Alternative Derivatives Research Articles

Alternative milk derivatives do not reduce weaner pig performance

Animal Production Science (continuing Australian Journal of Experimental Agriculture) publishes original research into applied agriculture including animal production, animal-plant interactions, pasture and fodder crops, field crops, extension and horticulture

Interfacial properties of highly soluble crayfish protein derivatives

Abstract An analysis of the interfacial behaviour of two alternative protein derivatives with high solubility has been carried out at two different pH values (2 and 8). The protein derivatives (protein content higher than 50 wt.%) have a globular protein fraction mainly consisting of sarcoplasmic proteins (CFS); and a protein hydrolysate, (CFH), both obtained from crayfish surpluses. The physicochemical characterisation included protein solubility (higher than 80%) and surface charge as well as chemical analysis (elementary, sulfhydryl and disulphide groups). This was complemented with an interfacial characterization included measuring the surface pressure and surface dilatational measurements with a drop tensiometer, and interfacial shear rheology measurements performed using a double-wall-ring geometry. Whereas both types of protein derivative have significant interfacial activity (surface pressure between 20 and 40 mN/m), the difference in their behaviour is small In contrast, a strong influence of pH on the interfacial behaviour has been found for both soluble protein fractions. At pH 2, globular sarcoplasmic protein fraction yields lower surface pressures but highly viscoelastic interfaces, with 2D gel-like behaviour. At pH 8, on the other hand, CF proteins form quite rigid and more brittle interfaces, being resistant to dilatational deformations and showing high sensitivity to shear.

Pharmacokinetics and pharmacogenetics of Gemcitabine as a mainstay in adult and pediatric oncology: an EORTC-PAMM perspective.

Gemcitabine is an antimetabolite ranking among the most prescribed anticancer drugs worldwide. This nucleoside analog exerts its antiproliferative action after tumoral conversion into active triphosphorylated nucleotides interfering with DNA synthesis and targeting ribonucleotide reductase. Gemcitabine is a mainstay for treating pancreatic and lung cancers, alone or in combination with several cytotoxic drugs (nab-paclitaxel, cisplatin and oxaliplatin), and is an option in a variety of other solid or hematological cancers. Several determinants of response have been identified with gemcitabine, i.e., membrane transporters, activating and inactivating enzymes at the tumor level, or Hedgehog signaling pathway. More recent studies have investigated how germinal genetic polymorphisms affecting cytidine deaminase, the enzyme responsible for the liver disposition of gemcitabine, could act as well as a marker for clinical outcome (i.e., toxicity, efficacy) at the bedside. Besides, constant efforts have been made to develop alternative chemical derivatives or encapsulated forms of gemcitabine, as an attempt to improve its metabolism and pharmacokinetics profile. Overall, gemcitabine is a drug paradigmatic for constant searches of the scientific community to improve its administration through the development of personalized medicine in oncology.

Is matching ruthenium with dithiocarbamato ligands a potent chemotherapeutic weapon in oncology?

In the last years, several metal-based compounds have been designed and biologically investigated worldwide in order to obtain chemotherapeutics with a better toxicological profile and comparable or higher antiblastic activity than the clinically-established platinum-based drugs. In this context, researchers have addressed their attention to alternative nonplatinum derivatives able to maximize the anticancer activity of the new drugs and to minimize the side effects. Among them, a number of ruthenium complexes have been developed, including the compounds NAMI-A and KP1019, now in clinical trials. Here, we report the results collected so far for a particular class of ruthenium complexes - the ruthenium(II/III)-dithiocarbamates - which proved more potent than cisplatin in vitro, even at nanomolar concentrations, against a wide panel of human tumor cell lines.

Knockdown of Pin1 leads to reduced angiogenic potential and tumorigenicity in glioblastoma cells.

Glioblastoma is the most common and most aggressive type of primary brain tumor. Current approaches in the treatment of glioblastoma are not effective enough to increase patient survival or prevent recurrence following surgery. Consequently, the search for potential drug targets is ongoing. Peptidyl-prolyl cis/trans isomerase NIMA-interacting 1 (Pin1), an isomerase that is overexpressed in various tumors, has become an attractive molecule in cancer research. Pin1 has been reported to regulate proteins involved in essential cellular pathways that mediate cell proliferation, cell cycle progression, differentiation and apoptosis, by altering their stability and function. The results of the present study revealed that knockdown of Pin1 in glioblastoma cells using RNA interference or the selective Pin1 inhibitor, juglone, suppressed the tumorigenic features by reducing cell growth, migration and angiogenic potential. Furthermore, knockdown of Pin1 decreased the levels of vascular endothelial growth factor and matrix metallopeptidase 9, and also triggered apoptosis. Due to the fundamental roles of Pin1 in promoting tumorigenesis, Pin1 inhibitory molecules, including juglone, or alternative synthetic derivatives hold potential for the development of clinical countermeasures against glioblastoma.

Total synthesis of dihydrolysergic acid and dihydrolysergol: development of a divergent synthetic strategy applicable to rapid assembly of D-ring analogs

The total syntheses of dihydrolysergic acid and dihydrolysergol are detailed based on a Pd(0)-catalyzed intramolecular Larock indole cyclization for the preparation of the embedded tricyclic indole (ABC ring system) and a subsequent powerful inverse electron demand Diels–Alder reaction of 5-carbomethoxy-1,2,3-triazine with a ketone-derived enamine for the introduction of a functionalized pyridine, serving as the precursor for a remarkably diastereoselective reduction to the N-methylpiperidine D-ring. By design, the use of the same ketone-derived enamine and a set of related complementary heterocyclic azadiene [4+2] cycloaddition reactions permitted the late stage divergent preparation of a series of alternative heterocyclic derivatives not readily accessible by more conventional approaches.

Increased efficiency in small molecule organic solar cells through the use of a 56-π electron acceptor--methano indene fullerene.

Organic solar cells (OSCs) offer the possibility of harnessing the sun's ubiquitous energy in a low-cost, environmentally friendly and renewable manner. OSCs based on small molecule semiconductors (SMOSCs) – have made a substantial improvement in recent years and are now achieving power conversion efficiencies (PCEs) that match those achieved for polymer:fullerene OSCs. To date, all efficient SMOSCs have relied on the same fullerene acceptor, PCBM, in order to achieve high performance. The use of PCBM however, is unfavourable due to its low lying LUMO level, which limits the open-circuit voltage (VOC). Alternative fullerene derivatives with higher lying LUMOs are thus required to improve the VOC. The challenge, however, is to prevent the typical concomitant decrease in the short circuit current density (JSC) when using a higher LUMO fullerene. In this communication, we address the issue by applying methano indene fullerene, MIF, a bis-functionalised C60 fullerene that has a LUMO level 140 mV higher than PCBM, in solution processed SMOSCs with a well known small molecule donor, DPP(TBFu)2. MIF-based devices show an improved VOC of 140 mV over PC61BM and only a small decrease in the JSC, with the PCE increasing to 5.1% (vs. 4.5% for PC61BM).

Synthesis, Cytotoxicity, and Phase-Solubility Study of Cyclodextrin Click Clusters

To explore the possibility of cyclodextrin click clusters (CCCs) as a new cyclodextrin-based excipient, we prepared three different CCCs; heptakis{6-(4-hydroxymethyl-1H-[1,2,3]triazol-1-yl)-6-deoxy}-β-cyclodextrin (HT-β-CD), heptakis{6-(4-hydroxymethyl-1H-[1,2,3]triazol-1-yl)-6-deoxy}{2,3-di-O-methyl}-β-cyclodextrin (HT-β-CD(OMe)2 ), and heptakis{6-(4-sulfonylmethyl-1H-[1,2,3]triazol-1-yl)-6-deoxy}-β-cyclodextrin (ST-β-CD). The CCCs were prepared using copper(I)-catalyzed azide-alkyne cycloaddition from 6-azido-6-deoxy-β-CD and their water solubility, cytotoxicity, and drug-solubilizing effect were investigated. Water turbidity testing of the CCCs showed that the minimum water solubility of the CCCs is at least 20 times higher than that of β-CD. An MTT cell viability assay performed on HeLa cells demonstrated a low cytotoxicity of the CCCs compared with 2,6-dimethyl-β-cyclodextrin. HT-β-CD(OMe)2 and ST-β-CD did not demonstrate any cytotoxicity within the experimental concentration (∼5 mM) like 2-hydroxypropyl-β-CD. A phase-solubility study of prednisolone with the CCCs suggested that CCCs showed increased solubility of prednisolone in the presence of increasing concentrations of the CCCs. The comparison between the conventional CD derivatives and CCCs on solubility, cytotoxicity, and binding property implies that CCCs are alternative cyclodextrin derivatives useful for overcoming the restrictions of conventional cyclodextrin chemistry.

Self‐Assembled Cages from the Electroactive Bis(pyrrolo)tetrathiafulvalene (BPTTF) Building Block

AbstractA family of di‐ and tetratopic redox‐active ligands designed to generate discrete self‐assembled metallacages is described, including UV/Vis spectrometry and cyclic voltammetry studies, X‐ray diffraction on single crystals, and DFT calculations. A significant degree of conjugation between the π‐donating bis(pyrrolo)tetrathiafulvalene (BPTTF) and the electron‐withdrawing coordinating pyridyl units is observed. The tetrapyridyl ligand is able to self‐assemble in the presence of cis‐protected PtII complexes to produce the first examples of BPTTF‐based cages endowed with a cavity prone to guest encapsulation. These metallacages undergo an original chemical conversion upon being heated in DMSO to afford Pt–dithiolene complexes, one of which was characterized by XRD. This reaction could be extended to alternative BPTTF derivatives.

2D QSAR Studies on Series of Human Beta-secretase (BACE-1) Inhibitors

β-secretase (BACE-1) plays a pivotal role in the β-Amyloid plaques formation, which is responsible for progressive cognitive and memory loss commonly found in Alzheimer disease patients. As a consequence, it has been considered as a good target for drug development efforts. Early work focused on the synthesis of peptidomimetics, but poor pharmacokinetics profile prevented advancing lead compounds to clinical trials. As an alternative, aminoimidazoles, aminohydantoins and aminopyridines derivatives that inhibit BACE-1 were designed. Herein we report statistically sound descriptor- based (r(2) = 0.87, q(2) = 0.85, 6 PCs) and fragment-based (r(2) = 0.91, q(2) = 0.84, 6 PCs) QSAR models, that show high predictive ability (r(2)pred = 0.84, averaged r(2)m=0.78) and underscore polar interactions that are important for BACE-1 inhibition.

ChemInform Abstract: Zirconium Catalyzed Chemoselective Synthesis of New Amido‐Substituted Benzo[b]furans via a One‐Pot Reaction.

AbstractThe one‐pot three‐component reaction of arylglyoxals (II), benzamide (III) and phenol derivatives (I) and (V) in the presence of a Zr‐catalyst affords chemoselectively benzofurans (IV) and (VI), resp., rather than alternative oxazole derivatives.

Zirconium Catalyzed Chemoselective Synthesis of New Amido-Substituted Benzo[b]furans via a One-Pot Reaction

The one-pot three-component reaction of arylglyoxals (II), benzamide (III) and phenol derivatives (I) and (V) in the presence of a Zr-catalyst affords chemoselectively benzofurans (IV) and (VI), resp., rather than alternative oxazole derivatives.

A special issue on the renin–angiotensin system

The first elements of an endocrine pressor system, today known as the renin–angiotensin system, were discovered some 100 years ago. Soon after its discovery, the clinical relevance of the renin–angiotensin system became apparent, and since then, intense research has continuously uncovered new facets of the diverse functions of the renin–angiotensin system. Classically considered an endocrine system that regulates blood pressure and volume homoeostasis, the spectrum of functions of the renin–angiotensin system has been expanded to include several non-hemodynamic elements, including prohypertrophic and pro-fibrotic effects, among others. These novel aspects of the renin–angiotensin system are generally more apparent under pathophysiological conditions, but they may also be relevant during normal growth and differentiation. Several recent reviews have covered a broad range of aspects regarding the regulation and function of the systemic and the newly discovered local renin–angiotensin systems [1, 2]. With Pfluger's Special Issue on the renin–angiotensin system, we have attempted to cover the key elements that account for the regulation of the renin–angiotensin system and address the most important aspects of its functional output. Furthermore, compared to the majority of recent reviews, we aimed to include new trends and developments, some of which are still controversial and preliminary, but all of which have what we consider a high potential for research progress in the next years. The articles of this Special Issue were assembled with the goal of ensuring that even the most highly specialized contributions would be informative and relevant for the broad readership of our journal. The articles of the Special Issue encompass the entire cascade of the renin–angiotensin system, starting with the substrate angiotensinogen, moving on to the control of renin expression and secretion as the rate-limiting step of the cascade, and eventually addressing the effectors of the renin–angiotensin system, such as the classical angiotensin II AT receptors, the newly discovered angiotensin receptor-associated proteins, the highly controversial (pro)renin receptor, and receptors for alternative derivatives such as angiotensin (1–7), for which the biological relevance is just beginning to be uncovered. Further contributions address new aspects of the local renin–angiotensin systems, like the intra-renal and the brain renin–angiotensin system. The Special Issue concludes with articles that integrate the renin–angiotensin system into a broader context, such as the regulation of body fluid composition and the regulation of metabolic rate. Given the clinical relevance of the renin–angiotensin system, these more integrative articles are particularly focused on data from humans. We thank all the experts in the field who contributed to this Special Issue—it is your time and commitment that have made this collection of articles a success.

Neuroactive steroids with perfluorobenzoyl group

During an initial study in searching for the alternative derivatives suitable for photolabeling of neuroactive steroids, perfluorobenzoates and perfluorobenzamides in position 17 of 5β-androstan-3α-ol were synthesized from the corresponding 17-hydroxy and 17-amino derivatives. After transformation into glutamates or sulfates, 17α-epimers had comparable inhibitory activity at NMDA receptors to the natural neurosteroid (20-oxo-5β-pregnan-3β-yl sulfate), however, were more potent (2- to 36-fold) than their 17β-substituted analogs. In one case, fluorine in position 4′ of perfluorobenzoate group was substituted with azide and activity of the final glutamate was retained comparing with the corresponding perfluorobenzoate. The series was expanded with perfluorobenzoyl derivatives of pregnanolone: Perfluorobenzamide of glutamate and perfluorobenzoate of 11α-hydroxy pregnanolone were prepared and tested. From nine tested compounds, four of them exhibit very good inhibition activity and can serve as promising leads for photolabeling experiments.

Inducible Alkylation of DNA by a Quinone Methide–Peptide Nucleic Acid Conjugate

The reversibility of alkylation by a quinone methide intermediate (QM) avoids the irreversible consumption that plagues most reagents based on covalent chemistry and allows for site specific reaction that is controlled by the thermodynamics rather than kinetics of target association. This characteristic was originally examined with an oligonucleotide QM conjugate, but broad application depends on alternative derivatives that are compatible with a cellular environment. Now, a peptide nucleic acid (PNA) derivative has been constructed and shown to exhibit an equivalent ability to delivery the reactive QM in a controlled manner. This new conjugate demonstrates high selectivity for a complementary sequence of DNA even when challenged with an alternative sequence containing a single T/T mismatch. Alternatively, alkylation of noncomplementary sequences is only possible when a template strand is present to colocalize the conjugate and its target. For efficient alkylation in this example, a single-stranded region of the target is required adjacent to the QM conjugate. Most importantly, the intrastrand self-adducts formed between the PNA and its attached QM remained active and reversible over more than 8 days in aqueous solution prior to reaction with a chosen target added subsequently.

Pension Fund Use of Alternative Investments and Derivatives: Regulation, Industry Practice and Implementation Issues

The financial and economic crisis had a profound impact on the financial position of pension funds in most countries. Whilst the magnitude of these losses is primarily related to the severity of the crisis, it appears that shortcomings in the implementation of investment strategies significantly amplified the deterioration of the financial position of some pension funds. In particular, many pension funds have increasingly invested in alternative investment categories and complex products in recent years. Subsequently, the financial and economic crisis heightened the concern of pension regulatory and supervisory authorities regarding pension funds’ use of alternative investments and derivatives. The Organisation for Economic Co-operation and Development (OECD) and International Organisation of Pension Supervisors (IOPS) conducted a survey across the IOPS and OECD member base to evaluate pension funds’ exposure to alternative investments and derivatives. The information garnered from the survey and discussed in this paper, provides a valuable indication of pension fund practices with respect to these investments and establishes whether the IOPS ‘Good Practices in the Risk Management of Alternative Investments by Pension Funds’ are being implemented. This paper is divided into five main sections. The first section reviews the regulation in place which aims to manage the potential risk exposures that alternative investments and derivatives present. This provides a useful backdrop for then evaluating the current market practices of pension funds’ investment in such instruments. The second section canvasses the implementation issues that a number of pension funds have faced in attempting to implement their investment strategies with the inclusion of alternative and derivative instruments. The third section highlights the potential risks that pension funds face when investing in alternative investments and derivatives, followed by the fourth section reviewing current risk management practices observed by pension funds in managing these risk exposures. The paper finally concludes with observations which can be translated into lessons for consideration by supervisory authorities when developing future pension fund regulation and supervision practices of alternative investments and the use of derivatives, whilst also taking into account the IOPS Good Practices.

Molecular Recognition of the Antiretroviral Drug Abacavir: Towards the Development of a Novel Carbazole-Based Fluorosensor

Due to their optical and electro-conductive attributes, carbazole derivatives are interesting materials for a large range of biosensor applications. In this study, we present the synthesis routes and fluorescence evaluation of newly designed carbazole fluorosensors that, by modification with uracil, have a special affinity for antiretroviral drugs via either Watson–Crick or Hoogsteen base pairing. To an N-octylcarbazole-uracil compound, four different groups were attached, namely thiophene, furane, ethylenedioxythiophene, and another uracil; yielding four different derivatives. Photophysical properties of these newly obtained derivatives are described, as are their interactions with the reverse transcriptase inhibitors such as abacavir, zidovudine, lamivudine and didanosine. The influence of each analyte on biosensor fluorescence was assessed on the basis of the Stern–Volmer equation and represented by Stern–Volmer constants. Consequently we have demonstrated that these structures based on carbazole, with a uracil group, may be successfully incorporated into alternative carbazole derivatives to form biosensors for the molecular recognition of antiretroviral drugs.

Physicochemical Characterization of Creatine N-Methylguanidinium Salts

ABSTRACTCreatine is widely used as a dietary supplement for body builders to enhance athletic performance. As the monohydrate, its low solubility in water and high dose lead to water retention and gastrointestinal discomfort. Hence, alternative creatine derivatives with enhanced water solubility and potential therapeutic advantages have been synthesized. As a zwitterionic compound, creatine can form salts at the N-methyl guanidinium or carboxylic acid functional groups. In this study, we determined the aqueous solubilities and partition coefficients of six N-methyl guanidinium salts of creatine compared to those of creatine monohydrate; two of these were new salts, namely, creatine mesylate and creatine hydrogen maleate. The aqueous solubilities of the salts were significantly more than that of creatine monohydrate with the hydrochloride and mesylate being 38 and 30 times more soluble, respectively. The partition coefficients of the creatine salts were very low indicating their relatively high polarity. Permeabilities of creatine pyruvate, citrate, and hydrochloride in Caco-2 monolayers were compared to that of creatine monohydrate. Aside from the creatine citrate salt form that had reduced permeability, there were no significant differences in permeability characteristics in Caco-2 monolayers. Typical of an amphoteric compound, creatine is least soluble in the pH region near the isoelectric point.

High-dose erythropoietin alters platelet reactivity and bleeding time in rodents in contrast to the neuroprotective variant carbamyl-erythropoietin (CEPO)

The haematopoietic hormone erythropoietin (EPO) has neuroprotective properties and is currently being explored for treatment of stroke and other neurological disorders. Short-term, high-dose treatment with EPO seems to improve neurological function of stroke patients but may be associated with increased thrombotic risk, whereas alternative non-erythropoietic neuroprotective derivatives of EPO, such as carbamylated EPO (CEPO), may be devoid of such side-effects. We investigated the effects of short-term, high-dose treatment with EPO and CEPO on platelet function and haemostasis in healthy mice and rats. Animals received three daily doses of EPO or CEPO (50 microg/kg), and blood was compared with respect to alterations in haematology and platelet reactivity. In rats, treatment with EPO increased the haematocrit to >50% and the mean platelet volume by 37%, while CEPO had no effect on these parameters. Platelets from EPO-treated rats showed an increased sensitivity to thrombin receptor agonist peptides and elevated plasma levels of soluble P-selectin (sP-selectin) were found in treated mice. Further indicators of platelet hyperreactivity in EPO, but not CEPO-treated animals, were significantly increased aggregatory responses to collagen in whole blood and platelet-rich plasma (PRP). The increased platelet reactivity was paralleled by a decreased bleeding time after tail transection in rats. Samples from EPO-treated rats showed an attenuated response to ADP in whole blood aggregometry and thrombelastography (TEG) platelet mapping but not in apyrase-treated PRP, suggesting involvement of ADP receptor desensitization. These findings suggest that while EPO affects various aspects of platelet function, CEPO is devoid of such effects.

Review article: high‐dose aminosalicylates to induce and maintain remissions in ulcerative colitis

Sulfasalazine was the first aminosalicylate to be used for induction and maintenance therapy of ulcerative colitis (UC). Initial trials demonstrated a dose response that was compromised by dose-related intolerance. Recognition that the 5-aminosalicylic acid moiety (5-ASA, mesalazine) is the active ingredient of sulfasalazine has allowed the development of sulpha-free formulations of mesalazine and alternative azo-bond derivatives (olsalazine, balsalazide) that substantially reduce the dose-related (and allergic) consequences of the sulfapyridine moiety of sulfasalazine. Dose-ranging studies of mesalazine formulations for induction of remission have demonstrated increased efficacy of oral mesalazine up to 4-4.8 g/day, particularly in patients with more moderate disease activity. Combination therapy with oral and rectal mesalazine provide additional efficacy for patients with both distal and extensive colitis. The mesalazine formulations have dose-related benefits without dose-related side effects. In contrast, the azo-bond formulations are compromised by secretory diarrhoea at doses providing greater than 2-2.4 g/day of mesalazine. There are less data regarding dose-related benefits of aminosalicylates to maintain remissions in UC greater than 1.6 g/day of mesalazine, although the absence of dose-related side effects allows continuation of the same inductive dose through maintenance treatment without dose-related toxicity.