Synthesis of benzofuran derivatives—II A new synthesis of visnagin

Starting with 2-methyl-5:7-dihydroxychromone, an allyl group is introduced into the 6-position by Claisen migration of a 5-allyl ether. The initial protection of the 7-hydroxyl is best effected by tosylation. If the tosyl group is removed before Claisen migration and the C-allyl compound subjected to ozonolysis and ring closure, norvisnagin is obtained in a poor yield and can be methylated to visnagin. In an alternative method the tosyl group is removed just before ozonolysis. For this purpose the previous methylation of the 5-position is advantageous. This route gives visnagin directly in good yield.     

Fluxional sulfonyl derivatives of troponoids and colchicinoids

In what represents the first examples of fluxional sulfonyl derivatives, the tosyl group in the couple 4-isopropyltropone/6-isopropyltropone (3/4), the tosyl or mesyl groups in the couple colchicine/isocolchicine (5/6 or 7/8), and the tosyl group in the couples of colchicinoids 9/10 and 11/12, were observed to undergo thermally-induced shift between the two tropolone-like oxygen atoms, likely via a bipyramidal intermediate; recycling of tosylates or mesylates of biologically inactive isocolchicinoids into the corresponding tosylates or mesylates of biologically active colchicinoids affords synthetic value to the unselective tosylation or mesylation of colchiceine.     

Synthese totale de deux ethoxycarbonyl-4 cephemes fonctionnalises ou non en position 7 par un groupement phtalimido

The total synthesis of two 4-ethoxycarbonyl cephems is described. For one of these, an amino group at the 7 position, protected as a phtalimido, is introduced. This modification provides a structure which closely resembles that of biologically active cephalosporins.     

Synthesis of 4-alkoxy-8-hydroxyquinolines

Quinolines with a hydroxyl group at the 8-position and an alkoxy group at the 4-position are rare compounds. In this paper the synthesis of five 4-alkoxy-8-hydroxyquinolines is reported. The key reaction in the synthetic route is a selective protection of the hydroxyl group at C-atom 8 in 4,8-dihydroxyquinoline with a tosyl group and the hydrolytic removal of the protective group after the alkylation. The tosyl group is stable during the alkylations with various alkylating agents in the presence of sodium hydride.     

Facile and regioselective synthesis of novel 2,4-disubstituted-5-fluoropyrimidines as potential kinase inhibitors

2,4-Disubstituted-5-fluoropyrimidine is a biologically active molecular core seen in various anticancer agents such as 5-fluorouracil (5-FU). As part of a programme aimed at discovering kinase inhibitors, routes to two series of novel compounds (5-fluoropyrimidine-2-carboxamides and 5-fluoropyrimidine-4-carboxamides) were successfully executed. For the first series, regioselective substitution at the 4-position of the pyrimidine with an amine (HNR¹R²) was achieved, followed by preparation of the amide at the 2-position. The route to the second series involved introduction of the methoxy protecting group at the 4-position, which allowed subsequent amine substitution to occur at the 2-position. The 4-amide substituent was finally introduced by direct conversion of the 4-methoxy into a 4-chloro group followed by transformation into an amide by palladium catalysis.     

New approach to asymmetrically substituted methoxypyrazines, derivatives of wine flavors

An original synthetic route to asymmetrically substituted methoxypyrazine (MP) derivatives is described. The first step of the synthesis is achieved by condensation of 1,2-aminoalcohols with Boc-protected aliphatic aminoacids followed by cycloimine formation and aromatization via chlorination. Introduction of methoxy group was then achieved by alkoxy-de-halogenation. The use of primary or secondary aminopropanol enabled the direct and selective introduction of methyl group, in 5- or 6-position, which can be easily functionalized. Aromatization of diketopiperazine, prepared from l-valine and l-glutamic acid dimethyl ester, made possible a direct introduction of a functionalized alkyl chain. These reactions are also suitable for the synthesis of naturally-occurring MPs such as wine flavor components and biologically active substances.     

Selective synthesis of 14β-amino taxanes

The base induced deprotonation of H-14 of 7-triethylsilyl- (7-TES-) and 7-tert-butoxycarbonyl- (7-BOC-) protected 13-oxo-baccatins gave the corresponding enolates, which were selectively aminated with electrophilic nitrogen donors, such as azodicarboxylates and tosyl azide. In particular, tosyl azide gave the corresponding 7-BOC- and 7-TES-13-oxo-14β-azido-baccatin III. Alternatively, the last compound was prepared via NaN₃ induced azidation of the 13-silyl enol ether of 7-TES-13-oxo-baccatin III under oxidative (cerium ammonium nitrate) conditions. The 13-silyl enol ether was obtained in a multistep process by DBU induced silylation of 7-TES-13-oxo-baccatin III. The 7-TES-13-oxo-14β-azido-baccatin III was used as a key intermediate for the synthesis of a new family of antitumour taxanes containing amino based functional groups at the C-14 position, such as: 14β-azido, 14β-amino, 14β-amino 1, 14-carbamate, 14β-amino 1, 14-thiocarbamate, and 14β-amino N-tert-butoxycarbonyl-1,14-carbamate.     

Design, synthesis, and characterization of a series of cytochrome P(450) 3A-activated prodrugs (HepDirect prodrugs) useful for targeting phosph(on)ate-based drugs to the liver

A new class of phosphate and phosphonate prodrugs, called HepDirect prodrugs, is described that combines properties of rapid liver cleavage with high plasma and tissue stability to achieve increased drug levels in the liver. The prodrugs are substituted cyclic 1,3-propanyl esters designed to undergo an oxidative cleavage reaction catalyzed by a cytochrome P(450) (CYP) expressed predominantly in the liver. Reported herein is the discovery of a prodrug series containing an aryl substituent at C4 and its use for the delivery of nucleoside-based drugs to the liver. Prodrugs of 5'-monophosphates of vidarabine, lamivudine (3TC), and cytarabine as well as the phosphonic acid adefovir were shown to cleave following exposure to liver homogenates and exhibit good stability in blood and other tissues. Prodrug cleavage required the presence of the aryl group in the cis-configuration, but was relatively independent of the nucleoside and absolute stereochemistry at C4. Mechanistic studies suggested that prodrug cleavage proceeded via an initial CYP3A-catalyzed oxidation to an intermediate ring-opened monoacid, which subsequently was converted to the phosph(on)ate and an aryl vinyl ketone by a beta-elimination reaction. Studies in primary rat hepatocytes and normal rats comparing 3TC and the corresponding HepDirect prodrug demonstrated the ability of these prodrugs to effectively bypass the rate-limiting nucleoside kinase step and produce higher levels of the biologically active nucleoside triphosphate.     

Nanoparticles Synthesis from Corn Cob (Xylan) and Their Potential Application as Colon-Specific Drug Carrier

Summary: Corn Cob based Xylan, a natural polysaccharide extracted from agro-waste may be used as a tool to deliver drugs especially to the colon because of their timely retention in the physiological environment of stomach and small intestine and can only be degraded in colon by vast anaerobic microflora like bifidobacterium. The objective of present research study is to incorporate the drug namely 5-aminosalicylic acid (5-ASA) into xylan macromolecular backbone, either by surface adsorption or by intermolecular covalent bond formation so that absorption of drugs is prevented in upper gastrointestinal tract (GIT). To achieve the above objective, xylan prodrug of 5-ASA was synthesized via activation of carboxylic acid with N,N-carbonyldiimidazole. The structure of obtained xylan prodrug was evaluated by means FT-IR spectroscopy. The ester carbonyl absorption band was observed at 1690 cm⁻¹ in addition to the bands originated from 5-ASA and xylan. The resulting prodrug and xylan itself assembled into spherical nanoparticles were analyzed by scanning electron microscopy. The prodrug of 5-ASA was synthesized which might be active against inflammatory bowel diseases, a novel thought towards advanced drug delivery from xylan based nanoparticles will be presented.     

Synthesis and comparison of physicochemical, transport, and antithrombic properties of a cyclic prodrug and the parent RGD peptidomimetic

Cyclic prodrug 1 was derived from RGD peptidomimetic 2 by linking the amino and carboxylic acid groups via an (acyloxy)alkoxy linker. The formation of a cyclic prodrug can transiently alter the physicochemical properties of the RGD peptidomimetic. Cyclic prodrug 1 was synthesized via the key intermediate 8, and the synthesis of this key intermediate was accomplished using two different routes. Cyclic prodrug 1 has a smaller hydrodynamic radius and higher membrane interaction potential than those of the parent RGD peptidomimetic 2. The cell membrane permeation of cyclic prodrug 1 is twice that of the parent peptidomimetic 2. The prodrug-to-drug conversion can be carried out in isolated porcine esterase as well as human plasma. The cyclic prodrug is more stable at pH 4 than pH 7, and is very unstable at pH 10. The cyclic prodrug has antithrombic activity, suggesting that it can be converted to the RGD peptidomimetic in platelet-rich plasma (PRP).     

An Expeditious Synthesis of β-Indolylketones Catalyzed by p-Toluenesulfonic Acid (PTSA) Using Ultrasonic Irradiation

The investigation of the chemistry of indoles has been, and continues to be, one of the most active areas of heterocyclic chemistry.[1] In particular, β-indolylketones have received much attention as important building blocks for the synthesis of many natural products and other biologically active compounds.[2] In continuation of our work in the synthesis of indole derivates,[3] we describe the remarkable catalytic of PTSA as a cheaper catalyst in ultrasound-accelerated Michael reaction of indole with α, β-unsaturated ketones (2), which provide one of the most efficient routes to the synthesis of β-indolyketones. In all cases, the substitution on the indole nucleus occurred exclusively at the 3-position, and N-alkylation products have not been observed. In addition, the structure of 3a was further confirmed by single crystal X-ray crystallography.     

Self-association of an amphipathic helix peptide inhibitor of HIV-1 integrase assessed by electro spray ionization mass spectrometry in trifluoroethanol/water mixtures

Establishing the auto-associative properties of a molecule in solution can be important for determination of its structure and function. EAA26 (VESMNEELKKIIAQVRAQAEHLKTAY) has been designed to inhibit HIV-1 integrase via formation of a stable coiled-coil structure with a nearly homologous segment in the enzyme. The latter catalyzes the permanent incorporation of a DNA copy of the retrovirus genome into host cell DNA, and is thus essential to the life of the retrovirus. This makes integrase an obvious drug target in the therapy of AIDS. The present work has demonstrated, using electrospray ionization mass spectrometry (ESI-MS), that EAA26 is monomeric in pure water, and tetrameric and dimeric at respectively low and medium concentrations of 2,2,2-trifluoroethanol (TFE), and again monomeric at higher TFE concentrations. Thus, the apolar solvent TFE may contribute to either stabilization or disruption of the intermolecular hydrophobic contacts depending on its concentration in aqueous solution. Previous NMR and ultracentifugation results are thus confirmed, indicating the reliability of ESI-MS for defining the self-association state of biologically relevant peptides in both water and organic-water solutions.     

Synthesis of Xylan-Click-Quaternized Chitosan via Click Chemistry and Its Application in the Preparation of Nanometal Materials

For the high-valued utilization of hemicelluloses and for realizing the controllable synthesis of NPs, this paper’s aim is to combine xylan, chitosan and nanometal materials at the same time. In this research study, firstly, propargyl xylan was synthesized via nucleophilic substitution reaction between xylan and propargyl bromide in NaOH solution. On the other hand, a tosyl group was introduced onto the 6th position of synthesized quaternized chitosan (QCS), and the azide group replaced the tosyl group to obtain 6-amido-QCS (QCS-N₃). The synthesis conditions of the above reactions were optimized. Subsequently, the novel xylan-click-QCS polymer was obtained via click reaction between terminal alkyne groups on the xylan chains and azide groups on QCS. Then, AgNPs and AuNPs were synthesized by adopting the xylan-click-QCS polymer as the reducing and stabilizing agent, and the reaction conditions were optimized to obtain well-dispersed and highly stable nanoparticles. There were two kinds of Ag nanomaterials, with diameters of 10~20 nm and 2~5 nm, respectively, indicating the formation of Ag nanoclusters, except for Ag nanoparticles, in this reaction. The diameter of the synthesized AuNPs was 20~30 nm, which possessed a more uniform size distribution. The Ag nanoclusters with a smaller size (2~5 nm) could inhibit MCF-7 cell proliferation effectively, indicating their application potential in cancer therapy. The study gives a new approach to the high-value utilization of biopolymers.     

Synthesis of functionalized furopyrazines as restricted dipeptidomimetics

Herein, an efficient synthetic approach to a furopyrazine scaffold with four points of diversity, starting from 2(1H)-pyrazinones, with dipeptomimetic properties, is presented. R-groups corresponding to amino acid side chains were introduced during the 2(1H)-pyrazinone and subsequent furopyrazine formation. The furopyrazine scaffold was further functionalized with an amino- and a carboxy-terminus resulting in a conformationally restricted dipeptidomimetic scaffold. The carboxy-terminus was introduced via a chemoselective vinylation of the 7-position followed by oxidative cleavage, while the amino-terminus was obtained via Buchwald–Hartwig amidation of the 2-position of the scaffold. The versatility of the synthetic method was demonstrated by the synthesis of a small library of diversely substituted furopyrazines having various amino acid side chains on the four points of diversity. Evaluation with an X-ray structure of the scaffold and computational analysis supports the exploitation of the furopyrazine scaffold as a restricted dipeptide mimic, which can mimic the two central residues of a β-turn.     

A new synthesis of lysophosphatidylcholines and related derivatives. Use of p-toluenesulfonate for hydroxyl group protection

A new stereoselective synthesis of lysophosphatidylcholines is reported. The synthesis is based upon (1) the use of 3-p-toluenesulfonyl-sn-glycerol to provide the stereocenter for construction of the optically active lysophospholipid molecule, (2) tetrahydropyranylation of the secondary alcohol function to achieve orthogonal protection of the sn-2- and sn-3-glycerol positions, and (3) elaboration of the phosphodiester headgroup using a 2-chloro-1,3,2-dioxaphospholane/trimethylamine sequence. In the course of developing the synthesis it has been discovered that methoxyacetate displacement of the sn-3-p-toluenesulfonate yields a reactive methoxyacetyl ester, which in turn can be selectively cleaved with methanol/tert-butylamine, while the ester group at the sn-1-position remains unaffected. The sequence has been shown to be suitable for preparation of spectroscopically labeled lysophosphatidylcholines. One of these compounds was readily converted to a double-labeled mixed-chain phosphatidylcholine applicable for real-time fluorescence resonance energy transfer (FRET) assay of lipolytic enzymes. In addition, the work led to new synthetic strategies based on chemoselective manipulation of the tosyl group in the presence of other base-labile groups such as FMOC derivatives that are often used for the protection of amino and hydroxyl groups in syntheses.     

Prodrugs of 9-benzyl-8-hydroxy-2-(2-hydroxyethylthio)adenine: potent interferon inducing agents in monkeys

In order to improve the oral bioavailability of 9-benzyl-8-hydroxy-2-(2-hydroxyethylthio)adenine (SM-295072), a potent interferon (IFN) inducing agent, we synthesized prodrugs of it by utilizing the hydroxy groups at the C(2)-side chain and/or the C(8)-position. The carbonate prodrug at the C(8)-position was more effective than that at the C(2)-side chain for oral absorption in rats. Among the compounds prepared, compound 6 demonstrated the most preferable prodrug properties, and the maximum plasma concentration of 6 was approximately 4-fold higher than that of SM-295072. Furthermore, compound 6 was dose-dependently absorbed in monkeys by oral administration, and exhibited a potent IFN-inducting activity that correlated well with its plasma drug concentration.     

Photochemical ring opening of 7-benzoyl- and 7-methoxycarbonyldibenzonorcaradienes. competing 1,2-hydrogen shift and cyclization reactions of 1,3-diradicals

[see reaction]. The UV irradiation of dibenzonorcaradienes bearing an acyl or alkoxycarbonyl substituent in the 7-position results in formation of substituted phenanthrenes, as well as cis-trans isomerization of the starting material. This reaction apparently proceeds via intermediate formation of a short-lived (tau = 1-20 ns) 1,3-diradical, which is produced by photochemical cleavage of one cyclopropane bond, while no evidence of alpha-carbonylcarbene formation was found.     

Squaric acid-based peptidic inhibitors of matrix metalloprotease-1

[structure: see text] A series of squaric acid-peptide conjugates were synthesized and evaluated as inhibitors of MMP-1. The cyclobut-3-enedione core was substituted at the 3-position with several functional groups, such as -N(alkyl)OH, -NHOH, and -OH, that are designed to bind to the zinc atom in the active site of the metalloprotease. The 4-position of the cyclobut-3-enedione was derivatized with mono- or dipeptides that are designed to bind in the S1' and S2' subsites of the enzyme, and position the metal chelating group appropriately in the active site for binding to zinc. Positional scanning revealed that -N(Me)OH provided the highest level of inhibition among the chelating groups that were tested, and Leu-Tle-NHMe was the preferred amino acid sequence. A combination of these groups yielded an inhibitor with an IC50 value of 95 microM. For one inhibitor, conversion of one of the carbonyl groups on the cyclobut-3-enedione core to a thiocarbonyl group resulted in a 18-fold increase in potency, and yielded a compound with an IC50 value of 15 microM.     

Thionium ion initiated medium-sized ring formation: the total synthesis of asteriscunolide D

The first synthesis of the biologically active humulene natural product asteriscunolide D has been accomplished in nine steps without the use of protecting groups. The challenging 11-membered ring was forged via a diastereoselective thionium ion initiated cyclization, which constitutes a formal aldol disconnection to form a strained macrocycle. A stereospecific thioether activation-elimination protocol was developed for selective E-olefin formation, thus providing access to the most biologically active asteriscunolide. The absolute stereochemical configuration was established by the Zn-ProPhenol catalyzed enantioselective addition of methyl propiolate to an aliphatic aldehyde to afford a γ-hydroxy propiolate as a handle for butenolide formation via Ru-catalyzed alkene-alkyne coupling.     

Novel Polyhedral Silsesquioxanes [POSS(OH)32] as Anthracycline Nanocarriers—Potential Anticancer Prodrugs

Anthracyclines belong to the anticancer drugs that are widely used in chemotherapy. However, due to their systemic toxicity they also exert dangerous side effects associated mainly with cardiovascular risks. The pathway that is currently often developed is their chemical and physical modification via formation of conjugated or complexed prodrug systems with a variety of nanocarriers that can selectively release the active species in cancer cells. In this study, six new nanoconjugates were synthesized with the use of polyhedral oligosilsesquioxanes [POSS(OH)₃₂] as nanocarriers of the anticancer drugs anthracyclines—doxorubicin (DOX) and daunorubicin (DAU). These prodrug conjugates are also equipped with poly(ethylene glycol) (PEG) moieties of different structure and molecular weight. Water-soluble POSS, succinic anhydride modified (SAMDOX and SAMDAU) with carboxylic function, and PEGs (PEG1, PEG2 and PEGB3) were used for the synthesis. New nanoconjugates were formed via ester bonds and their structure was confirmed by NMR spectroscopy (¹H-NMR, ¹³C-NMR, ¹H-¹³C HSQC, DOSY and ¹H-¹H COSY), FTIR and DLS. Drug release rate was evaluated using UV-Vis spectroscopy at pH of 5.5. Release profiles of anthracyclines from conjugates 4–9 point to a range of 10 to 75% (after 42 h). Additionally, model NMR tests as well as diffusion ordered spectroscopy (DOSY) confirmed formation of the relevant prodrugs. The POSS-anthracycline conjugates exhibited prolonged active drug release time that can lead to the possibility of lowering administered doses and thus giving them high potential in chemotherapy. Drug release from conjugate 7 after 42 h was approx. 10%, 33% for conjugate 4, 47% for conjugate 5, 6, 8 and 75% for conjugate 9.