(R P,R P)-Bis[(3-menthyloxy)(phenyl)­phosphino­yl] disulfide

The molecule of the title compound, C32H48O4P2S2, has 2 symmetry, the mid-point of the S—S bond being located on a twofold rotation axis. The two tetra­hedral P units are linked by a S—S bond with a P—S—S—P torsion angle is 131.19 (6)°. The dihedral angle between two phenyl rings is 12.66 (13)°. The cyclo­hexane ring of the menthoxyl group displays a chair conformation. Weak inter­molecular C—H⋯O hydrogen bonding is present in the crystal structure

Kinetic studies of novel inhibitors of endomorphin degrading enzymes

Endomorphins (EMs), two endogenous μ-opioid receptor selective ligands, are attractive lead compounds for opioid-based pain management studies. However, these peptides are quickly degraded by peptidases, in particular by dipeptidylpeptidase IV (DPP IV) and aminopeptidase M (APM). Targeting enzymatic degradation is one approach to prolong endomorphin activity. In this study we characterized the action of two new inhibitors of similar to endomorphins structure, Tyr-Pro-Ala-NH2 (EMDB-2) and Tyr-Pro-Ala-OH (EMDB-3), which were designed earlier in our laboratory. The presented data give evidence that EMDB-2 and EMDB-3 are potent inhibitors of enzymes responsible for endomorphin cleavage. These compounds are stable and easily synthesized. EMDB-2 and EMDB-3 are competitive inhibitors of both, DPP IV and APM, with Ki values in micromolar range. They are less potent than diprotin A in protecting EMs against DPP IV but more potent than actinonin in protecting these peptides against APM

Late Medieval and Modern Vessels from Przeworsk Culture Cemeteries at Żdżarów, Sochaczew County and Nadkole, Węgrów County

Two hundred and eleven cremation graves from the Roman Period and Early Migration Period, as well as nineteen other ancient features have been discovered at a heavily damaged cemetery of the Przeworsk Culture at Żdżarów in western Mazovia1. In the top part of grave 103, dated based on the presence of terra sigillata pottery from the Dicanus workshop in Pfaffenhofen from ca 230–260 AD, a poorly visible re-cut containing one clay vessel covered with a fragment of the bottom part of another was recorded (Fig. 1:a.b, 3); no human bones were found inside2. The vessels can be dated to the 14th–15th century, possibly even to the beginning of the 16th century. A different situation presents itself in the case of a cemetery of the Przeworsk Culture at Nadkole 2, in eastern Mazovia6. In addition to 157 graves from the Early Roman Period, clear traces of various modern cuts have been unearthed. The lower part of a cremation burial pit, probably from phase B2, was found under one of them. In the cut itself, fragments of four broken and incompletely preserved wheel-thrown vessels fired in a reducing atmosphere were discovered7. The pots that have been completely (Fig. 2:a.b) or partially (Fig. 2:d) reconstructed can be dated to the beginning or first half of the 16th century. Nevertheless, the end of the 18th century, or even the middle of the 19th century in rural areas, should be considered as the upper limit of occurrence of such potteryth. The fourth vessel is a very unevenly fired bowl, with a polished pattern on the inside (Fig. 2:c). This ornament indicates that it may have been tableware. This bowl should be dated to the 14th–15th century13 or later, assuming this chronology as its lower limit. An interpretation of both pottery assemblages described is not easy. In the case of Żdżarów, it seems possible to link the finds to child burials in clay vessels, known from the late Middle Ages and Modern period. Such graves, dating from the 14th to the 19th century, are known from several sites in Poland, almost exclusively in northern Mazovia15.16. The undoubtedly intentional burials at much older cemeteries, such as the four foetal burials in three vessels dating to 14th–15th century discovered at a Lusatian cemetery at Ożumiech, Przasnysz County19, are particularly interesting. No traces of bone were found in the Żdżarów vessel; however, as it was not possible to conduct specialist analyses of the fill at the time, it is not known whether it originally covered some form of burial or whether it was related to unspecified cult practices. The precise manner in which the vessel was dug into the top part of a much older grave pit (Fig. 3) shows not only the ritual character of the deposit itself, but also the ability to recognise a burial site abandoned a thousand years earlier. The archaeological context of the vessels from Nadkole suggests that they were a secondary deposit in the cut that destroyed the grave from phase B2 of the Roman Period29. In their case, there are no reasons to associate them with child burials or assign them a cult function; nor can they be considered a remnant of a late medieval or modern settlement, as no features from that period were discovered in the examined part of the site. The pottery published here shows that local populations from the late Middle Ages and Modern period either used (Żdżarów) or at least visited (Nadkole) much older cemeteries. This phenomenon is still very poorly researched, so every similar case requires a particularly thorough interpretation, based not only on a formal analysis of the feature itself and the pottery contained within, but also on the results of indispensable biochemical studies. It is worth noting that biochemical analyses of vessel contents conducted in Germany have recently confirmed the early modern custom of interring placentas (Nachgeburtsbestattung) in clay pots buried in the basements of homes27

A new and expeditious synthesis of all enantiomerically pure stereoisomers of rosaprostol, an antiulcer drug

Four enantiomerically pure stereoisomers of rosaprostol (1), an antiulcer drug, were efficiently synthesized from the enantiomers of 2-(dimethoxyphosphoryl)-3-hexylcyclopentanone (3) as chiral substrates. The latter were obtained by resolution of racemic 3 with (+)-(R)-1-(1-naphthyl)ethylamine. The conversion of (+)-3 into rosaprostol stereoisomer (−)-1a was accomplished in four steps in 56% overall yield. According to the same protocol, the second stereoisomer (+)-1c was obtained from (−)-3 in 55% overall yield. A slightly improved procedure of the last two steps of the transformation of (+)-3 into (−)-1a allowed an increase in the overall yield to 64%. The remaining two stereoisomers, (−)-1b and (+)-1d, were obtained from (−)-1a and (+)-1c in 71 and 68% yield, respectively, by a two-reaction sequence, in which a Mitsunobu inversion of configuration at C-5 was the key step

A new and expeditious synthesis of all enantiomerically pure stereoisomers of rosaprostol, an antiulcer drug

Abstract Four enantiomerically pure stereoisomers of rosaprostol (1), an antiulcer drug, were efficiently synthesized from the enantiomers of 2-(dimethoxyphosphoryl)-3-hexylcyclopentanone (3) as chiral substrates. The latter were obtained by resolution of racemic 3 with (+)-(R)-1-(1-naphthyl)ethylamine. The conversion of (+)-3 into rosaprostol stereoisomer (−)-1a was accomplished in four steps in 56% overall yield. According to the same protocol, the second stereoisomer (+)-1c was obtained from (−)-3 in 55% overall yield. A slightly improved procedure of the last two steps of the transformation of (+)-3 into (−)-1a allowed an increase in the overall yield to 64%. The remaining two stereoisomers, (−)-1b and (+)-1d, were obtained from (−)-1a and (+)-1c in 71 and 68% yield, respectively, by a two-reaction sequence, in which a Mitsunobu inversion of configuration at C-5 was the key step. 223

The Therapeutic Potential of Naturally Occurring Peptides in Counteracting SH-SY5Y Cells Injury

Peptides have revealed a large range of biological activities with high selectivity and efficiency for the development of new drugs, including neuroprotective agents. Therefore, this work investigates the neuroprotective properties of naturally occurring peptides, endomorphin-1 (EM-1), endomorphin-2 (EM-2), rubiscolin-5 (R-5), and rubiscolin-6 (R-6). We aimed at answering the question of whether well-known opioid peptides can counteract cell injury in a common in vitro model of Parkinson’s disease (PD). Antioxidant activity of these four peptides was evaluated by the 2-diphenyl-1-picrylhydrazyl radical (DPPH) scavenging activity, oxygen radical absorbance capacity (ORAC), and ferric-reducing antioxidant power (FRAP) assays, while neuroprotective effects were assessed in a neurotoxic model induced by 6-hydroxydopamine (6-OHDA) in a human neuroblastoma cell line (SH-SY5Y). The mechanisms associated with neuroprotection were investigated by the determination of mitochondrial membrane potential (MMP), reactive oxygen species (ROS) production, and Caspase-3 activity. Among the tested peptides, endomorphins significantly prevented neuronal death induced by 6-OHDA treatment, decreasing MMP (EM-1) or Caspase-3 activity (EM-2). Meanwhile, R-6 showed antioxidant potential by FRAP assay and exhibited the highest capacity to recover the neurotoxicity induced by 6-OHDA via attenuation of ROS levels and mitochondrial dysfunction. Generally, we hypothesize that peptides’ ability to suppress the toxic effect induced by 6-OHDA may be mediated by different cellular mechanisms. The protective effect caused by endomorphins results in an antiapoptotic effect (mitochondrial protection and decrease in Caspase-3 activity), while R-6 potency to increase a cell’s viability seems to be mediated by reducing oxidative stress. Our results may provide new insight into neurodegeneration and support the short peptides as a potent drug candidate to treat PD. However, further studies should be conducted on the detailed mechanisms of how tested peptides could suppress neuronal injuries

Novel glycosylated endomorphin-2 analog produces potent centrally-mediated antinociception in mice after peripheral administration

We report the synthesis and pharmacological characterization of a novel glycosylated analog of a potent and selective endogenous mu-opioid receptor (MOP) agonist, endomorphin-2 (Tyr-Pro-Phe-Phe-NH2, EM2), obtained by the introduction in position 3 of the tyrosine residue possessing the glucose moiety attached to the phenolic function via a beta-glycosidic bond. The improved blood-brain barrier permeability and enhanced antinociceptive effect of the novel glycosylated analog suggest that it may be a promising template for design of potent analgesics. Furthermore, the described methodology may be useful for increasing the bioavailability and delivery of opioid peptides to the CNS. (C) 2013 Elsevier Ltd. All rights reserved