Design, Synthesis and Cytotoxic Activity of Novel 2,3-disubstituted Pyrazine Derivatives

Pyrazine derivatives possess numerous pharmacological effects including but not limited to antiviral, antibiotic, antifungal, diuretic, anticonvulsant, antidiabetic, analgesic and anti proliferative effect. Consequently, interest has been shown by researchers in the field of pyrazine-based drug synthesis and many of the synthesized derivatives succeeded to reach the clinical field. A promising research discipline was concerned in utilizing the antiproliferative and cytotoxic activity of pyrazine derivatives -that is attributed to various mechanisms one of which is protein kinase inhibition- in designing new anti-cancer agents. In this study a set of disubstituted pyrazine derivatives has been designed and synthesized through a sequential nucleophilic substitution of chlorine atoms of 2,3-dichloropyrazine with amines or other nucleophiles. The synthesized derivatives were purified using several chromatographic techniques, and characterized by (1H-NMR, 13C-NMR, FT-IR, and MS (ESI)) spectroscopy. The mono-substituted pyrazine derivative A-7 (7) and three of its disubstituted analogues (YAN1(18), YAN-2 (19), and YAN-3(20)) were in vitro screened for their biological activity against two forms of acute myeloid leukemia cells (Molm-13). The viability of the cells was determined using WST-1 assay. Initial results of the tested derivatives showed that A-7 (7) was more potent than its analogues with IC50 of 18 and 39 µM against Molm-13 (sh-p53) and Molm-13 (empty vector) respectivelyThe biological activity of mono and disubstituted pyrazine derivatives was predicted using PASS software. Initial results demonstrated that A13 (13), A14 (14), YAN-7 (24), and YAN-8 (25) exhibited predicted activities as antineoplastic agents and signal transduction pathway inhibitors with relatively high Pa values. The previously mentioned compounds shared also the same mechanism of action “protein kinase inhibitor” with Pa values larger than 0.8SAR derived from PASS and initial biological activity screening results proved that the activity of the synthesized derivative is highly affected by the site and type of the substituent on the pyrazine ring. 2,3-disubstituted derivatives showed better Pa values when compared to the corresponding 2,5-disubstituted ones. In addition, amine substituents at positions 2 and 3 of pyrazine ring were preferred over alkoxide substituents in terms of antineoplastic activity. It was noticed that 1-(5-trifluoromethylpyridin-2-yl)-piperazine and 2-aminopyridine pharmacophores were the most active amine substituents. In order to gain an insight into the binding mode of pyrazine derivatives with CDK-2, a series of sixteen derivatives were docked with inactive monomeric cyclin dependent kinase-2 using SwissDock software. Results were compared with ‘Aloisine B‟, a well-known CDK-2 inhibitor. In terms of binding mode, pyrazine derivatives occupied the CDK-2 ATP binding site and made hydrogen bonds to the kinase backbone within the hinge sequence that links the two lobes of the kinase. The docked derivatives exhibited different binding affinities to the target, YAN-8 (25) showed the highest full fitness value (-1422.14 kcal/mol) among the synthesized derivatives. Moreover, both the full fitness and energy values indicated that YAN-8 (25) has higher affinity to the target in comparison to the known inhibitor Aloisine B (-1406.92 kcal/mol). Finally, the concept of drug likeness of the synthesized derivatives was investigated using the rule of five. Results revealed that all of the tested derivatives successfully met the rule of 5requirements except YAN-9 (26) and YAN-10 (27) which possessed molecular weights larger than 500 Daltons.

Recent Advances in Minisci-Type Reactions.

Reactions that involve the addition of carbon-centered radicals to basic heteroarenes, followed by formal hydrogen atom loss, have become widely known as Minisci-type reactions. First developed into a useful synthetic tool in the late 1960s by Minisci, this reaction type has been in constant use over the last half century by chemists seeking to functionalize heterocycles in a rapid and direct manner, avoiding the need for de novo heterocycle synthesis. Whilst the originally developed protocols for radical generation remain in active use today, they have been joined in recent years by a new array of radical generation strategies that allow use of a wider variety of radical precursors that often operate under milder and more benign conditions. The recent surge of interest in new transformations based on free radical reactivity has meant that numerous choices are now available to a synthetic chemist looking to utilize a Minisci-type reaction. Radical-generation methods based on photoredox catalysis and electrochemistry have joined approaches which utilize thermal cleavage or the in situ generation of reactive radical precursors. This review will cover the remarkably large body of literature that has appeared on this topic over the last decade in an attempt to provide guidance to the synthetic chemist, as well as a perspective on both the challenges that have been overcome and those that still remain. As well as the logical classification of advances based on the nature of the radical precursor, with which most advances have been concerned, recent advances in control of various selectivity aspects associated with Minisci-type reactions will also be discussed

Development of hydrogen isotope exchange methodologies for the deuteration of aromatic substrates

This thesis entails the development of practical and cost-efficient deuteration methodologies. The first C–H activation and deuteration of aromatic substrates using an earth-abundant manganese catalyst and transient directing groups was reported. Secondly, the transient directing group strategy was transferred to a ruthenium-catalyzed hydrogen isotope exchange reaction. Lastly, the electronic characteristics of pyridine derivatives were harnessed for a transition metal-free deuteration protocol. The results are expected to inspire future developments in sustainable hydrogen isotope exchange.In dieser Dissertation wurden praktische und kosteneffiziente Deuterierungsreaktionen entwickelt. Die erste C-H-Aktivierung und Deuterierung von aromatischen Substraten mittels eines häufig vorkommenden Mangankatalysators und transienter dirigierender Gruppen (TDG) wird beschrieben. Weiterhin wurde die TDG-Strategie auf eine rutheniumkatalysierte Isotopenaustauschreaktion übertragen. Schließlich wurden die elektronischen Eigenschaften von Pyridinderivaten für eine übergangsmetallfreie Deuterierung genutzt. Es wird erwartet, dass die Ergebnisse weitere nachhaltige Deuterierungen inspirieren

Alkali-metal-mediated synergistic effects in polar main group organometallic chemistry

The development of synthetic chemistry since the early 1900s owes much to the service of organolithium reagents. Brilliant bases (e.g., deprotonating C–H bonds), nucleophiles (e.g., adding to unsaturated molecules), and transfer agents (e.g., delivering ligands to other metals), these versatile virtuosi and to a lesser extent the organic derivatives of the other common alkali metals sodium and potassium have proved indispensable in both academia and technology. Today these monometallic compounds are still utilized widely in synthetic campaigns, but in recent years they have been joined by an assortment of bimetallic formulations that also contain an alkali metal but in company with another metal. These bimetallic formulations often exhibit unique chemistry that can be interpreted in terms of synergistic effects, for which the alkali metal is essential, though it is often the second metal that performs the synthetic transformation. Here, this “alkali-metal-mediated” chemistry is surveyed focusing mainly on bimetallic formulations containing two alkali metals or an alkali metal paired with magnesium, calcium, zinc, aluminum, or gallium. In this International Year of the Periodic Table (IYPT), we ponder whether a Pairiodic Table of Element Pairs will emerge in the future

Iron-catalyzed cross-coupling of arylboronic acids with unactivated N-heterocycles and quinones under microwave heating

Traditional C-C cross-coupling reactions generally rely on the use of expensive and sometimes toxic metal catalysts, such as palladium or ruthenium. These methods generally require two functionalized reagents, which can increase reaction cost. In the interests of sustainability and reduced costs there has been considerable interest in catalysis using earth-abundant metals, such as iron, as well as in C-H activation reactions. One example of a C-H activation reaction is the Minisci reaction, which is a radical reaction that couples N-heteroarenes to a variety of organic species. Recently a variation of the Minisci reaction was discovered in which arylboronic acids, which are relatively cheap and easily available, are coupled to N-heteroarenes or quinones using either a silver or iron catalyst. This process occurs under air and at low temperatures, but requires long reaction times, has a somewhat limited scope, and is not regioselective. This thesis concerns the application of microwave heating to this reaction, in an attempt to mitigate these issues. Microwave heating has not been previously applied to the Minisci reaction, and in fact there are relatively few reports on radical reactions under microwave heating. The reaction between pyrazine and arylboronic acids under microwave heating was first optimized. Ultimately, optimization led to similar product yields, but reactions that previously required 12 — 48 h could be conducted in 25 min. The reaction scope was then examined. The scope of arylboronic acids when reacted with pyrazine was somewhat limited, as strong electron-withdrawing and electron-donating groups were not tolerated. Examination of the reaction mixtures revealed that two previously unobserved side reaction were taking place; first, a reaction in which the boronic acid moiety was replaced by a hydroxyl group, and second, N-heteroarene homo-coupling. The reaction scope with quinones was found to be similar to literature reports, but reactions still occurred at a much higher rate. The reaction was successfully extended to hydroquinones, but attempts to further expand scope to enones, imines, and other conjugated compounds were unsuccessful. Finally, the scope of reactions with N-heteroarenes was examined and was found to be similar to literature reports. The application of microwave heating did not significantly affect the regiochemical outcomes of the reaction

Org. semin. abstr.

Issued by: University of Illinois, Department of Chemistry and Chemical Engineering, 1962-1963/semester I-; University of Illinois at Urbana-Champaign, Department of Chemistry, <1982-83-

The application of ESCA to structure and bonding with particular reference to synthesis and surface modification of polymers

Electron mean free paths as a function of kinetic energy have been measured by the substrate overlayer technique forin-situ polymerised films of polyparaxylylene, using a Ti(_ka1,2) (hv = 4510 eV) X-ray source. The results are compared with those previously reported at lower kinetic eneraies using Mg(_ka1,2) (1254 eV) and A1(_ka1,2) (1487 eV) photon sources ESCA is used to study structure, bonding and reactivity of polymeric materials, in particular those prepared by R.F. (radio-frequency), "glow discharge techniques", (plasma polymerisation) .Plasma polymerised films of perfluoropyridine have been investigated for a range of operating parameters, in both free-standing and in-situ reactors. A comparison of the stoichiometries and rates of deposition has been drawn with plasma polymers produced under comparable conditions from perfluoro and pentafluorobenzenes. Ultra thin polymers produced by plasma techniques from three isomeric perfluorinated diazines (pyrazine, pyrimidine and pyridazine) have been investigated. The polymer produced from the 1,2-diazine is discussed in some detail. A combination of ESCA and microanalytical studies show that the C:F and C:N stoichiometrics are closely similar to those for the starting monomers, over a range of operating parameters. The surface hydrolysis of these polymers with water as a function of time has been studied. The rates of polymer deposition are discussed as a function of the composite parameter W/FM. The rates of deposition reveal distinctive differences between the isomeric diazines and those of plasma polymer films for isomeric fluorinated benzenes. Laminate films based on LDPE and PET adhesively bonded with polyurethane adhesives have been investigated by ESCA. The change of surface chemistry of these films has been compared with the non-laminated base polymer of LDPE and PET. Migration and segregation phenomena in the laminates has been investigated. ESCA has been used to investigate the surface chemistry of heat treated LDPE (low and high-slip agent) and PET. The results indicate that thermally promoted reactions at the surface may well be different than those in the bulk