PD 151746

PD 151746 is a potent and selective inhibitor of calpain with Ki value of 0.26 μM for μ-Calpain.

Calpain is a calcium-dependent, non-lysosomal cysteine protease that expressed in mammals and many other organisms. Calpain plays an important role in cell mobility and cell cycle progression.

PD 151746 is a cell-permeable, potent and selective calpain inhibitor. PD151746 significantly inhibited NMDA-induced α-spectrin breakdown product (SBDP) of 145 kDa and completely inhibited the fragmentation of calmodulin-dependent protein kinase II-α (CaMPK-IIα) and nitric oxide synthase (nNOS), which were cleaved by calpain [1]. In cerebellar granule cells, PD151746 inhibited serum/potassium (S/K) withdrawal induced apoptosis by 29% through inhibition of calpain. Also, PD151746 inhibited the increase of MEF2 phosphorylation and cdk5/p25 formation and inhibited caspase-3 activity [2]. In human hepatoma G2 cells, PD151746 significantly reduced insulin-stimulated glycogen synthesis and increased the amount of protein tyrosine phosphatase-ε (PTPε), which suggested that calpain played an important role in regulation of insulin-stimulated glycogen synthesis [3]. In HEK-293 cells expressing human formyl peptide receptor (hFPR) or hFPR-like 1 (hFPRL1), PD151746 increased cytoplasmic free Ca2+ ([Ca2+]i) [4].

References:
[1].  Hajimohammadreza I, Raser KJ, Nath R, et al. Neuronal nitric oxide synthase and calmodulin-dependent protein kinase IIalpha undergo neurotoxin-induced proteolysis. J Neurochem, 1997, 69(3): 1006-1013.
[2].  Verdaguer E, Alvira D, Jiménez A, et al. Inhibition of the cdk5/MEF2 pathway is involved in the antiapoptotic properties of calpain inhibitors in cerebellar neurons. Br J Pharmacol, 2005, 145(8): 1103-1011.
[3].  Meier M, Klein HH, Kramer J, et al. Calpain inhibition impairs glycogen syntheses in HepG2 hepatoma cells without altering insulin signaling. J Endocrinol, 2007, 193(1): 45-51.
[4].  Fujita H, Kato T, Watanabe N, et al. Stimulation of human formyl peptide receptors by calpain inhibitors: homology modeling of receptors and ligand docking simulation. Arch Biochem Biophys, 2011, 516(2): 121-127.

Co-expression of AFAP1-AS1 and PD-1 predicts poor prognosis in nasopharyngeal carcinoma.[Pubmed:28380458]

Oncotarget. 2017 Jun 13;8(24):39001-39011.

Nasopharyngeal carcinoma (NPC) carries a high potential for metastasis and immune escape, with a great risk of relapse after primary treatment. Through analysis of whole genome expression profiling data in NPC samples, we found that the expression of a long non-coding RNA (lncRNA), actin filament-associated protein 1 antisense RNA 1 (AFAP1-AS1), is significantly correlated with the immune escape marker programmed death 1 (PD-1). We therefore assessed the expression of AFAP1-AS1 and PD-1 in a cohort of 96 paraffin-embedded NPC samples and confirmed that AFAP1-AS1 and PD-1 are co-expressed in infiltrating lymphocytes in NPC tissue. Moreover, patients with high expression of AFAP1-AS1 or PD-1 in infiltrating lymphocytes were more prone to distant metastasis, and NPC patients with positive expression of both AFAP1-AS1 and PD-1 had the poorest prognosis. This study suggests that AFAP1-AS1 and PD-1 may be potential therapeutic targets in NPC and that patients with co-expression of AFAP1-AS1 and PD-1 may be ideal candidates for future clinical trials of anti-PD-1 immune therapy.

Mechanistic insight into the regioselectivity of Pd(ii)-catalyzed C-H functionalization of N-methoxy cinnamamide.[Pubmed:28379232]

Dalton Trans. 2017 Apr 19;46(16):5288-5296.

Computational studies have been applied to gain insight into the mechanism of Pd(ii) catalyzed alpha-C-H functionalization of N-methoxy cinnamamide. The results show that the whole catalytic cycle proceeds via sequential six steps, including (i) catalyst Pd(t-BuNC)2 oxidation with O2, (ii) O-H deprotonation, (iii) t-BuNC migratory insertion to the Pd-C bond, (iv) acyl migration, (v) C-H activation and (vi) reductive elimination. The regioselectivity for different C-H activation sites depends on the coordination structures of alpha-C or beta-C to the palladium(ii) center. The coordination of alpha-C to the palladium(ii) center shows a regular planar quadrilateral structure, which is stable. However, the beta-C coordinating to the palladium(ii) center mainly exhibits a distorted quadrilateral structure, which is relatively unstable. Thus, the barrier of alpha-C-H activation is much lower than that of beta-C-H activation. The present results provide a deep understanding of the site-selectivity of C-H activation.

Three 1D cyanide-bridged M(Ni, Pd, Pt)-Mn(II) Coordination Polymer: Synthesis, Crystal Structure and Magnetic Properties.[Pubmed:28380238]

Acta Chim Slov. 2017 Mac;64(1):215-220.

Three tetracyanide-containing building blocks K2[M(CN)4] (M = Ni, Pd, Pt) and one semi-closed macrocycle seven-coordinated manganese(II) compound have been employed to assemble cyanide-bridged heterometallic complexes, resulting in three cyanide-bridged MII-MnII complexes: [Mn(L)][Ni(CN)4] . 2H2O (1) [Mn(L)][Pd(CN)4] (2) and [Mn(L)][Pt(CN)4] (3) (L = 2,6-bis[1-(2-(N-methylamino)ethylimino)ethyl]pyridine). Single-crystal X-ray diffraction analysis shows their similar one-dimensional structure consisting of the alternating [Mn(L)]2+ species and [M(CN)4]2- building blocks, generating a cyanide-bridged neutral polymeric chain. In all three isostructural complexes the coordination geometry of manganese ion is a slightly distorted pentagonal-bipyramidal with the two cyanide nitrogen atoms at the trans positions and N5 coordinating mode at the equatorial plane from ligand L. Investigation over magnetic properties of these complexes reveals very weak antiferromagnetic interaction between neighboring Mn(II) ions bridged by the long NC-M-CN unit. A best-fit to the magnetic susceptibility of complexes 1-3 leads to the magnetic coupling constant of J = -0.081, -0.103 and -0.14 cm-1, respectively.

Pd-Catalyzed Autotandem Reactions with N-Tosylhydrazones. Synthesis of Condensed Carbo- and Heterocycles by Formation of a C-C Single Bond and a C horizontal lineC Double Bond on the Same Carbon Atom.[Pubmed:28379703]

Org Lett. 2017 Apr 21;19(8):2034-2037.

A new Pd-catalyzed autotandem reaction is introduced that consists of the cross-coupling of a benzyl bromide with a N-tosylhydrazone followed by an intramolecular Heck reaction with an aryl bromide. During the process, a single and a double C-C bond are formed on the same carbon atom. Two different arrangements for the reactive functional groups are possible, rendering great flexibility to the transformation. The same strategy led to 9-methylene-9H-fluorenes, 9-methylene-9H-xanthenes, 9-methylene-9,10-dihydroacridines, and also dihydropyrroloisoquinoline and dihydroindoloisoquinoline derivatives.

PD151746 is a calpain inhibitor, shows a 20-fold selectivity for u-calpain (Ki = 0.26 ± 0.03 μM) over m-calpain (Ki = 5.33 ± 0.77 μM).

PD 151746,179461-52-0,Natural Products, buy PD 151746 , PD 151746 supplier , purchase PD 151746 , PD 151746 cost , PD 151746 manufacturer , order PD 151746 , high purity PD 151746