors

2001

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Trisubstituted cyclopropanes have previously been established as rigid replacements of dipeptide arrays in several biological systems. Toward further evaluating the utility of these dipeptide mimics in the design of novel CA(1)A(2)X-based inhibitors of Ras farnesyltransferase (FTase), the conformationally constrained, diastereomeric pseudopeptides CAbuPsi[COcpCO]FM 7-9, the flexible analogue CAbuPsi[CHOHCH(2)]FM (10), and the tetrapeptide CAbuFM (6) were prepared. The orientations of the two peptide backbone substituents and the phenyl group on the cyclopropane rings in 7-9were specifically designed to probe selected topological features of the hydrophobic binding pocket of the A(2) subsite of FTase. The syntheses of the requisite trisubstituted cyclopropane carboxylic acid 22 and the diastereomeric cyclopropyl lactones 32a,b featured diastereoselective intramolecular cyclopropanations of chiral allylic diazoacetates and a new method for introducing side chains onto the C-terminal amino acid of cyclopropane-derived dipeptide replacements via the opening of an N-Boc-aziridine with an organocuprate. These cyclopropane intermediates were then converted into the targeted FTase inhibitors 7-9 by standard peptide coupling techniques. The pseudopeptides 7-9 were found to be competitive inhibitors of Ras FTase with IC(50)s of 1055 nM for 7, 760 nM for 8, and 7200 nM for 9. The flexible analogue 10 of these constrained inhibitors exhibited a IC(50) of 320 nM and hence was slightly more potent than 7 and 8. All of these pseudopeptides were less potent than the tetrapeptide parent CAbuFM (6), which had an IC(50) of 38 nM. Because 7 and 8 are approximately equipotent, it appears that the orientation of the peptide backbone substituents on the cyclopropane rings in 7 and 8 do not have any significant effect on binding affinity and that multiple binding modes are possible without significant changes in affinity. On the other hand, this flexibility does not extend to the orientation of the side chain of the A(2) residue as 7 and 8 were both nearly 1 order of magnitude more potent than 9. Comparison of the relative potencies of 6 and 10 suggests that the amide linkage between the A(1) and the A(2) residues of CA(1)A(2)X-derived FTase inhibitors is important.

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Section: Introductionmentioning

confidence: 99%

Cyclopropane-Derived Peptidomimetics. Design, Synthesis, and Evaluation of Novel Ras Farnesyltransferase Inhibitors

2001

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“…Although the introduction of a retro amide at P2‘−P3‘ of 4 was detrimental to potency, comparing the activities of 10 and 11 demonstrates for the first time that cyclopropane-containing pseudopeptides can have significantly higher activities than their flexible analogues. We previously found that rigidified pseudopeptides incorporating replacements derived from 2 were either equipotent or less active than their flexible derivatives. − , The present results thus clearly signal that further investigations are necessary to understand the basis of these differences and to establish the scope and utility of cyclopropane-derived isosteres related to 3 .…”

Section: Discussionmentioning

confidence: 52%

“…To evaluate 1,2,3-trisubstituted cyclopropane derivatives of 2 and 3 as peptide isosteres, we developed a number of efficient methods for the enantioselective syntheses of cyclopropanes bearing functionally diverse substituents . Cyclopropanes, primarily those related to 2 , were then incorporated as rigid replacements into biologically active inhibitors of renin, HIV-1 protease, and Ras farnesyltransferase, as well as enkephalin analogues 8 and SH2 antagonists . Cyclopropanes have also been used by others as peptide mimics .…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and Evaluation of Matrix Metalloprotease Inhibitors Bearing Cyclopropane-Derived Peptidomimetics as P1‘ and P2‘ Replacements

et al. 2002

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We have previously used trisubstituted cyclopropanes as peptide replacements to induce conformational constraints in known pseudopeptide inhibitors of a number of important enzymes. Cyclopropane-derived peptide mimics are novel in that they are among the few replacements that locally orient the peptide backbone and the amino acid side chain in a predefined manner. Although these dipeptide isosteres have been employed to orient amino acid side chains mimicking the gauche(-) conformation of chi(1)-space, their ability to project the side chains into an anti orientation has not been evaluated. As a first step toward this goal, the conformationally constrained pseudopeptides 8 and 10 and their corresponding flexible analogues 9 and 11 were prepared and tested as inhibitors of matrix metalloproteinases (MMPs). These compounds are analogues of 4 and 5, which were known to be potent MMP inhibitors. The anti orientations of the isopropyl side chain in 8 and the aromatic ring in 10 relative to the peptide backbone substituents on the cyclopropane were predicted to correspond to the known orientations of the P1' and P2' side chains of 5 when bound to MMPs. Hence, 8 and 10 were designed explicitly to probe topological features of the S1' or the S2' binding pockets of the MMPs. They were also designed to explore the importance of the P1'-P2' amide group, which is known to form highly conserved hydrogen bonds in several MMP-inhibitor complexes, and the viability of introducing a retro amide linkage between P2' and P3'. Pseudopeptides 8 and 9 were found to be weak competitive inhibitors of a series of MMPs. Any entropically favorable conformational constraints that were induced by the cyclopropane in 8 were thus overwhelmed by the loss of the hydrogen bonding capability associated with the P1'-P2' amide group. On the other hand, compounds 10 and 11, which contain a P2'-P3' retro amide group, were modest competitive inhibitors of a series of MMPs. The results obtained for 10 and 11 suggest that there may be a loss of hydrogen bonding capability associated with introducing the P2'-P3' retro amide group. However, because the conformationally constrained pseudopeptide 10 was significantly more potent than its flexible analogue 11, trisubstituted cyclopropanes related to 3 may serve as useful rigid dipeptide replacements in some biologically active pseudopeptides.

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“…Toward identifying peptide replacements that would satisfy the above criteria and serve as useful tools to help elucidate the biologically active conformation of oligopeptides, we launched a program to evaluate the cyclopropanes 2 (-XaaΨ[COcpCO]Yaa-), and 3 (-XaaΨ[NHcpNH]Yaa-) as novel mimics of the dipeptide 1 . − The cyclopropane ring in 2 incorporates the α-carbon, the nitrogen, and the β-carbon of the amino acid Yaa, whereas the cyclopropane in 3 replaces the α-carbon, the carbonyl carbon, and the β-carbon atom of Yaa. Preliminary molecular modeling studies to identify low-energy conformations of 2 and 3 indicated that when the backbone substituents were trans, the φ- or ψ-angle would be locked, and a local β-strand structure, a motif commonly found in inhibitors bound to enzyme active sites, would be preferred.…”

Section: Introductionmentioning

confidence: 99%

“…As proof of the concept, we first introduced truncated analogues of trans- 2 into a number of potent pseudopeptide inhibitors of renin . We have since incorporated replacements related to 2 and 3 in inhibitors of HIV-1 protease 6 and matrix metalloproteinases, , and others have used such cyclopropane-derived mimics in non-peptide fibrinogen receptor antagonists .…”

Section: Introductionmentioning

confidence: 99%

Cyclopropane-Derived Peptidomimetics. Design, Synthesis, and Evaluation of Novel Enkephalin Analogues

et al. 2000

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It is known that peptide mimics containing trans-substituted cyclopropanes stabilize extended conformations of oligopeptides, and molecular modeling studies now suggest that the corresponding cis-cyclopropane dipeptide isosteres could stabilize a reverse turn. To begin to assess this possibility, a series of cis-substituted cyclopropanes were incorporated as replacements of the Gly(2)-Gly(3) and Phe(4)-Leu(5) dipeptide subunits in Leu-enkephalin (H(2)N-Tyr-Gly-Gly-Phe-Leu-OH), which is believed to bind to opiod receptors in a conformation containing a beta-turn. General methods for the synthesis of the cyclopropane-containing dipeptide isosteres -XaaPsi[COcpCO]Yaa- and -XaaPsi[NHcpNH]Yaa-were developed by a sequence that featured the enantioselective cyclization of allylic diazoacetates catalyzed by the chiral rhodium complexes Rh(2)[(5S)-MEPY](4) and Rh(2)[(5R)-MEPY](4). A useful modification of the Weinreb amidation procedure was applied to the opening of the intermediate lactones with dipeptides, and a novel method for the synthesis of substituted diaminocyclopropanes was also developed. The Leu-enkephalin analogues were tested in a panel of binding and functional assays, and although those derivatives containing cyclopropane replacements of the Gly(2)-Gly(3) exhibited low micromolar affinity for the mu-receptor, analogues containing such replacements for the Phe(4)-Leu(5) subunit did not bind with significant affinity to any of the opioid receptors. These results are discussed.

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Conformationally restricted peptide isosteres. 2.1 Synthesis and in vitro potency of dipeptide renin inhibitors employing a 2-alkylsulfonyl-3-phenylcyclopropane carboxamide as a P3 amino acid replacement

Cited by 19 publications

References 7 publications

Cyclopropane-Derived Peptidomimetics. Design, Synthesis, and Evaluation of Novel Ras Farnesyltransferase Inhibitors

Cyclopropane-Derived Peptidomimetics. Design, Synthesis, and Evaluation of Novel Ras Farnesyltransferase Inhibitors

Design, Synthesis, and Evaluation of Matrix Metalloprotease Inhibitors Bearing Cyclopropane-Derived Peptidomimetics as P1‘ and P2‘ Replacements

Cyclopropane-Derived Peptidomimetics. Design, Synthesis, and Evaluation of Novel Enkephalin Analogues

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