Carbamic Acid Tert-butyl Ester Research Articles

The Bispidinone Derivative 3,7-Bis-[2-(S)-amino-3-(1H-indol-3-yl)-propionyl]-1,5-diphenyl-3,7-diazabicyclo[3.3.1]nonan-9-one Dihydrochloride Induces an Apoptosis-Mediated Cytotoxic Effect on Pancreatic Cancer Cells In Vitro.

Pancreatic cancer (PC) is a complex, heterogeneous disease with a dismal prognosis. Current therapies have failed to improve survival outcomes, urging the need for discovery of novel targeted treatments. Bispidinone derivatives have yet to be investigated as cytotoxic agents against PC cells. The cytotoxic effect of four bispidinone derivatives (BisP1: 1,5-diphenyl-3,7-bis(2-hydroxyethyl)-3,7-diazabicyclo[3.3.1]nonan-9-one; BisP2: 3,7-bis-(2-(S)-amino-4-methylsulfanylbutyryl)-1,5-diphenyl-3,7-diazabicyclo[3.3.1]nonan-9-one dihydrochloride; BisP3: [2-{7-[2-(S)-tert-butoxycarbonylamino-3-(1H-indol-3-yl)-propionyl]-9-oxo-1,5-diphenyl-3,7-diazabicyclo[3.3.1]non-3-yl}-1-(S)-(1H-indol-3-ylmethyl)-2-oxoethyl]-carbamic acid tertbutyl ester; BisP4: 3,7-bis-[2-(S)-amino-3-(1H-indol-3-yl)-propionyl]-1,5-diphenyl-3,7-diazabicyclo[3.3.1]nonan-9-one dihydrochloride) was assessed against PC cell lines (MiaPaca-2, CFPAC-1 and BxPC-3). Cell viability was assessed using a Cell Counting Kit-8 (CCK-8) colorimetric assay, while apoptotic cell death was confirmed using fluorescence microscopy and flow cytometry. Initial viability screening revealed significant cytotoxic activity from BisP4 treatment (1 µM–100 µM) on all three cell lines, with IC50 values for MiaPaca-2, BxPC-3, and CFPAC-1 16.9 µM, 23.7 µM, and 36.3 µM, respectively. Cytotoxic treatment time-response (4 h, 24 h, and 48 h) revealed a 24 h treatment time was sufficient to produce a cytotoxic effect on all cell lines. Light microscopy evaluation (DAPI staining) of BisP4 treated MiaPaca-2 PC cells revealed dose-dependent characteristic apoptotic morphological changes. In addition, flow cytometry confirmed BisP4 induced apoptotic cell death induction of activated caspase-3/-7. The bispidinone derivative BisP4 induced an apoptosis-mediated cytotoxic effect on MiaPaca-2 cell lines and significant cytotoxicity on CFPAC-1 and BxPC-3 cell lines. Further investigations into the precise cellular mechanisms of action of this class of compounds are necessary for potential development into pre-clinical trials.

End Functionalized Nonionic Water-Dispersible Conjugated Polymers.

2,7-Dibromofluorene monomers carrying two or four oligo(ethylene glycol) (OEG) side chains are synthesized. Heck coupling between the monomers and 1,4-divinylbenzene followed by end capping with [4-(4-bromophenoxy)butyl]carbamic acid tert-butyl ester leads to two nonionic water-dispersible poly(fluorene-alt-1,4-divinylenephenylene)s end-functionalized with amine groups after hydrolysis. In water, the polymer with a lower OEG density (P1) has poor water dispersibility with a quantum yield of 0.24, while the polymer with a higher OEG density (P2) possesses excellent water-dispersibility with a high quantum yield of 0.45. Both polymers show fluorescence enhancement and blue-shifted absorption and emission maxima in the presence of surfactant sodium dodecyl sulfate and dodecyltrimethylammonium bromide. The polymers are also resistant to ionic strength with minimal nonspecific interactions to bovine serum albumin. When biotin is incorporated into the end of the polymer backbones through N-hydroxysuccinimide/amine coupling reaction, the biotinylated polymers interact specifically with streptavidin on solid surface.

Synthetic and Crystallographic Studies of (9-Ethyl-9H-carbazol-3-yl)-carbamic acid tert-butyl ester

The title compound (9-ethyl-9H-carbazol-3-yl)-carbamic acid tert-butyl ester was prepared from 3-amino-9-ethylcarbazole and di-tert-butyldicarbonate (Boc anhydride) in good yield. It was characterized by elemental analysis, FT-NMR, FT-IR spectroscopy and subjected to single crystal X-ray diffraction studies. The compound crystallizes in monoclinic space group P21/c with unit cell dimensions are a = 13.5218(8) A, b = 12.7624(7) A, c = 10.1352(6) A, β = 100.784(6)°, V = 1718.15(17) A3, D x = 1.200 Mg m−3, and Z = 4. According to X-ray diffraction studies the molecule is in a non planar conformation except for the carbazole moiety and having a dihedral angle of 30.239(89)° between the plane of the carbazole and amide moieties. The molecules are packed in a zig-zag manner and strong N–H···O [C(4) motif] intermolecular hydrogen bonding, weak C–H···π [C(5) motif] and π–π stacking interaction stabilize the crystal packing. The thermal analysis of single crystal was determined by DSC and TGA.

DFT study of Raman spectra of phosphorus-containing dendrons built from cyclotriphosphazene core with terminal carbamate and ester groups

The FT Raman spectra of the zero (Gv0) and first generations (Gv1) of phosphorus-containing dendrons with terminal carbamate groups and one ester function and [2-(4-hydroxyphenyl)ethyl]-carbamic acid tert-butyl ester (C) have been recorded and analyzed. The lines of free ν(CO) bonds are not observed in the experimental Raman spectrum of C and thus association of carbamate groups by hydrogen bonds occur. The frequencies of ν(CO) lines in the experimental Raman spectrum reveal the presence of the different types of H-bonds in the amorphous state of Gv0. Density functional theory (DFT) calculations of C gave geometrical parameters for the t-g-, g-g-, tg-, gg-conformers. The most stable is the gg-conformer. The structural optimization and normal mode analysis were performed for dendrons on the basis of the DFT. The calculated geometrical parameters, harmonic vibrational frequencies and Raman intensities are predicted in a good agreement with the experimental data. The experimental Raman spectra of dendrons were interpreted by means of potential energy distribution. Relying on DFT calculations the lines of a core, repeating units and terminal groups of dendrons were assigned.The polarizabilities and lipophilicity of dendrons were estimated.

Crystal Structure of {4-[3-(4-Fluoro-phenyl)-acryloyl]-phenyl}-carbamic acid tert-butyl ester

The crystal structure of {4-[3-(4-fluoro-phenyl)-acryloyl]-phenyl}-carbamic acid tert-butyl ester has been determined by X-ray diffraction, title compound crystallized in orthorhombic, P21/n space group with unit cell parameters a = 10.100(3) A, b = 18.201(5) A, c = 10.829(3) A; α = 90°, β = 111.15(4)°, γ = 90°. The crystal structure of compound was stabilized by N–H…O intermolecular hydrogen bonding, the molecules are linked by C–H…F, C–H…O and C–H…H–C intermolecular interactions. The two benzenes rings are non planar with dihedral angle 11.11° and contains a single C=C double bond in a trans (E) configuration.

Bromomaleimide-linked bioconjugates are cleavable in mammalian cells.

Bromomaleimide-linked bioconjugates are cleavable in mammalian cells.

N-Heterocyclic Carbene-Amide Rhodium(I) Complexes: Structures, Dynamics, and Catalysis

The amide-functionalized imidazolium salts [BocNHCH2CH2ImR]X (R = Me, X = I, 1a; R = benzyl, X = Br, 1b; R = trityl, X = Cl, 1c) bearing increasingly bulky N-alkyl substituents were prepared in high yields by direct alkylation of the (2-imidazol-1-yl-ethyl)carbamic acid tert-butyl ester; 1c is a crystalline solid also characterized by X-ray diffraction. These salts are precursors for the synthesis of rhodium(I) complexes [Rh(NBD)X(NHC)] (NHC = 1-(2-NHBoc-ethyl)-3-R-imidazolin-2-ylidene; X = Cl, R = Me (3a), R = benzyl (3b), R = trityl (3c); X = I, R = Me (4a)). All the complexes display restricted rotation about the metal–carbene bond; however, while the rotation barriers calculated for 3a,b and 4a matched the experimental values, unexpectedly this was not true in the case of 3c, where the experimental value was equal to that obtained for compound 3b (58.6 kJ mol–1) and much smaller with respect to the calculated one (100.0 kJ mol–1). The catalytic activity of the neutral rhodium(I) complexes 3a–c in the ...

DFT calculations of structure and vibrational spectra of dendron built of cyclotriphosphazene core with terminal carbamate and ester groups

FTIR and FT-Raman spectra of dendron built of the cyclotriphosphazene core with five carbamate and one ester functions ( G 0) and [2-(4-hydroxyphenyl)ethyl]-carbamic acid tert-butyl ester ( C) have been recorded at various temperatures between 16 and 70 °C. The bands of free ν(N–H) and ν(C O) bonds are not observed in the IR spectra of C in the crystalline state and in the melt, and thus association of carbamate groups by hydrogen bonds occur. The frequencies of ν(N–H) and ν(C O) bands in the IR spectra reveal the presence of the different types of H-bonds in the amorphous state of G 0. Density functional theory (DFT) calculations of C gave vibrational frequencies and intensity of IR bands for the t-g-, g-g-, tg-, gg-conformers. The most stable is the gg-conformer. The bond lengths, bond angles, frequencies and intensity of bands in the IR spectra of dendron obtained by DFT show the best agreement with experimental data. Relying on DFT calculations a complete assignment of vibrations is proposed for different parts of dendron. The ionization energy IE, electron affinity EA and global softness of G 0 are higher than that of C. The most reactive places in C are OH, NH and C O groups. The local softness of C O bond of carbamate group in G 0 for nucleophilic attack is lower than that of methylbenzoate group.

Base dependent purported synthesis of congested 2-aminobenzylamines and tetrahydro-2-oxoquinazolines from 2-pyranones

An expeditious and concise synthesis of highly congested 2-amino-3-aminomethyl-5-methylsulfanyl/- sec-aminobiphenyl-4-carbonitrile 4 and 1- tert-butoxycarbonyl-6- sec-amino-8-aryl-5-cyano-2- oxo-1,2,3,4-tetrahydroquinazoline 5 has been delineated through base catalyzed ring transformation of 6-aryl-4-methylsulfanyl/- sec-amino-2 H-pyran-2-one-3-carbonitrile 1 with 1,3-bis( tert-butoxycarbonylamino)-2-propanone 2, followed by TFA catalyzed hydrolysis of the intermediate [3- tert-butoxycarbonylaminomethyl-4-cyano-5-methylsulfanyl/- sec-aminobiphenyl-2-yl]carbamic acid tert-butyl ester 3 in moderate yield. The mechanism of formation of 5 has been established through isolation and transformation of the intermediate 3 to the 1- tert-butoxycarbonyl-6- sec-amino-8-aryl-5-cyano-2- oxo-1,2,3,4-tetrahydroquinazoline.

Newborn Screening for Pompe Disease by Measuring Acid α-Glucosidase Activity Using Tandem Mass Spectrometry

Pompe disease, caused by the deficiency of acid alpha-glucosidase (GAA), is a lysosomal storage disorder that manifests itself in its most severe form within the first months of life. Early detection by newborn screening is warranted, since prompt initiation of enzyme replacement therapy may improve morbidity and mortality. We evaluated a tandem mass spectrometry (MS/MS) method to measure GAA activity for newborn screening for Pompe disease. We incubated 3.2-mm punches from dried blood spots (DBS) for 22 h with the substrate [7-benzoylamino-heptyl)-{2-[4-(3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yloxy)-phenylcarbamoyl]- ethyl}-carbamic acid tert-butyl ester] and internal standard [7-d(5)-benzoylamino-heptyl)-[2-(4-hydroxy-phenylcarbamoyl)-ethyl]-carbamic acid tertbutyl ester]. We quantified the resulting product and internal standard using MS/MS. We assessed inter- and intrarun imprecision, carryover, stability, and correlation between enzyme activities and hematocrit and punch location and generated a Pompe disease-specific cutoff value using routine newborn screening samples. GAA activities in DBS from 29 known Pompe patients were <2 micromol/h/L. GAA activities in routine newborn screening samples were [mean (SD)] 14.7 (7.2) micromol/h/L (n = 10,279, median 13.3, 95% CI 14.46-14.74 micromol/h/L) and in normal adult samples 9.3 (3.3) micromol/h/L (n = 229, median 9, 95% CI 8.88-9.72 micromol/h/L). GAA activity was stable for 28 days between 37 degrees C and -80 degrees C. Carryover could not be observed, whereas intrarun and interrun imprecision were <10%. The limit of detection was 0.26 micromol/h/L and limit of quantification 0.35 micromol/h/L. The measurement of GAA activities in dry blood spots using MS/MS is suitable for high-throughput analysis and newborn screening for Pompe disease.

Aβ46 Is Processed to Aβ40 and Aβ43, but Not to Aβ42, in the Low Density Membrane Domains

Gamma-secretase cleaves the transmembrane domain of beta-amyloid precursor protein at multiple sites referred to as gamma-, epsilon-, and zeta-cleavage sites. We previously showed that N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT), a potent dipeptide gamma-secretase inhibitor, causes differential accumulation of longer amyloid beta-proteins (Abetas) within Chinese hamster ovary cells co-expressing beta C-terminal fragment and wild-type presenilin 1 (C99/wtPS1 cells). In this study, we used sucrose density gradient centrifugation to fractionate the membranes from C99/wtPS1 cells that had been pretreated with DAPT. We found that accumulating Abeta46 localized exclusively to low density membrane (LDM) domains. Incubating the Abeta46-accumulating LDM domains at 37 degrees C produced Abeta40, Abeta42, Abeta43, and beta-amyloid precursor protein intracellular domain. The addition of L685,458 completely prevented beta-amyloid precursor protein intracellular domain generation and resulted in a large decrease in the level of Abeta46 and the concomitant appearance of Abeta40 and Abeta43 but not Abeta42. Further addition of DAPT suppressed the production of Abeta40/43 and abolished the decrease in the amount of Abeta46. These data indicate that preaccumulated Abeta46 is processed by gamma-secretase to Abeta40/43 but not to Abeta42 in the LDM domains. The amount of newly produced Abeta40 and Abeta43 was roughly equivalent to the decrease in the amount of Abeta46. Temporal profiles did not show a maximal concentration for Abeta43, suggesting that Abeta46 is processed to Abeta40 and Abeta43 through a nonsuccessive process.

Synthesis and Evaluation of the Antiproliferative Activities of Derivatives of Carboxyalkyl Isoflavones linked to N-t-Boc-hexylenediamine

The isoflavones biochanin A ( 1a), genistein ( 1b), and daidzein ( 4) at concentrations >20 microM inhibit cell growth of various cancer cell lines. To enhance the antiproliferative activities of these compounds, we synthesized three analogs, 2-[3-carboxy-(6-tert-butoxycarbonylamino)-hexylamino-propyl]-7,5-dihydroxy-4'-methoxyisoflavone ( 3a), 2-[3-[N-[6-(tert-butoxycarbonyl)-aminohexyl]]-caboxamidopropyl]-5,7,4'-trihydroxyisoflavone ( 3b), and 5-{2-[3-(4-hydroxy-phenyl)-4-oxo-4 H-chromen-7-yloxy]-acetylamino}-pentyl)-carbamic acid tert-butyl ester ( 6). When cancer cells expressing predominantly estrogen receptor mRNA of the beta- relative to alpha-subtype were treated with 3a, 3b, or 6, DNA synthesis was inhibited in a dose-dependent manner, ranging from 15 to 3000 nmol/L, with little inhibitory effect in normal vascular smooth muscle cells. Compound 6 was the most potent one, and its antiproliferative effect in cancer cells was modulated by estrogen and by the apoptosis inhibitor Z-VADFK. When tested in vivo, compound 6 decreased tumor volume of ovarian xenografts by 50%, with no apparent toxicity. Compound 6 may be a promising agent for therapy of cancer either alone or in combination with chemotherapeutic agents.

3-tert-butoxycarbonylamino-pyridine-2-carboxylic Acid

To the carbamic acid tert-butylester 1 (1.03 g, 4.08 mmol) in methanol (15 ml) was added 1.4 equivalents of NaOH (2N).[...]

A novel route for the synthesis of highly congested aryl-tethered 2-aminobenzylamines through ring transformation of 2-pyranones

An innovative and efficient synthesis of highly congested 2-amino-3-aminomethyl-5-methylsulfanyl/ sec-aminobiphenyl-4-carbonitriles 4 has been delineated through base catalyzed ring transformation of 6-aryl-4-methylsulfanyl/ sec-amino-2 H-pyran-2-one-3-carbonitriles 1 with Boc-protected 1,3-diamino-2-propanone 2, followed by TFA catalyzed hydrolysis of the intermediate [3- tert-butoxycarbonylaminomethyl-4-cyano-5-methylsulfanyl/ sec-aminobiphenyl-2-yl]carbamic acid tert-butyl ester 3 in moderate yields as the TFA salts.

Practical Synthesis of Blepharismone, a Mating Inducing Pheromone of Blepharisma japonicum.

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Practical synthesis of blepharismone, a mating inducing pheromone of Blepharisma japonicum

Both enantiomers of blepharismone, a mating inducing pheromone produced by type II cells of Blepharisma japonicum, were synthesized via the Stille cross-coupling reaction of [4-( tert-butyl-dimethyl-silanyloxy)-2-trimethylstannanyl-phenyl]-carbamic acid tert-butyl ester with an acid chloride derived from ( S)- and ( R)-malic acid as a key reaction. The mating inducing activity of synthetic ( S)-blepharismone was as effective as that of the natural one. The enantiomer ( R)-blepharismone showed no mating inducing activity.

Longer Forms of Amyloid β Protein: Implications for the Mechanism of Intramembrane Cleavage by γ-Secretase

Gamma-cleavage of beta-amyloid precursor protein (APP) in the middle of the cell membrane generates amyloid beta protein (Abeta), and epsilon-cleavage, approximately 10 residues downstream of the gamma-cleavage site, releases the APP intracellular domain (AICD). A significant link between generation of Abeta and AICD and failure to detect AICD41-99 led us to hypothesize that epsilon-cleavage generates longer Abetas, which are then processed to Abeta40/42. Using newly developed gel systems and an N-end-specific monoclonal antibody, we have identified the longer Abetas (Abeta1-43, Abeta1-45, Abeta1-46, and Abeta1-48) within the cells and in brain tissues. The production of these longer Abetas as well as Abeta40/42 is presenilin dependent and is suppressed by {1S-benzyl-4R-[1S-carbamoyl-2-phenylethylcarbamoyl-1S-3-methylbutylcarbamoyl]-2R-hydroxy-5-phenylpentyl}carbamic acid tert-butyl ester, a transition state analog inhibitor for aspartyl protease. In contrast, N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester, a potent dipeptide gamma-secretase inhibitor, builds up Abeta1-43 and Abeta1-46 intracellularly, which was also confirmed by mass spectrometry. Notably, suppression of Abeta40 appeared to lead to an increase in Abeta43, which in turn brings an increase in Abeta46, in a dose-dependent manner. We therefore propose an alpha-helical model in which longer Abeta species generated by epsilon-cleavage is cleaved at every three residues in its carboxyl portion.

Isotope labeled ?HEA/HEE? moiety in the synthesis of labeled HIV-protease inhibitors?Part II

[2H5]-Amprenavir and [2H 5]-saquinavir have been prepared from a common labeled precursor (1S, 2S)-(1-oxiranyl-2-[2H5]phenylethyl)-carbamic acid tert-butyl ester, 1. Both of these compounds are in the ‘HEA’ class of HIV protease inhibitors. [2H5]-Indinavir, a representative of the ‘HEE’ group of protease inhibitors, has also been synthesized. In the case of indinavir, 1S-(2,2-dimethyl-8, 8a-dihydro-3aH-indeno-[1,2-d]-oxazol-3R-yl)-2-oxiranylmethyl-3-[2H5]phenylpropan-1-one, 11, provided the [phenyl-2H5]-HEE core structure for synthesis of the desired labeled compound. Copyright © 2005 John Wiley & Sons, Ltd.

Biotransformation of β-amino nitriles: the role of the N-protecting group

N-Tolylsulfonyl- and N-butyloxycarbonyl-protected β-amino nitriles were prepared to study the effect of the N-protecting group on the biotransformation of the β-amino nitriles to the corresponding β-amino amides and acids. The bioconversions were carried out by using whole cells of Rhodococcus sp. R312 and Rhodococcus erythropolis NCIMB 11540. The bioconversion products of five-membered carbocyclic nitriles were mainly the respective acids whereas the carbocyclic six-membered nitriles were accumulated at the stage of the amide. Benefits of the enzymatic compared with the chemical hydrolysis of β-amino nitriles are the mild reaction conditions for the transformation of the nitrile group in the presence of acid or base labile N-protecting groups. In the present work we concentrated on this chemoselectivity of the biotransformation rather than its potential enantioselectivity, which will be subject of future investigations. Thus, some new compounds were prepared: (±)-(2-cyano-cyclohexyl) carbamic acid tert-butyl ester (4a), (±)-(2-carbamoyl-cyclopentyl) carbamic acid tert-butyl ester (3b) and (±)-(2-carbamoyl-cyclohexyl) carbamic acid tert-butyl ester (4b).

Process Research on [(2S)-(3-Fluorophenyl)-(1S)-(5-oxotetrahydrofuran- 2-yl)ethyl]carbamic Acid tert-Butyl Ester, a Lactone Intermediate for an Aspartyl Protease Inhibitor

Two processes for the preparation of lactone [2S-(3-fluorophenyl)-1S-(5-oxotetrahydrofuran-2-yl)ethyl]carbamic acid tert-butyl ester 1 starting from S-BOC-(3-fluorophenyl)alanine 3 are described. (S)-(3-Fluorophenyl)alanine N-methyl-N-methoxy amide 10, the Weinreb amide of 3, was reacted with 2-(2-1,3-dioxanyl)ethylmagnesium bromide to provide key intermediate ketoacetal 11. To achieve high yields for this conversion, the N−H of the BOC group in Weinreb amino acid amide 10 was deprotonated first with a simple Grignard reagent (methyl or benzylmagnesium halide) followed by Barbier reaction with magnesium metal and 2-(2-bromoethyl)-1,3-dioxane. The acetal group in 11 was opened oxidatively with ozone, and the resulting ester 15 was reduced selectively at low temperature with N-Selectride. Alternatively, the ketone moiety in 11 was reduced diastereoselectively with aluminum triisopropoxide in 2-propanol to give the undesired (R,S)-diastereomeric alcohol. The alcohol was converted to the mesylate which was heated in solution to cause formation of oxazolidinone 19 through displacement of the mesylate group by the carbonyl moiety of the BOC group with loss of tert-butyl alcohol. This intramolecular reaction provided the desired (S,S)-diastereomer. Finally, acetal 19 was converted to nitrile 20 with hydroxylamine hydrochloride in ethanol with catalytic toluenesulfonic acid at reflux. Basic aqueous hydrolysis of nitrile 20 followed by treatment with di-tert-butyl dicarbonate provided 1. While the second process was longer, the inexpensive reagents, simple reaction conditions, and high yields made it the process of choice. Both processes have been run on a multikilogram scale.