Formation of a pseudo-β-hairpin motif utilizing the Ant–Pro reverse turn: consequences of stereochemical reordering

Nair, Roshna V.; Kotmale, Amol S.; Dhokale, Snehal; Gawade, Rupesh L.; Puranik, Vedavadi G.; Rajamohanan, Pattuparambil R.; Sanjayan, Gangadhar J.

doi:10.1039/c3ob42016g

Cited by 13 publications

(7 citation statements)

References 69 publications

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“…Addition of ab ase significantly increases the reaction rate but has ad eleterious effect on enantioselectivity.T hus,w ec oncluded that the mechanistic complexity of the reaction necessitates wellbalanced reaction conditions to separate the acetylation of 3 and the decarboxylation. [15] Incorporation of a d-Pro-Aib-turn (12), frequently used by Miller et al, [11a, 16] or an 2-Abz-d-Pro pseudo-b-hairpin (13), [17] resulted in 5% and 8% ee,r espectively.W ea lso studied (S)-tetramisol (14)a nd the chiral (S)-Scheme 2. We were able to monitor the reaction by GC-MS and observed some of the intermediates (see the Supporting Information, Figure S2).…”

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confidence: 99%

The Enantioselective Dakin–West Reaction

et al. 2016

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Here we report the development of the first enantioselective Dakin-West reaction, yielding a-acetamido methylketones with up to 58 %eewith good yields.T wo of the obtained products were recrystallized once to achieve up to 84 %ee. The employed methylimidazole-containing oligopeptides catalyze both the acetylation of the azlactone intermediate and the terminal enantioselective decarboxylative protonation. We propose ad ispersion-controlled reaction path that determines the asymmetric reprotonation of the intermediate enolate after the decarboxylation.Even though the Dakin-West (DW) reaction dates back to 1928, [1] it is still one of the most effective synthetic procedures to prepare a-acylamido ketones from primary a-amino acids. [2] Generally,t he treatment of an amino acid with an acid anhydride and base,t ypically pyridine,a te levated temperature provides the desired product upon liberation of CO 2 (Scheme 1). Numerous modifications of the original reaction conditions were developed, [2] including catalytic variants, [3] broadening its scope and applicability.U nsurprisingly,the DW reaction found application in the preparation of a-acylamido ketones as valuable precursors for various biologically active compounds, [4] and even in Woodwards fundamental total synthesis of strychnine. [5] Remarkably,n o asymmetric variant has been developed to date,thus restricting the use of this important reaction in modern synthetic chemistry.

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confidence: 99%

The Enantioselective Dakin–West Reaction

et al. 2016

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“…While 2‐Abz containing peptides have been designed to adopt unique turn conformations in model peptides, biological activities were not intended, other than our own recently reported tyrocidine A analogues . Having established that d ‐Phe‐2‐Abz is a promising motif for a designed β‐hairpin, both in this work and our previous reports, we decided to use this motif to design acyclic cationic AMPs with potential β‐hairpin structure .…”

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confidence: 99%

Acyclic peptides incorporating the d‐Phe‐2‐Abz turn motif: Investigations on antimicrobial activity and propensity to adopt β‐hairpin conformations

Cameron

Varnava

Edwards

et al. 2018

Journal of Peptide Science

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Three linear peptides incorporating d-Phe-2-Abz as the turn motif are reported. Peptide 1, a hydrophobic β-hairpin, served as a proof of principle for the design strategy with both NMR and CD spectra strongly suggesting a β-hairpin conformation. Peptides 2 and 3, designed as amphipathic antimicrobials, exhibited broad spectrum antimicrobial activity, with potency in the nanomolar range against Staphylococcus aureus. Both compounds possess a high degree of selectivity, proving non-haemolytic at concentrations 500 to 800 times higher than their respective minimal inhibitory concentrations (MICs) against S. aureus. Peptide 2 induced cell membrane and cell wall disintegration in both S. aureus and Pseudomonas aeruginosa as observed by transmission electron microscopy. Peptide 2 also demonstrated moderate antifungal activity against Candida albicans with an MIC of 50 μM. Synergism was observed with sub-MIC levels of amphotericin B (AmB), leading to nanomolar MICs against C. albicans for peptide 2. Based on circular dichroism spectra, both peptides 2 and 3 appear to exist as a mixture of conformers with the β-hairpin as a minor conformer in aqueous solution, and a slight increase in hairpin population in 50% trifluoroethanol, which was more pronounced for peptide 3. NMR spectra of peptide 2 in a 1:1 CD CN/H O mixture and 30 mM deuterated sodium dodecyl sulfate showed evidence of an extended backbone conformation of the β-strand residues. However, inter-strand rotating frame Overhauser effects (ROE) could not be detected and a loosely defined divergent hairpin structure resulted from ROE structure calculation in CD CN/H O. The loosely defined hairpin conformation is most likely a result of the electrostatic repulsions between cationic strand residues which also probably contribute towards maintaining low haemolytic activity.

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“…To determine how the DOX portion of the molecule is oriented with respect to the peptide structure, MD simulations were carried out. The peptidomimetic portion was folded like a beta-turn-type of structure (pseudo turn)[42, 43] from linker to Phe with Arg and Anapa at the corners of the turn structure (Fig. 7A).…”

Section: Resultsmentioning

confidence: 99%

Design of a doxorubicin-peptidomimetic conjugate that targets HER2-positive cancer cells

Pallerla

Gauthier

Sable

et al. 2017

European Journal of Medicinal Chemistry

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Doxorubicin (DOX) belongs to the anthracycline class of drugs that are used in the treatment of various cancers. It has limited cystostatic effects in therapeutic doses, but higher doses can cause cardiotoxicity. In the current approach, we conjugated a peptidomimetic (Arg-aminonaphthylpropionic acid-Phe, compound 5) known to bind to HER2 protein to DOX via a glutaric anhydride linker. Antiproliferative assays suggest that the DOX-peptidomimetic conjugate has activity in the lower micromolar range. The conjugate exhibited higher toxicity in HER2-overexpressed cells than in MCF-7 and MCF-10A cells that do not overexpress HER2 protein. Cellular uptake studies using confocal microscope experiments showed that the conjugate binds to HER2-overexpressed cells and DOX is taken up into the cells in 4 h compared to conjugate in MCF-7 cells. Binding studies using surface plasmon resonance indicated that the conjugate binds to the HER2 extracellular domain with high affinity compared to compound 5 or DOX alone. The conjugate was stable in the presence of cells with a half-life of nearly 4 h and 1 h in human serum. DOX is released from the conjugate and internalized into the cells in 4 h, causing cellular toxicity. These results suggest that this conjugate can be used to target DOX to HER2-overexpressing cells and can improve the therapeutic index of DOX for HER2-positive cancer.

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Formation of a pseudo-β-hairpin motif utilizing the Ant–Pro reverse turn: consequences of stereochemical reordering

Cited by 13 publications

References 69 publications

The Enantioselective Dakin–West Reaction

The Enantioselective Dakin–West Reaction

Acyclic peptides incorporating the d‐Phe‐2‐Abz turn motif: Investigations on antimicrobial activity and propensity to adopt β‐hairpin conformations

Design of a doxorubicin-peptidomimetic conjugate that targets HER2-positive cancer cells

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