Cyclobutane-containing peptides: Evaluation as novel metallocarboxypeptidase inhibitors and modelling of their mode of action

Fernández, Daniel; Torres, Elisabeth; Avilés, Francesc X.; Ortuño, Rosa M.; Vendrell, Josep

doi:10.1016/j.bmc.2009.04.035

Cited by 42 publications

(18 citation statements)

References 28 publications

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“…In fact, molecules with a cyclobutane core have recently shown promise as agonists of glucagon-like peptide-1 (GLP-1) receptor in vitro and in vivo 41 , 42 . In addition, the conformational rigidity of the cyclobutane has been utilized in the development of peptidomimetic inhibitors of metallocarboxypeptidases 43 . Our work expands the utility of cyclobutane-containing molecules as novel AR inhibitors in models of CRPC.…”

Section: Discussionmentioning

confidence: 99%

Inhibiting androgen receptor nuclear entry in castration-resistant prostate cancer

et al. 2016

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Clinical resistance to the second-generation antiandrogen enzalutamide in castration resistant prostate cancer (CRPC), despite persistent androgen receptor (AR) activity in tumors, highlights the unmet medical need for next generation antagonists. We have identified and characterized tetra-aryl cyclobutanes (CBs) as a new class of competitive AR antagonists that exhibit a unique mechanism of action. These CBs are structurally distinct from current antiandrogens (hydroxyflutamide, bicalutamide, and enzalutamide), and inhibit AR-mediated gene expression, cell proliferation, and tumor growth in several models of CRPC. Conformational profiling revealed that CBs stabilize an AR conformation resembling an unliganded receptor. Using a variety of techniques, it was determined that the AR:CB complex was not recruited to AR-regulated promoters and, like apo AR, remains sequestered in the cytoplasm bound to heat shock proteins. Thus, we have identified third generation AR antagonists whose unique mechanism of action suggests that they may have therapeutic potential in CRPC.

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Section: Discussionmentioning

confidence: 99%

Inhibiting androgen receptor nuclear entry in castration-resistant prostate cancer

et al. 2016

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“…NMR spectra were recorded in CDCl 3 or DMSO-d 6 for 1 H at 500 or 600 MHz and for 13 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 25 obtained, DMAP (0.2 eq. ), Et 3 N (2.5 eq.)…”

Section: Methodsmentioning

confidence: 99%

“…Even though their size is usually too small for the formation of 10-14 helices, 9 defined conformational bias in solution has been described for dimers and tetramers of conformationally constrained cyclobutane and norbornene derivatives. 13 In derivatives of cis-(R,S)-2-aminocyclobutane-1-carboxylic acid, the formation of an intra-residual six-membered hydrogen-bonded ring (6-strand) was described for the protected 5 parent compound, as well as for the series of all-cis homo-oligomers, from dimer to octamer. 11 Cyclobutane β-dipeptides have been used as a selfassembling component in functional organic fibers for the preparation of conducting materials.…”

Section: Introductionmentioning

confidence: 99%

Secondary Structure of Short β-Peptides as the Chiral Expression of Monomeric Building Units: A Rational and Predictive Model

et al. 2012

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Chirality of the monomeric residues controls and determines the prevalent folding of small oligopeptides (from di- to tetramers) composed of 2-aminocyclobutane-1-carboxylic acid (ACBA) derivatives with the same or different absolute and relative configuration. The cis-form of the monomeric ACBA gives rise to two conformers, namely, Z6 and Z8, while the trans-form manifests uniquely as an H8 structure. By combining these subunits in oligo- and polypeptides, their local structural preference remains, thus allowing the rational design of new short foldamers. A lego-type molecular architecture evolves; the overall look depends only on the conformational properties of the structural building units. A versatile and efficient method to predict the backbone folds of designed cyclobutane β-peptides is based on QM calculations. Predictions are corroborated by high-resolution NMR studies on selected stereoisomers, most of them being new foldamers that have been synthesized and characterized for the first time. Thus, the chiral expression of monomeric building units results in the defined secondary structures of small oligomers. As a result of this study, a new set of chirality controlled foldamers is provided to probe as biocompatible biopolymers.

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“…[20,21] Beyond the realmso f secondary structure design,t he use of cis-ACBC and trans-ACBC as constituents of peptide derivatives with specific biological activities has significantly increased recently. [22][23][24][25][26][27][28][29] Numerous experimental approaches have been proposed in order to obtain ag reater knowledge of the hydrogen-bonding proclivity of foldamer building blocks, relying mainly on crystallography as well as NMR or IR spectroscopy.C haracterization of some dipeptides prepared from the b-AAs shown in Figure 1has previously been carriedout by using IR absorption spectroscopy in the amide A, I, and II regions, either in rare gas matrices [17] or in solution. [15,16,19] These spectra,h owever, present the drawback of being potentially affected in solution by aggregation phenomena or solvent-related signal shifting and/or broadening, or in matrices by site effects.…”

Section: Introductionmentioning

confidence: 99%

Intrinsic Folding Proclivities in Cyclic β‐Peptide Building Blocks: Configuration and Heteroatom Effects Analyzed by Conformer‐Selective Spectroscopy and Quantum Chemistry

Alauddin

Gloaguen

Brenner

et al. 2015

Chemistry A European J

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This work describes the use of conformer-selective laser spectroscopy following supersonic expansion to probe the local folding proclivities of four-membered ring cyclic β-amino acid building blocks. Emphasis is placed on stereochemical effects as well as on the structural changes induced by the replacement of a carbon atom of the cycle by a nitrogen atom. The amide A IR spectra are obtained and interpreted with the help of quantum chemistry structure calculations. Results provide evidence that the building block with a trans-substituted cyclobutane ring has a predilection to form strong C8 hydrogen bonds. Nitrogen-atom substitution in the ring induces the formation of the hydrazino turn, with a related but distinct hydrogen-bonding network: the structure is best viewed as a bifurcated C8/C5 bond with the N heteroatom lone electron pair playing a significant acceptor role, which supports recent observations on the hydrazino turn structure in solution. Surprisingly, this study shows that the cis-substituted cyclobutane ring derivative also gives rise predominantly to a C8 hydrogen bond, although weaker than in the two former cases, a feature that is not often encountered for this building block.

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Cyclobutane-containing peptides: Evaluation as novel metallocarboxypeptidase inhibitors and modelling of their mode of action

Cited by 42 publications

References 28 publications

Inhibiting androgen receptor nuclear entry in castration-resistant prostate cancer

Inhibiting androgen receptor nuclear entry in castration-resistant prostate cancer

Secondary Structure of Short β-Peptides as the Chiral Expression of Monomeric Building Units: A Rational and Predictive Model

Intrinsic Folding Proclivities in Cyclic β‐Peptide Building Blocks: Configuration and Heteroatom Effects Analyzed by Conformer‐Selective Spectroscopy and Quantum Chemistry

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