Acetic Analogues Research Articles

Neo-5,10-seco-clerodane diterpenoids from Schnabelia terniflora

Three new neo-5,10-seco-clerodane diterpenoids (1–3), four previously undescribed ethoxy/methoxy acetal analogues (4–7), one new etherified labdane diterpenoid (8), and seven known diterpenoids (9–15) were isolated from the whole plant of Schnabelia terniflora. Their structures were established on the basis of extensive spectroscopic analysis, single-crystal X-ray diffraction data, calculated electronic circular dichroism (ECD), and Mo2(OAc)4-induced circular dichroism. Compounds 2 and 3 represent the first examples of neo-5,10-seco-clerodane diterpenoids containing a 1H-pyrrole-2,5-dione and a pyrrolidine-2,5-dione moiety, respectively. A plausible biosynthetic pathway for 1–3 is proposed. All diterpenoids were evaluated for their cytotoxic activity against non-small-cell lung cancer lines (A549 and H460) and gastric cancer lines (HGC27 and AGS). Among them, 2 and 14 showed moderate cytotoxicity against four cell lines.

Human metabolism of the semi-synthetic cannabinoids hexahydrocannabinol, hexahydrocannabiphorol and their acetates using hepatocytes and urine samples.

Hexahydrocannabinol (HHC), hexahydrocannabiphorol (HHCP) and their acetates, HHC-O and HHCP-O, respectively, are emerging in Europe as alternatives to tetrahydrocannabinol (THC). This study aimed to elucidate the metabolic pathways of the semi-synthetic cannabinoids HHC, HHCP, HHC-O and HHCP-O from incubation with human hepatocytes. The metabolites of HHC were also identified in authentic urine samples. HHC, HHCP, HHC-O and HHCP-O were incubated with primary human hepatocytes for 1, 3 and 5 h. Authentic urine samples from cases screened positive for cannabis in blood using ELISA but confirmed negative were analysed both non-hydrolysed and hydrolysed for HHC metabolites. Potential metabolites were identified using ultra-high performance liquid chromatography (UHPLC) coupled to a quadrupole time-of-flight mass spectrometer (QToF-MS). HHC and HHCP were primarily metabolised through monohydroxylation (monoOH), followed by oxidation to a carboxylic acid metabolite. HHC-O and HHCP-O were rapidly metabolised to HHC and HHCP, respectively. In authentic urine samples, 18 different metabolites were identified, and 99.3% of hydroxylated metabolites were glucuronidated. 11-OH-HHC, 5'OH-HHC and another metabolite with a monoOH on the side chain were the only metabolites present in all 16 urine samples. The metabolism of HHC and HHCP were similar, although the longer alkyl side chain of HHCP (heptyl) led to greater hydroxylation on the side chain than HHC (pentyl). The use of HHC and HHCP can be differentiated from the use of THC and other phytocannabinoids, but the use of the acetate analogues may not be differentiable from their non-acetate analogues.

Synthesis, Herbicidal Activity, and Structure-Activity Relationships of O-Alkyl Analogues of Khellin and Visnagin.

Khellin and visnagin furanochromones were recently reported as potential new bioherbicides with phytotoxic activities comparable to those of some commercially available herbicides. In this study, we examined the effect of O-alkylation and O-arylalkylation of both khellin and visnagin on its effect on herbicidal and antifungal activity. Synthetic analogues included O-demethyl khellin and visnagin, acetylated O-demethyl khellin and visnagin, O-benzylated demethyl khellin and visnagin, four O-demethyl alkylated khellin analogues, and six O-demethyl alkylated visnagin analogues, many of which are reported here for the first time. Both acetate analogues of khellin and visnagin indicated more activity as herbicides on Lemna pausicostata than visnagin, with IC50 values of 71.7 and 77.6 μM, respectively. Complete loss of activity for all O-alkyl analogues with a carbon chain length of greater than 14 carbons was observed. The O-demethyl butylated visnagin analogue was the most active compound with an IC50 of 47.2 μM against L. pausicostata. O-Demethyl ethylated analogues of both khellin and visnagin were as effective as khellin. In the antifungal bioautography bioassay against Colletotrichum fragariae at 100 μg, the only active O-alkyl and O-arylalkyl analogues were O-ethylated, O-butylated, and O-benzylated visnagin analogues with zones of inhibition of 10, 9, and 9 mm, respectively, an effect comparable to that of visnagin and khellin.

Discovery of neo-Clerodane Diterpenoids from Ajuga campylantha as Neuroprotective Agents against Ferroptosis and Neuroinflammation.

Twelve new neo-clerodane diterpenoids, eight undescribed methoxy/ethoxy acetal analogues, and one new nor-iridane monoterpenoid were isolated from Ajuga campylantha. Their structures were elucidated using a combination of spectroscopic data, quantum chemical calculations, and X-ray crystallography. This research reveals the distinctive structural features of A. campylantha diterpenes, including distinct C rings and 4,18-double bonds, distinguishing them from diterpenes of other plants in the Ajuga genus. Compound 2 represents the first example of a 19(5→6)-abeo-clerodane formed through a Wagner-Meerwein rearrangement. The isolated compounds were assessed for their neuroprotective effects against RSL3-induced ferroptosis in HT22 cells and LPS-induced neuroinflammation in BV-2 cells. Notably, compound 7 inhibits ferroptosis (EC50 = 10 μM) with a potentially new mechanism of action. The preliminary structure-activity relationship studies revealed that the furan-clerodane diterpenoids possess potential ferroptosis inhibitory activity, while the lactone-clerodanes do not. This study represents the first report of furan-containing clerodanes within the Ajuga genus, providing fresh insights into the phytochemistry and pharmacological potential of A. campylantha.

Effect of the type of N-substituent in the benzo-18-azacrown-6 compound on copper(II) chelation: complexation, radiolabeling, stability in vitro, and biodistribution in vivo.

In this work, we synthesized two new benzo-18-azacrown-6 ethers bearing picolinate and pyridine pendant arms and studied the copper complexes of these ligands, as well as those of an acetate analog. All considered ligands were capable of forming mono- and dinuclear complexes due to their large size and large number of donor sites. Among all forms of complexes, the coordination of cations inside the macrocycle has only been shown for the mononuclear form of the acetate complex, while out-cage coordination has been observed for other forms. Electrochemical studies have shown the instability of the mononuclear form of the complex with the pyridine ligand to the reduction in the range of redox potentials of bioreductants. The stabilities of labeled acetate complexes with "in-cage" coordination of the cation and picolinate with "out-cage" coordination were compared in an excess of serum and superoxide dismutase; while the former turned out to be unstable to transchelation, the latter was stable throughout the experiment. Additional studies in biologically relevant media were performed for the picolinate complex and demonstrated its stability in vitro. The biodistribution of this complex in mice after 6 hours post-injection demonstrates a slow excretion from the body; however, the accumulation is noticeably lower than that of free copper cations.

The effect of blood BHBA level on fertility in sheep

The aim of this study was the effect of pre-synchronization blood BHBA level on pregnancy rates of sheep in the non-breeding season. For this purpose, 100 Merino/Merino crossbred ewe, aged 2-4 years, who have given one birth before, were used in the study. For synchronization purposes, progesterone containing sponges 60 mg Medroxyprogesteron acetate (MPA) analogue, were administered intravaginally for 14 days. BHBA (betahydroxybutyric acid) measurement was made by drawing blood in each animal on the day of administration. 500-700 IU PMSG was injected at the time of sponge withdrawal. Oestrus was observed 24 hours after sponge withdrawal with the help of teaser ram. Animals which was in estrus were hand mated. Pregnancy status was recorded with the help of ultrasound using the transrectal probe in the interval 35-45 days after mating. All of the synchronized animals were determined to be in estrus and their mating were performed. As a result of the pregnancy examination, 57 (57%) of the animals became pregnant and 43 (43%) did not become pregnant. Blood BHBA values were measured in the range of 0.12 mmol/L -0.66 mmol/L (n:100) in present study and the average of BHBA as 0.35±0.083 mmol/L was determined. While blood BHBA level of pregnant animals was found as 0.29±0.005 mmol/L, blood BHBA level of non-pregnant sheep was found to be 0.41±0.073 mmol/L, which was statistically significant (p<0.001). In addition, it was determined that there was a strong negative correlation between blood BHBA level and pregnancy rates in sheep (r = −0.719, p<0.001). As a result, it was concluded that there was no study in the literature about the relationship between the fertility parameters of sheep and the blood BHBA level in the mentioned period, and it was concluded that the presented study made a significant contribution to the literature. It has been concluded that a higher fertility success can be achieved from animals with low BHBA levels, that fertility rates can be increased by regulating the energy balance of animals with high BHBA levels, and that the study can be a criterion to be considered in achieving the target of 3 lambing in 2 years in terms of herd management in sheep breeding.

DFT and CBS Study of Ethyl Acetate Conformers in the Neutral Hydrolysis

First-principles calculations are commonly used to search for possible transition states in reaction kinetics studies, which are such a challenge to observe experimentally. However, computationally studying the reaction is also challenging because of, inter alia, the Basis Set Incompleteness Error (BSIE). Accordingly, we utilized density functional theory-based calculations and the complete basis set method, to confirm the conformational effect in the neutral hydrolysis of three ethyl acetate analogs: ethyl formate, ethyl acetate, and ethyl fluoroacetate. The results showed that both methods yielded activation energy span, which implies that the conformational effect in the ethyl acetate neutral hydrolysis is not due to the BSIE. The results also demonstrated the importance of polarization and diffuse function in a basis set. The former was to improve the ground state geometry, and the latter was to increase the activation energy.

Novel Hybrid Benzoazacrown Ligand as a Chelator for Copper and Lead Cations: What Difference Does Pyridine Make.

A synthetic procedure for the synthesis of azacrown ethers with a combination of pendant arms has been developed and the synthesized ligand, characterized by various techniques, was studied. The prepared benzoazacrown ether with hybrid pendant arms and its complexes with copper and lead cations were studied in terms of biomedical applications. Similarly to a fully acetate analog, the new one binds both cations with close stability constants, despite the decrease in both constants. The calculated geometry of the complexes correlate with the data from X-ray absorption and NMR spectroscopy. Coordination of both cations differs due to the difference between the ionic radii. However, these chelation modes provide effective shielding of cations in both cases, that was shown by the stability of their complexes in the biologically relevant media towards transchelation and transmetallation.

Cationic-palladium catalyzed regio- and stereoselective syn-1,2-dicarbofunctionalization of unsymmetrical internal alkynes

π-Extended tetrasubstituted olefins are widely found motifs in natural products, leading drugs, and agrochemicals. Thus, development of modular strategies for the synthesis of complex all-carbon-substituted olefins always draws attention. The difunctionalization of unsymmetrical alkynes is an attractive approach but it has remained faced with regioselectivity issues. Here we report the discovery of a regio- and stereoselective syn-1,2-dicarbofunctionalization of unsymmetrical internal alkynes. A cationic Pd-catalyzed three-component coupling of aryl diazonium salts, aryl boronic acids (or olefins) and yne-acetates enables access to all-carbon substituted unsymmetrical olefins. The transformation features broad scope with labile functional group tolerance, building broad chemical space of structural diversity (94 molecules). The value of this synthetic method is demonstrated by the direct transformation of natural products and drug candidates containing yne-acetates, to enable highly substituted structurally complex allyl acetate analogues of biologically important compounds. Synthetic versatility of the carboxylate bearing highly substituted olefins is also presented. The reaction outcome is attributed to the in situ formation of stabilized cationic aryl-Pd species, which regulates regioselective aryl-palladation of unsymmetrical yne-acetates. Control experiments reveal the synergy between the carboxylate protecting group and the cationic Pd-intermediate in the regioselectivity and reaction productivity; density functional theory (DFT) studies rationalize the selectivity of the reaction.

Total synthesis and stereochemical assignment of bipolamide A acetate.

Asymmetric total synthesis of an acetate analogue of the endophytic unstable secondary metabolite bipolamide A has been achieved for the first time adopting a convergent approach. The key feature of this synthesis includes Evans's asymmetric ethylation, Wittig olefination, Takai olefination, stereoselective Grignard addition and intermolecular Heck coupling. This eventually developed a synthetic route of the rarely found branched amine bearing an acyloin moiety. Our synthesis finally established unambiguously the stereochemistry of the unassigned C-8 center of the naturally occurring unstable bipolamide A.

A bioorthogonal chemical reporter for fatty acid synthase–dependent protein acylation

Mammalian cells acquire fatty acids (FAs) from dietary sources or via de novo palmitate production by fatty acid synthase (FASN). Although most cells express FASN at low levels, it is upregulated in cancers of the breast, prostate, and liver, among others, and is required during the replication of many viruses, such as dengue virus, hepatitis C, HIV-1, hepatitis B, and severe acute respiratory syndrome coronavirus 2, among others. The precise role of FASN in disease pathogenesis is poorly understood, and whether de novo FA synthesis contributes to host or viral protein acylation has been traditionally difficult to study. Here, we describe a cell-permeable and click chemistry–compatible alkynyl acetate analog (alkynyl acetic acid or 5-hexynoic acid [Alk-4]) that functions as a reporter of FASN-dependent protein acylation. In an FASN-dependent manner, Alk-4 selectively labels the cellular protein interferon-induced transmembrane protein 3 at its known palmitoylation sites, a process that is essential for the antiviral activity of the protein, and the HIV-1 matrix protein at its known myristoylation site, a process that is required for membrane targeting and particle assembly. Alk-4 metabolic labeling also enabled biotin-based purification and identification of more than 200 FASN-dependent acylated cellular proteins. Thus, Alk-4 is a useful bioorthogonal tool to selectively probe FASN-mediated protein acylation in normal and diseased states.

Synthesis of 1ʹ-acetoxychavicol acetate (ACA) analogues and their inhibitory activities against methicillin-resistant Staphylococcus aureus

A series of 1ʹ-acetoxychavicol acetate analogues were synthesised and evaluated for their antimicrobial activity against methicillin-resistant Staphylococcus aureus (MRSA) using broth microdilution technique. The minimum inhibitory concentration (MIC) was used to determine whether the compounds had potential as inhibitory agents against the MRSA ATCC 43300, and the compounds with antimicrobial potential (<2000 μg ml–1) were tested for minimum bactericidal concentration (MBC). Based on this assay, compound 1 exhibited potent antimicrobial activity with MIC value of 250 μg ml–1. Meanwhile, compounds 2 and 13 showed the moderate activity with MIC values of 500 μg ml–1, respectively.

Antimicrobial and antioxidant activities of hydrocarbon and oxygenated monoterpenes against some foodborne pathogens through in vitro and in silico studies

The present work describes the antimicrobial action of 25 monoterpenes (six hydrocarbons, five ketones, two aldehydes, six alcohols and six acetate analogues) against Gram-negative Escherichia coli and Gram-positive Staphylococcus aureus and antifungal activity against Aspergillus flavus. The antibacterial activity was evaluated by broth microdilution technique as a minimum inhibitory concentration (MIC) and the antifungal activity was performed by mycelia radial growth technique as the effective concentration causing 50% inhibition of the mycelial growth (EC50). The results showed that thymol and α-terpineol were the most potent against E. coli (MIC = 45 and 55 mg/L, respectively) and S. aureus (MIC = 135 and 225 mg/L, respectively). The results also showed that thymol displayed the maximum antifungal action against A. flavus with EC50 20 mg/L. Furthermore, the antioxidant activity was determined using N,N-dimethyl-1,4-phenylenediamine (DMPD) and the results showed that geraniol were the most potent compound (IC50 = 19 mg/L). Molecular docking studies indicated that the compounds displayed different binding interactions with the amino acid residues at the catalytic sites of N5-carboxyaminoimidazole synthetase and oxysterol binding protein Osh4 enzymes. Non-covalent interactions including van der Waals, hydrogen bonding as well as hydrophobic were observed between the compounds and the enzymes. A significant relationship was found between the docking score and the biological activity of the tested monoterpenes compared to the ceftriaxone and carbendazim as standard bactericide and fungicide, respectively. In silico ADMET properties were also performed and displayed potential for the development of promising antimicrobial agents. For these reasons, these compounds may be considered as potential ecofriendly alternatives in food preservation to delay or prevent the microbial infection and prolong the shelf life of food products.

Dinuclear Copper(II) 3,4,5-Tri-O-benzylgallate

Background:Ellagitannins have attracted much attention because of the biological and pharmacological activities. In the total synthesis of ellagitannins, 3,4,5-tri-O-benzylgallic acid has been a key compound to introduce the protected galloyl group. From the perspective of coordination chemistry, 3,4,5-tri-O-benzylgallic acid is an interesting carboxylate ligand which might be capable of dinuclear carboxylate complex. Such a dinuclear carboxylate complex might be interesting as a new example of copper acetate type complexes.Objectives:The objective of the work is to synthesize a copper acetate type complex by using 3,4,5-tri-O-benzylgallic acid and to see a new feature of copper acetate compounds, by elucidating the crystal structure, magnetic property, and adsorption property for N2gas.Methods:Copper(II) 3,4,5-tri-O-benzylgallate has been synthesized by a reaction of 3,4,5-tri-O-benzylgallic acid and copper(II) nitrate at pH=9 condition. The isolated complex was characterized using single-crystal X-ray structure analysis, XRD analysis, UV-visible spectroscopy, IR spectroscopy, and temperature dependence of magnetic susceptibility.Results:The crystal structure shows a crystallographically centrosymmetric dinuclear molecule with four carboxylato-bridges and axial dimethylformamide molecules and crystal dmf molecules [Cu···Cu 2.6345(12) Å]. In the crystal, 1D supramolecular assembly by π-π interaction between the benzyl aromatic rings of dinuclear molecules was observed. Temperature dependence of magnetic susceptibilities showed a considerable antiferromagnetic interaction between the two copper(II) ions (2J = –214 cm–1). Type-II gas-adsorption property was observed for N2.Conclusion:A key-compound for the total synthesis of ellagitannins, 3,4,5-tri-O-benzylgallic acid (Htbng), was shown to be a new ligand for the synthesis of dinuclear copper acetate analogue with a lantern-type core, extending the realm of copper acetate clusters.

Aspirin Attenuates the Bioactivation of and Platelet Response to Vicagrel in Mice.

Vicagrel, a novel acetate analogue of clopidogrel, exerts more potent antiplatelet effect than clopidogrel in rodents. Relevant evidence indicated that aspirin and vicagrel are the drug substrate for carboxylesterase 2. Accordingly, it is deduced that concomitant use of aspirin could attenuate the bioactivation of and platelet response to vicagrel. To clarify whether there could be such an important drug-drug interaction, the differences in both the formation of vicagrel active metabolite H4 and the inhibition of adenosine diphosphate-induced platelet aggregation by vicagrel were measured and compared between mice treated with vicagrel alone or in combination with aspirin. The plasma H4 concentration was determined by liquid chromatography-tandem mass spectrometry, and the inhibition of platelet aggregation by vicagrel was assessed by whole-blood platelet aggregation. Compared with vicagrel (2.5 mg·kg) alone, concurrent use of aspirin (5, 10, or 20 mg·kg) significantly decreased systemic exposure of H4, an average of 38% and 41% decrease in Cmax and AUC0-∞ in mice when in combination with aspirin at 10 mg·kg, respectively. Furthermore, concomitant use of aspirin (10 mg·kg) and vicagrel (2.5 mg·kg) resulted in an average of 66% reduction in the inhibition of adenosine diphosphate-induced platelet aggregation by vicagrel. We conclude that aspirin significantly attenuates the formation of vicagrel active metabolite H4 and platelet response to vicagrel in mice, and that such an important drug-drug interaction would appear in clinical settings if vicagrel is taken with aspirin concomitantly when marketed in the future.

The Acetate Proton Shuttle between Mutually Trans Ligands

This work addresses a counterintuitive observation in the reactivity of the well-known ruthenium complexes [Ru(X)H(CO)(PiPr3)2], according to which the 5-coordinate chloro complex (X = Cl, 1) is less reactive toward phenylacetylene than its 6-coordinate acetate analogue (X = κO2-OC(O)Me, 3), since 3 undergoes a hydride-to-alkenyl-to-alkynyl transformation, whereas the reaction of 1 stops at the alkenyl derivative. The experimental kinetics of the key alkenyl-to-alkynyl step in the acetate complex are compared to the results of DFT calculations, which disclose the ability of the acetate not only to assist the alkyne C–H activation step via a CMD mechanism but also to subsequently deliver the proton to the alkenyl ligand. Possible consequences of this mechanistic resource connecting mutually trans ligands are briefly discussed on the basis of reported chemoselectivity changes induced by carboxylate ligands in 1-alkyne hydrosilylations catalyzed by this type of ruthenium complexes.

Leveraging a "Catch-Release" Logic Gate Process for the Synthesis and Nonchromatographic Purification of Thioether- or Amine-Bridged Macrocyclic Peptides.

Macrocyclic peptides containing N-alkylated amino acids have emerged as a promising therapeutic modality, capable of modulating protein-protein interactions and an intracellular delivery of hydrophilic payloads. While multichannel automated solid-phase peptide synthesis (SPPS) is a practical approach for peptide synthesis, the requirement for slow and inefficient chromatographic purification of the product peptides is a significant limitation to exploring these novel compounds. Herein, we invent a "catch-release" strategy for the nonchromatographic purification of macrocyclic peptides. A traceless catch process is enabled by the invention of a dual-functionalized N-terminal acetate analogue, which serves as a handle for capture onto a purification resin and as a leaving group for macrocyclization. Displacement by a C-terminal nucleophilic side chain thus releases the desired macrocycle from the purification resin. By design, this catch/release process is a logic test for the presence of the key components required for cyclization, thus removing impurities which lack the required functionality, such as common classes of peptide impurities, including hydrolysis fragments and truncated sequences. The method was shown to be highly effective with three libraries of macrocyclic peptides, containing macrocycles of 5-20 amino acids, with either thioether- or amine-based macrocyclic linkages; in this latter class, the reported method represents an enabling technology. In all cases, the catch-release protocol afforded significant enrichment of the target peptides purity, in many cases completely obviating the need for chromatography. Importantly, we have adapted this process for automation on a standard multichannel peptide synthesizer, achieving an efficient and completely integrated synthesis and purification platform for the preparation of these important molecules.

Anti-proliferative, apoptotic induction, and anti-migration effects of hemi-synthetic 1'S-1'-acetoxychavicol acetate analogs on MDA-MB-231 breast cancer cells.

Nine analogs of 1′S-1′-acetoxychavicol acetate (ACA) were hemi-synthesized and evaluated for their anticancer activities against seven human cancer cell lines. The aim of this study was to investigate the anti-proliferative, apoptotic, and anti-migration effects of these compounds and to explore the plausible underlying mechanisms of action. We found that ACA and all nine analogs were non toxic to human mammary epithelial cells (HMECs) used as normal control cells, and only ACA, 1′-acetoxyeugenol acetate (AEA), and 1′-acetoxy-3,5-dimethoxychavicol acetate (AMCA) inhibited the growth of MDA-MB-231 breast cancer cells with a half-maximal inhibitory concentration (IC50) value of <30.0 μM based on 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay results, and were selected for further investigation. DNA fragmentation assays showed that these three compounds markedly induced apoptosis of MDA-MB-231 cells. Western blot analysis revealed increased expression levels of cleaved PARP, p53, and Bax, while decreased expression levels of Bcl-2 and Bcl-xL were seen after treatment, indicating that apoptosis was induced via the mitochondrial pathway. Moreover, ACA, AEA, and AMCA effectively inhibited the migration of MDA-MB-231 cells. They also downregulated the expression levels of pFAK/FAK and pAkt/Akt via the integrin β1-mediated signaling pathway. Collectively, ACA and its hemi-synthetic analogs, AEA and AMCA are seen as potential anticancer agents following their abilities to suppress growth, induce apoptosis, and inhibit migration of breast cancer cells.

Identification of ACA‐28, a 1′‐acetoxychavicol acetate analogue compound, as a novel modulator of ERK MAPK signaling, which preferentially kills human melanoma cells

The extracellular signal-regulated kinase (ERK) signaling pathway is essential for cell proliferation and is frequently deregulated in human tumors such as melanoma. Melanoma remains incurable despite the use of conventional chemotherapy; consequently, development of new therapeutic agents for melanoma is highly desirable. Here, we carried out a chemical genetic screen using a fission yeast phenotypic assay and showed that ACA-28, a synthetic derivative of 1'-acetoxychavicol acetate (ACA), which is a natural ginger compound, effectively inhibited the growth of melanoma cancer cells wherein ERK MAPK signaling is hyperactivated due to mutations in the upstream activating regulators. ACA-28 more potently inhibited the growth of melanoma cells than did the parental compound ACA. Importantly, the growth of normal human epidermal melanocytes (NHEM) was less affected by ACA-28 at the same 50% inhibitory concentration. In addition, ACA-28 specifically induced apoptosis in NIH/3T3 cells which were oncogenically transformed with human epidermal growth factor receptor-2 (HER2/ErbB2), but not in the parental cells. Notably, the ACA-28-induced apoptosis in melanoma and HER2-transformed cells was abrogated when ERK activation was blocked with a specific MEK inhibitor U0126. Consistently, ACA-28 more strongly stimulated ERK phosphorylation in melanoma cells, as compared in NHEM. ACA-28 might serve as a promising seed compound for melanoma treatment.

An analysis of clinical trials on the registration of similars of the original disease-modifying therapies

The article discusses the design and results of recently published study of an analog of the original glatiramer acetate. The necessity of the correct planning and analysis of the data of such studies is stressed, showing equal efficacy, tolerability and safety of analog and original drug. The optimal design of such studies, their duration, selection of primary endpoint, adequate assessment of clinical and MRI changes and side-effects are discussed. The authors reckon that it is impossible to plan studies the results of which are based on the design, i.e. the absence of differences from the original drug. The authors invite specialists in MS to participate in the discussion.