Online Peptide Guide

papers about Peptide

   Apr 21

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Figure 2.
The interactions of inhibitors 1 and 2 with Bcl-xL mutants. The structures of inhibitors 1 and 2 (top panel). The binding affinities of inhibitors 1 (dark gray) and 2 (light gray) for Bcl-xL mutants relative to wild type Bcl-xL as determined by a fluorescence polarization GSK212 assay (bottom panel). For each inhibitor, the data is shown as the Ki for a Bcl-xL mutant divided by the Ki for wild type Bcl-xL. The dashed line represents a 50-fold higher Ki for a Bcl-xL mutant relative to wild type Bcl-xL. Values shown are the average of three assays. Exact Ki values ± SEM are listed in Supplementary Table 2.
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Figure 3.
The interactions of various BH3 domains with Bcl-xL mutants. Aligned sequences of the BH3 domain peptides used in this study (top panel). The binding affinities of the BH3 domains from Bad (white), Bim (black), and Puma (gray) for Bcl-xL mutants relative to wild type Bcl-xL as determined by a fluorescence polarization competition assay (bottom panel). For each BH3 domain peptide, the data is shown as the Ki for a Bcl-xL mutant divided by the Ki for wild type Bcl-xL. The dashed line represents a 50-fold higher Ki for a Bcl-xL mutant relative to wild type Bcl-xL. Values shown are the average of three assays. Exact Ki values ± SEM are listed in Supplementary Table 3.


   Apr 20

GDC-0941 Scheme Synthesis of final compounds and Reagents

Scheme 1.
Synthesis GDC-0941 final compounds 1 and 3–11. Reagents and conditions: (a) phenylguanidine carbonate, DMF, 110 °C, 72%; (b) anilines, Pd(OAc)2, (±)-BINAP, K2CO3, DMF 80 °C, 48–54%, (c) KOH/EtOH, reflux, quant.; (d) amines, EDC, HOBt, DMF, DIPEA, rt, 60–93%.
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Scheme 2.
Synthesis of final compounds 12–25. Reagents and conditions: (e) KOH/EtOH, reflux, quant.; (f) 2,6-diethylaniline, EDC, HOBt, DMF, DIPEA, rt, 70%; (g) 2,6-diethylaniline, NaN(TMS)2, THF, 0 °C, 80%; (h) 45–46%, Pd2(dba)3, X-Phos, Cs2CO3, dioxane, 90 °C, 85–88%; (i) TFA, DMF, rt, quant.; (l) amines, TBTU, DMF, DIPEA, rt, 72–88%.
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Scheme 3.
Synthesis of intermediates 45 and 46. Reagents and conditions: (m) KI, NaNO2, HCl, 0 °C, 46–75%; (n) Boc2O, t-BuOH, DMAP, DCM, reflux, 62–91%.
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We observed the effect of the ortho-substitution (R1, Fig. 1) on the phenyl ring ( Table 1) and observed that, while the methyl-group (2) decreased the activity on Aur-A only, the methoxy-group (3) provided an oxidation increased inhibitory efficacy towards MPS1 if compared to CDK2/A and Aur-A but still maintained activity against PLK1. Replacement of the methoxy- with trifluoromethoxy-substituent (4) instead, abolished the activity on Aur-A and CDK2/A but also the inhibitory effect towards PLK1 and MPS1 was reduced ( Table 1).


   Apr 20

Our cathepsin cross screening efforts showed

Our cathepsin cross-screening efforts showed that the azepanone series was capable of producing potent inhibitors of cathepsin S; however, achieving high specificity versus cathepsins K and L appeared challenging. We chose to focus on optimization of the 7-methyl azepanone series as this ABT-737 series has better developability when compared to the 7-des-methyl series.31 Thus, we aimed to improve the selectivity of the series for cathepsin S over both cathepsins K and L. In the catalytic site, cathepsin S differs from cathepsin K and L mainly in the S2 and S3 regions (Fig. 2).32, 33 and 34 In the S2 pocket, cathepsin S is lined with glycine residues. This is in contrast to cathepsins K and L, both of which contain the larger alanine in the S2 pocket (CatS:G137, CatK:A134, CatL:A135). In addition, cathepsin K contains a bulkier Ala just after the catalytic histidine instead of a Gly (CatS:G165, CatK:A163, CatL:G164), as well as a Leu compared to a Val for cathepsin S (CatS:V162, CatK:L160, CatL:M161). Taken together, the S2 pocket of cathepsin S is slightly larger compared to cathepsin L and significantly larger compared to cathepsin K (see Fig. 2). This report details our efforts at modulating the selectivity profile via modification of the P2 substituent.


   Apr 20

Table Cytotoxicity of and IC values for OE

Table 1.
Cytotoxicity of 2 and 3. IC50 values for OE21 and HET-1A cell lines
Cell lineCompoundIC50 value, μM (μg/ml) ±SE
OE2120.77 (0.29) ± 0.13
Het-1a23.15 (1.18) ± 0.08
OE2130.44 (0.16) ± 0.005
Het-1a33.02 (1.11) ± 0.32
IC50, inhibitory concentration at 50% survival; SE, standard error.13
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Overall, the cytotoxicity shown Obatoclax very high and comparable to established anti-cancer drugs, for example, cisplatin, carboplatin and 5-fluorouracil, which are used in combination with radiotherapy.18 Notably, compounds 2 and 3 are more cytotoxic to cancer cells than for normal HET-1A cells. Compound 2 is in four times and 3 is seven times more effective towards the cancer cells compared to the normal cell line.
Figure 4.
IN Cell analysis of the HET-1A and OE21 live-cells incubated for 20 min and 2 h with 2.
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Thus, the assay described here can be used as a primary evaluation analysis of abnormal vs normal cells in vitro.


   Apr 20

The compounds and Estimated Ki of R conformers EKiR

The compounds 7 and 11, Estimated Ki of R-conformers (EKiR) were ~2-fold better than its S-counterpart, but exhibits ~17,000- and ~12,000-fold increased selectivity towards MAO-A, respectively. Compounds 22, EKiR was almost equal to EKiS against MAO-A as well as for MAO-B. The selectivity towards MAO-B PHA-680632 marginal and the S-conformer exhibits only ~0.1-fold better selectivity compared with its R-counterpart/racemate. Compound 27, EKiR was almost equal to EKiS against MAO-A, while against MAO-B EKiR was ~3-fold better than EKiS. Due to bronchi the molecule displayed ~4-, ~2- and ~6-fold selectivity towards MAO-A for racemate, R-conformers and S-conformer, respectively. Simulation results suggested that for compounds 7 and 11 the R-isomer exhibited improved selectivity but compounds 22 and 27 displayed a marginal improvement.
Figure 2.
Interaction of 7(R) and 7(S) with hMAO-A (PDB Code: 2BXR) and 22(R) and 22(S) with hMAO-B (PDB Code: 2BYB).
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   Apr 19

Coordination with zinc is the underlying

Coordination with zinc is the underlying reason for the difference in the internal electrostatic energies between Group A and Group B . To further explain the XL-888 differences between Group-A and Group-B, the average distances between ligands and the zinc cation were obtained from the last 1 ns trajectory. It turns out that the members of group A were within the coordination distance of the zinc ion, whereas those of group B stayed out of the distance limit of 2.4 ?. These average distances of the ligands to zinc versus the internal electrostatic interaction energies and the predicted binding free energies are shown in Appendix 6. As the distance between ligand and zinc decreases, ΔE ele,int and ΔGbind,predtest becomes more negative. As a result, the members in Group-A exhibited stronger inhibitory activities than those in Group-B. This peculiar relationship between the ligand-zinc distance and the electrostatic interaction energy strongly suggests that coordination with zinc is a crucial element in the ligand-binding process.


   Apr 19

Recently we reported that novel substituted

Recently, we reported that novel 7-substituted N2-(3-ethyl-4-methylphenyl)guanines (EMPGs, e.g., 2a–4a) and 7-substituted N2-(3,4-dichlorobenzyl)guanines (DCBGs, e.g., 5a–7a) were potent inhibitors of pol IIIC, and that the DCBGs were also active against pol IIIE species from both Gram and, with lower potency, Gram? bacteria.8 Importantly, both buy FG-4592 inhibited the enzymes by the same active site-directed, competitive mechanism previously established for ‘classical’ AU inhibitors.8 Based on the similarity of the structures of the AU and PG inhibitors bound to a cytosine residue in DNA (Fig. 1), we expanded our exploration into other heterocycles, such as 3-deazapurines and their 8-substituted derivatives. Such compounds would be expected to be DNA polymerase inhibitors and possess antibacterial activity. In this paper, we report the synthesis, structure determination, and in vitro biological activity of these compounds. Modest antibacterial activity of several compounds was observed in a S. aureus infection model in mice.Figure optionsDownload full-size imageDownload as PowerPoint slide


   Apr 18

Figure ORTEP diagram of a Figure optionsDownload full size imageDownload

Figure 7.
ORTEP diagram of 6a.
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The compounds 1a–6d were screened for their in vitro antimycobacterial activity against MTB by agar dilution method for the determination of minimum inhibitory concentration (MIC) in duplicate at 7.40 pH. At this PF-4981517 pH, the amine functionality of the compounds cannot be significantly protonated, and hence the free amine is responsible for the activity. The MIC is defined as the minimum concentration of compound required to completely inhibit the bacterial growth. The MICs of the synthesized compounds along with pharynx of the standard drugs for comparison are reported in Table 1 and Figure 8.
Table 1.
Antimycobacterial activities of 1a–6d against MTB.
CompoundArMIC (μM)CompoundArMIC (μM)
1aa4-ClC6H431.543e2-MeC6H48.14
1ba4-MeC6H470.324aaC6H514.45
1ca4-FC6H434.394b4-ClC6H43.11
1da2-ClC6H431.544c4-MeC6H46.79
1ea2- MeC6H470.324d4-MeOC6H412.68
1fa2-MeOC6H464.524e2-ClC6H43.11
2aaC6H561.954f2-MeC6H46.79


   Apr 18

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Table 2.
pKa, Caco-2 and oral exposure relationshipFigure optionsDownload full-size imageDownload as PowerPoint slide
CompdSpiroArR1MK2 IMAP EC50a (nM)Caco-2 PJ 34 nm/spKa b (pH 7.4)HLM/RLM (t1/2 min)AUC rat (μM h)c Log P
14-PiperidylIH4.319.3>60/>60<0.0061.7
3a4-PiperidylIIH5.909.1>60/>60<0.0062.4
3b4-PiperidylIIMe13108.1>60/>600.0782.8
3c4-PiperidylIIEt5988.6>60/>59.60.1543.4
223-PiperidylIIH11158.4>60/>600.4722.8
233-PiperidylIH28348.3>60/48.53.2102.0
243-PiperidylIIIH24208.456.7/42.1NTc1.0
253-PiperidylIVH21428.2>60/>600.8821.7
a–cSee Table 1.bExperimentally determined pKa values at pH 7.4.Full-size table
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Table 3.
Inhibitory MK2 activity of compounds 23–26Figure optionsDownload full-size imageDownload as PowerPoint slide
CompdStereoisomeraMK2 IMAP EC50b (nM)pHsp27 EC50c (μM)TNFα-THP1 EC50b (μM)TNFα-PBMC EC50e (μM)
23Rac.280.931.41.1
(S)-2317.40.500.850.45


   Apr 18

Acknowledgments The authors acknowledge the financial support of

Acknowledgments
The authors acknowledge the financial support of the Natural Science Foundation of Guangxi Province (No: 2010GXNSFD013019) and the Natural Science Foundation of Guangxi Province (No: 2010GXNSFA013052).
Keywords
Thiazoles; Amines; Dual activity; Malaria; Prion diseases
Malaria PLX4720 one of the most widespread infectious diseases known, with a particularly large number of cases occurring in tropical and subtropical regions. During 2009, approximately 200 million cases were reported in high-risk areas resulting in nearly 800,000 deaths.1 Development of new therapeutics, therefore, remains an area of intensive investigation, given both the worldwide prevalence of the disease, and the emergence of resistance towards existing drugs.
An interesting property of several antimalarial agents is their dual ability to also clear the disease-associated, protease-resistant isoform of prion protein (PrPSc) from persistently infected cells,2, 3 and 4 with such cell lines widely used as in vitro models of prion disease. Since no effective therapy yet exists for zone of elongation conditions, typified by Creutzfeldt–Jakob Disease (CJD) in humans and bovine spongiform encepthalopathy (BSE) in cattle, the identification of potential therapeutics remains an urgent requirement.