Ethyl Ester Analogue Research Articles

Borylation via iridium catalysed C-H activation: a new concise route to duocarmycin derivatives.

The synthesis of the ethyl ester analogue of the ultrapotent antitumour antibiotic seco-duocarmycin SA has been achieved in eleven linear steps from commercially available starting materials. The DSA alkylation subunit can be made in ten linear steps from the same precursor. The route involves C-H activation at the equivalent of the C7 position on indole leading to a borylated intermediate 9 that is stable enough for peptide coupling reactions but can be easily converted to the free hydroxyl analogue.

Coordination Chemistry and f-Element Complexation by Diethylenetriamine-N,N″-bis(acetylglycine)-N,N',N″-triacetic Acid.

Potentiometric and spectroscopic techniques were used to evaluate the coordination behavior and thermodynamic features of trivalent f-element complexation by diethylenetriamine-N,N″-bis(acetylglycine)-N,N',N″-triacetic acid (DTTA-DAG) and its di(acetylglycine ethyl ester) analogue [diethylenetriamine-N,N″-bis(acetylglycine ethyl ester)-N,N',N″-triacetic acid (DTTA-DAGEE)]. Protonation constants and stability constants of trivalent lanthanide complexes (except Pm3+) were determined by potentiometry. Six protonation sites and three metal-ligand complexes [ML2-, MHL-, and MH2L(aq)] were quantified for DTTA-DAG. Four protonation sites and one metal-ligand complex [ML(aq)] were observed for DTTA-DAGEE, consistent with the presence of two ester groups. Absorption spectroscopy was utilized to measure the stability constants for complexation of trivalent neodymium and americium by DTTA-DAG and trivalent neodymium by DTTA-DAGEE. The coordination environment of trivalent europium in the presence of DTTA-DAG was investigated at various acidities by luminescence lifetime measurements. Decay constants indicate one water molecule in the inner coordination sphere across the 1.0 < pH < 5.5 range, presumably due to octadentate coordination by DTTA-DAG. A trans-lanthanide pattern of complex stabilities for DTTA-DAG was found to be analogous to that observed for DTPA, with a ∼106 reduction of the complex stability. The lessened strength of complexation, relative to DTPA, was attributed to significant reduction of the total ligand basicity for DTTA-DAG due to the electronic influence of amide functionalization. When DTTA-DAG is used as an aqueous holdback complexant in liquid-liquid distribution experiments, the preferential coordination of Am3+ in the aqueous environment offers efficient An/Ln differentiation. The separation extends to pH 2 conditions, where the kinetics of phase transfer in such liquid-liquid systems are aided by the acid-catalyzed dissociation of a metal/aminopolycarboxylate complex.

Enaminones 11. An examination of some ethyl ester enaminone derivatives as anticonvulsant agents

In this paper, we investigated the previously synthesized anticonvulsant enaminone ethyl ester analogs using the computational gaussian 03 programs. The significant chemical features of the enaminone compounds that lead to positive anticonvulsant activity were identified. From our analyses, we believe that the neutrality of the phenyl ring may be important for binding in the hydrophobic pocket of the active site and that the binding of the phenyl substituent is the main reason why some analogs are active and others are inactive.

2-Chlorophenyl Zinc Bromide: A Convenient Nucleophile for the Mannich-Related Multicomponent Synthesis of Clopidogrel and Ticlopidine

A methodological study devoted to the Mannich-like multicomponent synthesis of the antiplatelet agent (±)-clopidogrel (7) and the ethyl ester analogue 6 is described. The process involves the formation of 2-chlorophenyl zinc bromide (2) and its subsequent reaction with an alkyl glyoxylate and 4,5,6,7-tetrahydrothieno[3,2-c]pyridine (3). We demonstrate that the organozinc reagent 2 also constitutes a very convenient nucleophile for the multicomponent synthesis of the benzylamine core of ticlopidine (9).

Discovery of Pyrrole−Indoline-2-ones as Aurora Kinase Inhibitors with a Different Inhibition Profile

A series of pyrrole-indolin-2-ones were synthesized, and their inhibition profile for Aurora kinases was studied. The potent compound 33 with phenylsulfonamido at the C-5 position and a carboxyethyl group at the C-3' position selectively inhibited Aurora A over Aurora B with IC50 values of 12 and 156 nM, respectively. Replacement of the carboxyl group with an amino group led to compound 47, which retained the activity for Aurora B and lost activity for Aurora A (IC50=2.19 microM). Computation modeling was used to address the different inhibition profiles of 33 and 47. Compounds 47 and 36 (the ethyl ester analogue of 33) inhibited the proliferation of HCT-116 and HT-29 cells and suppressed levels of the phosphorylated substrates of Aurora A and Aurora B in the Western blots.

A new class of potential anti-tuberculosis agents: Synthesis and preliminary evaluation of novel acrylic acid ethyl ester derivatives

Novel acrylic acid ethyl ester derivatives were synthesized and evaluated as potential agents against Mycobacterium species. A versatile and efficient copper-catalyzed coupling process was developed and used to prepare a library of substituted acrylic acid ethyl ester analogs. Minimum inhibitory concentration assays indicated that two of these compounds 3 and 4 have greater in vitro activity against Mycobacterium smegmatis than rifampin, one of the current, first-line anti-mycobacterial chemotherapeutic agents. Moreover, members of this new class of compounds appear to exhibit a specific anti-mycobacterial effect and do not inhibit the growth of the other Gram-positive or Gram-negative species tested.

Effect of methylene spacers on the spectral, electrochemical, and structural properties of bis(4,4′-disubstituted-2,2′-bipyridyl) ruthenium(ii) dye analogues

Two new ruthenium complexes, [Ru(L1OMe)2(NCS)2] and [Ru(L2OMe)2(NCS)2] (where L1OMe = 2,2'-bipyridine-4,4'-di(methyl ethanoate) and L2OMe = 2,2'-bipyridine-4,4'-di(methyl propionate)), have been synthesized and characterized using spectroscopic and electrochemical techniques. The [Ru(L2OMe)2(NCS)2] complex has also been characterized by X-ray diffraction studies and reveals a distorted octahedral coordination geometry about the ruthenium center. Cyclic voltammetry studies of both complexes exhibit quasi-reversible Ru(II/III) couples and a number of ligand reduction events. The complex with one methylene spacer between the bipyridyl ligand and the methyl ester functional group, [Ru(L1OMe)2(NCS)2], was particularly unstable under reducing conditions. The properties of these complexes are compared with the ethyl ester analogue of the N3 photosensitizer [Ru(L0OEt)2(NCS)2].

Structural Insights into Drug Processing by Human Carboxylesterase 1: Tamoxifen, Mevastatin, and Inhibition by Benzil

Human carboxylesterase 1 (hCE1) exhibits broad substrate specificity and is involved in xenobiotic processing and endobiotic metabolism. We present and analyze crystal structures of hCE1 in complexes with the cholesterol-lowering drug mevastatin, the breast cancer drug tamoxifen, the fatty acyl ethyl ester (FAEE) analogue ethyl acetate, and the novel hCE1 inhibitor benzil. We find that mevastatin does not appear to be a substrate for hCE1, and instead acts as a partially non-competitive inhibitor of the enzyme. Similarly, we show that tamoxifen is a low micromolar, partially non-competitive inhibitor of hCE1. Further, we describe the structural basis for the inhibition of hCE1 by the nanomolar-affinity dione benzil, which acts by forming both covalent and non-covalent complexes with the enzyme. Our results provide detailed insights into the catalytic and non-catalytic processing of small molecules by hCE1, and suggest that the efficacy of clinical drugs may be modulated by targeted hCE1 inhibitors.

Synthesis and Evaluation of Lasonolide A Analogues.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Synthesis and evaluation of lasonolide A analogues

Homolasonolide A and 10-desmethyllasonolide A are biologically less active than lasonolide A. The ethyl ester analogue of lasonolide A exhibited higher activity than the parent compound in some biological test.

Synthesis and Characterization of New Ortho-Acetyl or Ortho-bis- p -aminophenoxy Phosphonate Monomers

Some new aryl phosphonic acid ethyl ester analogs of acetyl salicylic acids, and bis- p -aminophenoxy-benzo-phosphonic acid ethyl esters have been prepared in good yield. Characterization by spectroscopic techniques indicates that in the phosphorus NMR spectra a significant change in chemical shift values between the starting phenolic phosphonate and both the corresponding derivative is observed; thus this up-field shift is very diagnostic for this type of compounds.

Simultaneous Preparation of Both Enantiomers of Juvenile Hormones Labeled at C-10 with Tritium at High Specific Activity

We report an improved method for the synthesis of high specific activity insect [10-3H]juvenile hormones (JH) I, II, and III which affords both enantiomers of each in high optical purity. A synthetic route for JH I was modified to give higher yields and purity. We increased the specific activity of the synthetic [10-3H]JHs using normal phase liquid chromatography optimized to give near baseline resolution of [10-3H]JHs and unlabeled JHs. Racemic [10-3H]JHs and their corresponding diol metabolites were enantiomerically separated using a chiral column eluted with 2-propanol:hexane. Acidic hydration of the unnatural antipode of the [10-3H]JHs gives the diol antipode with the same stereochemistry as that from epoxide hydrolase action on the natural JH antipode. The [10-3H]JH diol enantiomers can also be resolved with the same chiral column using a more polar solvent. The synthesis of high specific activity chiral ethyl ester analogs of JH I and II can also be accomplished using this synthetic route.

Conversion-Dependent Molecular Weight of the Polymer in Free Radical Polymerization of Captodative Substituted (Acyloxy)acrylates

The radical homopolymerization of captodatively substituted methyl α-acetoxyacrylate (MAA) is studied by comparing it with that of the α-trifluoroacetoxy, the α-butyryloxy, and the ethyl ester analogs at 40 °C. The yield of the polymer is much influenced by the acyloxy substituents, and the polymer molecular weight increases with conversion in bulk MAA and ethyl ester polymerizations in contrast to other polymerizations. Dilution of the MAA polymerization system, however, results in no increase in the polymer molecular weight during the polymerization. Some polymer−polymer interactions between captive and dative moieties in MAA polymer are discussed on the basis of the measurement of the viscosity of the polymerization system and the polymer solution.

Antitrypanosomal effects of polyamine biosynthesis inhibitors correlate with increases in Trypanosoma brucei brucei S-adenosyl-L-methionine.

We reported recently that administration of ([(Z)-4-amino-2-butenyl]methylamino)-5'-deoxyadenosine (MDL 73811), an enzyme-activated irreversible inhibitor of S-adenosyl-L-methionine decarboxylase (AdoMetDC; EC 4.1.1.50), a key enzyme in the synthesis of spermidine, cures African trypanosome infections in mice. The precise mechanism of action of MDL 73811 was not clear because a rapid disappearance of trypanosomes from the bloodstream of treated rats occurred before significant depletion of spermidine. Administration of MDL 73811 to Trypanosoma brucei brucei-infected rats resulted in a 70% decrease in parasitaemia within 1 h and a complete disappearance of parasites by 5 h. The reduction in parasitaemia was accompanied by complete inhibition of AdoMetDC activity by 10 min after injection of MDL 73811; inhibition was sustained for at least 4 h. Polyamine levels in trypanosomes were unaffected during the first 1 h in which the marked decrease in parasitaemia was observed, but parasite AdoMet levels increased 20-fold within this time. In contrast, exposure of cultured mammalian cells to MDL 73811 resulted in only a 1.5-2-fold increase in AdoMet levels over a 6 h time course. Experiments with inhibitors of ornithine decarboxylase (ODC) also suggested that the increased AdoMet levels might be an important factor for antitrypanosomal efficacy. Trypanosomes taken from rats treated for 36 h with eflornithine, an inhibitor of ODC, were depleted of putrescine and had markedly decreased spermidine levels. These organisms also had less than 10% of control AdoMetDC activity, and had elevated decarboxy AdoMet (greater than 4000-fold) and AdoMet (up to 50-fold) levels. The methyl ester of alpha-monofluromethyl-3,4-dehydro-ornithine (delta-MFMO-CH3), which cures murine T. b. brucei infections, and the ethyl ester analogue of this compound (delta-MFMO-C2H5), which does not cure this infection, become ODC inhibitors upon hydrolysis and thus were tested for their effects on trypanosomal polyamines, AdoMet and decarboxy AdoMet levels. Although both esters of delta-MFMO depleted trypanosomal polyamines, AdoMet and decarboxy AdoMet levels were elevated in T. b. brucei from infected mice treated with delta-MFMO-CH3 but not in parasites from mice treated with the delta-MFMO-C2H5. These data suggest that inhibition of AdoMetDC, either directly with MDL 73811 or indirectly with inhibitors of ODC, apparently leads to a trypanosome-specific elevation of AdoMet. It is possible that major changes in AdoMet, rather than changes in polyamines, may be responsible for the antitrypanosomal effects of these drugs.

Novel 1,4-dihydropyridine calcium antagonists. II. Synthesis and antihypertensive activity of 3-(4-(substituted amino)phenylalkyl)ester derivatives.

Novel 1,4-dihydropyridine derivatives bearing 3-[4-(substituted amino)phenylalkyl]ester side chains were prepared and tested for their antihypertensive activity in spontaneously hypertensive rats. Most compounds showed a more potent antihypertensive effect and a longer duration of action than nicardipine. The derivatives with a benzhydrylpiperazinyl and a benzhydrylpiperidinyl group were distinctive. 2-[4-(4-Benzhydryl-1-piperazinyl)phenyl]ethyl methyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate (4e), its 4-(4-cyano-2-pyridyl) analogue (4f), its 3-[4-(4-benzhydryl-1-piperazinyl)phenyl]propyl ester analogue (4h), its 2-[4-(4-benzhydryl-1-piperidinyl)phenyl]ethyl ester analogue (4j), and its 2-[4-(1-benzhydryl-4-piperidinyl)phenyl]ethyl ester analogue (4k) were selected as candidates for further pharmacological investigations.

Determination of the partial benzodiazepine receptor agonist Ro 16-6028 in plasma by capillary gas chromatography with nitrogen-selective detection after conversion into the ethyl ester derivative

A highly sensitive capillary gas chromatographic method was developed to determine plasma levels of a novel partial benzodiazepine receptor agonist in man following the very low therapeutic doses required for anxiolysis. The compound was isolated from plasma by liquid-liquid extraction at basic pH, converted into the ethyl ester analogue by a two-step procedure, separated from plasma constituents by capillary gas chromatography and quantified by means of nitrogen-selective detection. Because of the thermolabile tert.-butyl ester function, the agonist could not be gas chromatographed without degradation. Formation of the far more stable ethyl ester analogue was achieved by treatment with hydrogen chloride in ethanol, followed by an ethylation step with diazoethane. The high sensitivity of the new method (about 100 pg/ml, using 1-ml plasma specimens) allowed the monitoring of plasma levels of the agonist for up to 8 h (about three elimination half-lives) after a single 0.1-mg oral dose to human volunteers. The practicability of the procedure was demonstrated by the analysis of more than 600 plasma samples from clinical studies performed with human volunteers.

スルガトキシン合成に関するモデル実験(第6報)スルガトキシンに対応するエチルエステル誘導体とその立体異性体の合成 その1

Dehydrated surugatoxin ethyl ester analogue 14 was prepared from bromo-nitroketone 11. Alkaline hydrolysis [2% MeONa-MeOH, tetrahydrofuran (THF), room temperature] of 14 gave an enamine derivative 15 which was treated with OsO4 in THF to give a mixture of cis-diols 16α and 16β. Selective reduction of 16α with borane-pyridine complex in AcOH followed by debenzylation of the resulting monool 17 with 90% trifluoroacetic acid at 50°C for 15 min afforded a desired surugatoxin derivative 18. The structure and stereochemistry of 18 was unequivocally determined in a single crystal X-ray diffraction analysis.

Antinociceptive potency ratios for (+)- and (-)-4-dimethylamino-2,2-diphenylpentanoate (the ethyl ester analogue of methadone).

Antinociceptive potency ratios for (+)- and (-)-4-dimethylamino-2,2-diphenylpentanoate (the ethyl ester analogue of methadone).

Juvenile-Hormone Esterase in Insect Development: A Comparative Study

Juvenile-hormone (JH) esterase activity is found in the hemolymph of last larval (nymphal) instars of Periplaneta brunnea, Schistocerca vaga, Samia cynthia, and Tenebrio molitor, but not in Sarcophaga bullata. In Samia cynthia larvae maximum activity coincides with the JH inactivation preceding metamorphosis; in young Hyalophora cecropia moths the increase in JHE activity coincides with a sharp rise in the rate of JH synthesis. Pupal hemolymph of T. molitor has the highest activity of any species or stage tested. The enzymes of Samia cynthia and T. molitor hydrolyze JH-1 and ethyl ester analogs, whereas the Δ²-cis isomer of JH-I and isopropyl ester analogs (only tested with T. molitor hemolymph) are unaffected.

Activity of Guinea Pig Liver Transglutaminase toward Ester Analogs of Amide Substrates

Abstract Calcium-activated guinea pig liver transglutaminase catalyzes the hydrolysis and aminolysis of γ-glutamyl methyl and ethyl ester analogs of a specific amide substrate, benzyloxycarbonyl(Z)-l-glutaminylglycine. Kinetic comparisons of amine incorporation into the γ-n-methylamide, and the γ-methyl and ethyl esters of Z-l-glutamylglycine indicate that the same aycl-enzyme intermediate is formed from each of these substrates. The differences in catalytic efficiency toward these substrates are due to differences in rates of formation of this intermediate, and may be a consequence of different orientations of the leaving groups (—OR and —NHR) at the catalytic site of the enzyme. An aliphatic ester, methyl acetate, and its amide analog, N-methylacetamide, are about equally effective, although poor, substrates for transglutaminase. This, together with the fact that the acyl-enzyme intermediate is formed from the γ-methyl ester of Z-l-glutamylglycine and from its γ-N-methylamide at approximately the same rate, is strong evidence that C—O and C—N bonds are about equally susceptible to cleavage by transglutaminase. The ability of an alcohol to function as an acyl acceptor in a transglutaminase-catalyzed amide transfer reaction and the reversibility of the ester to amide conversion has been demonstrated with the use of a fluorescent-labeled alcohol derivative, N-(5 - dimethylaminonaphthalenesulfonyl) - 5 - amino - 1 - pentanol.