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Structure of 534-17-8

Chemical Structure| 534-17-8

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Zhang, Zhumin ; Sanders, Hailey S ; Dragun, Vivienne ; Cole, Sara ; Smith, Bradley D ;

Abstract: Compared to cultured 2D cell monolayers, 3D multicellular spheroids are more realistic tumor models. Nonetheless, spheroids remain under-utilized in preclinical research, in part, because there is a lack of fluorescence sensors that can noninvasively interrogate all the individual cells within a spheroid. This present study describes a deep-red fluorogenic molecular probe for microscopic imaging of cells that contain a high level of nitroreductase enzyme activity as a biomarker of cell hypoxia. A first-generation version of the probe produced “turnon” fluorescence in a 2D cell monolayer under hypoxic conditions; however, it was not useful in a 3D multicellular tumor spheroid because it only accumulated in the peripheral cells. To guide the probe structural optimization process, an intuitive theoretical membrane partition model was conceived to predict how a dosed probe will distribute within a 3D spheroid. The model identifies three limiting molecular diffusion pathways that are determined by a probe’s membrane partition properties. A lipophilic probe with high membrane affinity rapidly becomes trapped in the membranes of the peripheral cells. In contrast, a very hydrophilic probe molecule with negligible membrane affinity diffuses rapidly through the spheroid intercellular space and rarely enters the cells. However, a probe molecule with intermediate membrane affinity undergoes sequential diffusion in and out of cells and distributes to all the cells within a spheroid. Using the model as a predictive tool, a secondgeneration fluorescent probe was prepared with a smaller and more hydrophilic molecular structure, and optical sectioning using structured illumination or light sheet microscopy revealed roughly even probe diffusion throughout a tumor spheroid. The membrane permeation model is likely to be broadly applicable for the structural optimization of various classes of molecules and nanoparticles to enable even distribution within a tumor spheroid.

Keywords: tumor spheroid ; fluorescence microscopy ; hypoxia ; nitroreductase ; membrane partition coefficient

Purchased from AmBeed: ;

Fischer, Thomas ; Frasson, David ; Sievers, Martin ; Riedl, Rainer ;

Abstract: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) papain-like cysteine protease (PLpro) represents one of only two essential cysteine proteases involved in the regulation of viral replication. It, therefore, qualifies as a promising therapeutic target for the development of antiviral agents. We identified a previously synthesized protease inhibitor, resulting from an earlier project, as a PLpro inhibitor and crafted a structure-activity relationship around the hit, leading to the more potent inhibitors ZHAWOC6941 (17h) and ZHAWOC25153 (17o) displaying IC50 values of 8 and 7 µM, respectively. The two compounds represent a new class of PLpro inhibitors and, with single‐digit micromolar IC50 values, are comparable to inhibitors found in the literature.

Keywords: Inhibitor ; papain-like protease ; SARS-CoV-2 ; structure-activity relationship

Purchased from AmBeed: ; ; ;

Zhumin Zhang ; Jordan L. Chasteen ; Bradley D. Smith ;

Abstract: The chemosensor literature contains many reports of fluorescence sensing using polyaromatic hydrocarbon fluorophores such as pyrene, , or polyaryl(ethynylene), where the fluorophore is excited with ultraviolet light (<400 nm) and emits in the visible region of 400–500 nm. There is a need for general methods that convert these “turn-on” hydrocarbon fluorescent sensors into ratiometric sensing paradigms. One simple strategy is to mix the responsive hydrocarbon sensor with a second non-responsive dye that is excited by ultraviolet light but emits at a distinctly longer wavelength and thus acts as a reference signal. Five new cyanine dye cassettes were created by covalently attaching a pyrene, , or biphenyl(ethynylene) component as the ultraviolet-absorbing energy donor directly to the pentamethine chain of a deep-red cyanine (Cy5) energy acceptor. Fluorescence emission studies showed that these Cy5-cassettes exhibited large pseudo-Stokes shifts and high through-bond energy transfer efficiencies upon excitation with ultraviolet light. Practical potential was demonstrated with two examples of ratiometric fluorescence sensing using a single ultraviolet excitation wavelength. One example mixed a Cy5-cassette with a pyrene-based fluorescent indicator that responded to changes in Cu2+ concentration, and the other example mixed a Cy5-cassette with the fluorescent pH sensing dye, .

William E. Meador ; Timothy A. Lewis ; Abdul K. Shaik ; Kalpani Hirunika Wijesinghe ; Boqian Yang ; Amala Dass , et al.

Abstract: Fluorescence-based biological imaging in the shortwave infrared (SWIR, 1000–1700 nm) is an attractive replacement for modern in vivo imaging techniques currently employed in both medical and research settings. Xanthene-based fluorophores containing heterocycle donors have recently emerged as a way to access deep SWIR emitting fluorophores. A concern for xanthene-based SWIR fluorophores though is chemical stability toward ambient nucleophiles due to the high electrophilicity of the cationic fluorophore core. Herein, a series of SWIR emitting silicon-rosindolizine (SiRos) fluorophores with emission maxima >1300 nm (up to 1550 nm) are synthesized. The SiRos fluorophore photophysical properties and chemical stability toward nucleophiles are examined through systematic derivatization of the silicon-core alkyl groups, indolizine donor substitution, and the use of o-tolyl or o-xylyl groups appended to the fluorophore core. The dyes are studied via absorption spectroscopy, steady-state emission spectroscopy, solution-based cyclic voltammetry, time-dependent density functional theory (TD-DFT) computational analysis, X-ray diffraction crystallography, and relative chemical stability over time. Optimal chemical stability is observed via the incorporation of the 2-ethylhexyl silicon substituent and the o-xylyl group to protect the core of the fluorophore.

Purchased from AmBeed: ; ; ; ; ;

Samantha E. Sloane ;

Abstract: The similar nature of the hydrogen atom to its isotope, deuterium, allows for the simple exchange of hydrogen atoms for deuterium atoms in drug molecules to alter the absorption, distribution, metabolism, and excretion properties. Installing the deuterium functionality into a specific site in the molecule is essential. Selective hydrofunctionalization reactions of alkynes and alkenes using the highly reactive catalytic Cu–H species have been well developed, and synthetic organic chemistry methods to selectively incorporate one or two deuterium atoms into the benzylic site of organic compounds, a key metabolic position, are elusive. A Cu–H catalytic approach offers selectivity and reactivity to undergo a transfer hydrodeuteration of alkynes or alkenes. Initiating the reaction development with a transfer hydrogenation protocol demonstrated high chemoselectivity on a diverse array of aryl alkynes. Expanding this method to a transfer deuteration generated aryl alkane products with up to 5 deuterium atoms, 2 of which were located at the benzylic carbon. Preliminary regioselective results were explored, providing 2 deuterium atoms at the benzylic position and 2 hydrogen atoms at the homobenzylic position (Chapter 1). One deuterium atom was installed exclusively into aryl alkanes from aryl alkenes using a transfer hydrodeuteration reaction, and MRR, molecular rotational resonance spectroscopy, was explored as an analytical tool to detect different isotopic species present in the product mixture, confirming the highest selectivity reported to date (Chapter 2). Two deuterium atoms were installed selectively into the benzylic site of aryl alkanes from the transfer hydrodeuteration of aryl alkynes, forming ,-d2-alkane products, including complex small molecules. This was based on the electronic stability of the DTB-DPPBz ligand, which was explored both experimentally and computationally (Chapter 3). Exchanging the silane source for diphenylsilane and eliminating the alcohol allowed for a regio-, stereo-, and chemoselective hydrosilylation of aryl alkynes to be accomplished on biologically relevant small molecules, as well as 4 drug analogues, to access -E_x005f_x0002_vinylsilanes. Additionally, this protocol permitted the selective deuterosilylation reaction to access,-d2- alkane products (Chapter 4). Through extensive reaction development, optimization, and mechanistic exploration, highly selective methods of precision deuteration and hydrosilylation were achieved by using a Cu–H catalytic protocol.

Purchased from AmBeed: ;

Alternative Products

Product Details of [ 534-17-8 ]

CAS No. :534-17-8
Formula : Cs2CO3
M.W : 325.82
SMILES Code : [O-]C([O-])=O.[Cs+].[Cs+]
MDL No. :MFCD00010957
InChI Key :FJDQFPXHSGXQBY-UHFFFAOYSA-L
Pubchem ID :10796

Safety of [ 534-17-8 ]

GHS Pictogram:
Signal Word:Danger
Hazard Statements:H318-H361-H373
Precautionary Statements:P202-P260-P280-P305+P351+P338-P308+P313-P405

Computational Chemistry of [ 534-17-8 ] Show Less

Physicochemical Properties

Num. heavy atoms 6
Num. arom. heavy atoms 0
Fraction Csp3 0.0
Num. rotatable bonds 0
Num. H-bond acceptors 3.0
Num. H-bond donors 0.0
Molar Refractivity 6.77
TPSA ?

Topological Polar Surface Area: Calculated from
Ertl P. et al. 2000 J. Med. Chem.

63.19 Ų

Lipophilicity

Log Po/w (iLOGP)?

iLOGP: in-house physics-based method implemented from
Daina A et al. 2014 J. Chem. Inf. Model.

0.0
Log Po/w (XLOGP3)?

XLOGP3: Atomistic and knowledge-based method calculated by
XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry

-0.13
Log Po/w (WLOGP)?

WLOGP: Atomistic method implemented from
Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.

-2.45
Log Po/w (MLOGP)?

MLOGP: Topological method implemented from
Moriguchi I. et al. 1992 Chem. Pharm. Bull.
Moriguchi I. et al. 1994 Chem. Pharm. Bull.
Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.

-1.6
Log Po/w (SILICOS-IT)?

SILICOS-IT: Hybrid fragmental/topological method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

-0.44
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

-0.92

Water Solubility

Log S (ESOL):?

ESOL: Topological method implemented from
Delaney JS. 2004 J. Chem. Inf. Model.

-1.78
Solubility 5.43 mg/ml ; 0.0167 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Very soluble
Log S (Ali)?

Ali: Topological method implemented from
Ali J. et al. 2012 J. Chem. Inf. Model.

-0.74
Solubility 58.8 mg/ml ; 0.181 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Very soluble
Log S (SILICOS-IT)?

SILICOS-IT: Fragmental method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

1.49
Solubility 10000.0 mg/ml ; 30.8 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Soluble

Pharmacokinetics

GI absorption?

Gatrointestinal absorption: according to the white of the BOILED-Egg

Low
BBB permeant?

BBB permeation: according to the yolk of the BOILED-Egg

No
P-gp substrate?

P-glycoprotein substrate: SVM model built on 1033 molecules (training set)
and tested on 415 molecules (test set)
10-fold CV: ACC=0.72 / AUC=0.77
External: ACC=0.88 / AUC=0.94

No
CYP1A2 inhibitor?

Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.83 / AUC=0.90
External: ACC=0.84 / AUC=0.91

No
CYP2C19 inhibitor?

Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.80 / AUC=0.86
External: ACC=0.80 / AUC=0.87

No
CYP2C9 inhibitor?

Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set)
and tested on 2075 molecules (test set)
10-fold CV: ACC=0.78 / AUC=0.85
External: ACC=0.71 / AUC=0.81

No
CYP2D6 inhibitor?

Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set)
and tested on 1068 molecules (test set)
10-fold CV: ACC=0.79 / AUC=0.85
External: ACC=0.81 / AUC=0.87

No
CYP3A4 inhibitor?

Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set)
and tested on 2579 molecules (test set)
10-fold CV: ACC=0.77 / AUC=0.85
External: ACC=0.78 / AUC=0.86

No
Log Kp (skin permeation)?

Skin permeation: QSPR model implemented from
Potts RO and Guy RH. 1992 Pharm. Res.

-8.38 cm/s

Druglikeness

Lipinski?

Lipinski (Pfizer) filter: implemented from
Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev.
MW ≤ 500
MLOGP ≤ 4.15
N or O ≤ 10
NH or OH ≤ 5

0.0
Ghose?

Ghose filter: implemented from
Ghose AK. et al. 1999 J. Comb. Chem.
160 ≤ MW ≤ 480
-0.4 ≤ WLOGP ≤ 5.6
40 ≤ MR ≤ 130
20 ≤ atoms ≤ 70

None
Veber?

Veber (GSK) filter: implemented from
Veber DF. et al. 2002 J. Med. Chem.
Rotatable bonds ≤ 10
TPSA ≤ 140

0.0
Egan?

Egan (Pharmacia) filter: implemented from
Egan WJ. et al. 2000 J. Med. Chem.
WLOGP ≤ 5.88
TPSA ≤ 131.6

0.0
Muegge?

Muegge (Bayer) filter: implemented from
Muegge I. et al. 2001 J. Med. Chem.
200 ≤ MW ≤ 600
-2 ≤ XLOGP ≤ 5
TPSA ≤ 150
Num. rings ≤ 7
Num. carbon > 4
Num. heteroatoms > 1
Num. rotatable bonds ≤ 15
H-bond acc. ≤ 10
H-bond don. ≤ 5

1.0
Bioavailability Score?

Abbott Bioavailability Score: Probability of F > 10% in rat
implemented from
Martin YC. 2005 J. Med. Chem.

0.55

Medicinal Chemistry

PAINS?

Pan Assay Interference Structures: implemented from
Baell JB. & Holloway GA. 2010 J. Med. Chem.

0.0 alert
Brenk?

Structural Alert: implemented from
Brenk R. et al. 2008 ChemMedChem

0.0 alert: heavy_metal
Leadlikeness?

Leadlikeness: implemented from
Teague SJ. 1999 Angew. Chem. Int. Ed.
250 ≤ MW ≤ 350
XLOGP ≤ 3.5
Num. rotatable bonds ≤ 7

No; 1 violation:MW<0.0
Synthetic accessibility?

Synthetic accessibility score: from 1 (very easy) to 10 (very difficult)
based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties,
trained on 12'782'590 molecules and tested on 40 external molecules (r2 = 0.94)

2.4

Application In Synthesis of [ 534-17-8 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

  • Downstream synthetic route of [ 534-17-8 ]

[ 534-17-8 ] Synthesis Path-Downstream   1~8

  • 1
  • syn-2-chloro-5-fluoro-N-[4-(2-hydroxy-4-methyl-benzoylamino)-cyclohexyl]-nicotinamide [ No CAS ]
  • [ 827-99-6 ]
  • [ 534-17-8 ]
  • syn-5-fluoro-N-[4-(2-hydroxy-4-methyl-benzoylamino)-cyclohexyl]-2-(3-trifluoromethoxy-phenoxy)-nicotinamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
In methanol; diethyl ether; dichloromethane; N,N-dimethyl-formamide; Example 195 Syn-5-Fluoro-N-[4-(2-hydroxy-4-methyl-benzoylamino)-cyclohexyl]-2-(3-trifluoromethoxy-phenoxy)-nicotinamide syn-2-Chloro-5-fluoro-N-[4-(2-hydroxy-4-methyl-benzoylamino)-cyclohexyl]-nicotinamide (150 mg, 0.37 mmol, see preparation 67) was mixed with caesium carbonate (602 mg, 1.85 mmol) and <strong>[827-99-6]3-trifluoromethoxyphenol</strong> (240 mul, 1.85 mmol) in N,N-dimethylformamide (5 ml) and the reaction mixture was heated at 650C under a nitrogen atmosphere for 16 hours. The reaction mixture was cooled to room temperature and was partitioned between ethyl acetate and water. The aqueous layer was adjusted to pH 4 by addition of citric acid and the layers were separated. The organic layer was washed with water and dried over magnesium sulphate and concentrated in-vacuo. The residue was purified by chromatography on silica gel using methanol in dichloromethane as eluant (gradient from 0:100 to 1:99). The material isolated was further purified by chromatography on silica gel using methanol in dichloromethane (0.5:99.5). The material obtained was re-suspended in diethyl ether and the solid formed was isolated by filtration to give syn-5-fluoro-N-[4-(2-hydroxy-4-methyl-benzoylamino)-cyclohexyl]-2-(3-trifluoromethoxy-phenoxy)-nicotinamide as a white solid (54 mg). 1H NMR (400 MHz, DMSO-d6): delta 1.70 (m, 8H), 2.26 (s, 3H), 3.90 (m, 2H), 6.70 (m, 2H), 7.24 (m, 3H), 7.52 (m, 1H), 7.77 (d, 1H), 8.01 (d, 1H), 8.28 (s, 1H), 8.34 (m, 2H), 12.32 (s, 1H); LCMS (electrospray): m/z [M-H]- 546.
  • 2
  • [ 58929-72-9 ]
  • [ 19438-10-9 ]
  • [ 534-17-8 ]
  • methyl 3-(2-methoxyethoxy)benzoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
In N-methyl-acetamide; dichloromethane; Method K 3-(2-Methoxy-ethoxy)-benzoic acid methyl ester To a solution of methyl 3-hydroxybenzoate (5.7 g) and 2-bromoethylmethyl ether (5.2 g) in dimethylformamide (100 ml) was added caesium carbonate (24.3 g). The reaction mixture was stirred for 12 hours. The mixture was then patitioned between ethyl acetate (400 ml) and water (400 ml). The organic layer was separated, dried (MgSO4) and the solvent removed under reduced pressure. The residue was purified by flash chromatography (Biotage 12M, eluding iso-hexane then MeOH:dichloromethane 2:98) to give the product as a colourless oil (5.3 g). 1H NMR: (CDCl3) δ 3.44 (3H, s), 3.75 (2H, t), 3.89 (3H, s), 4.15 (2H, t), 7.13 (1H, ddd), 7.32 (1H, t), 7.57 (1H, dd), 7.62 (1H, dt).
  • 3
  • [ 74204-00-5 ]
  • [ 534-17-8 ]
  • [ 96-32-2 ]
  • [ 331415-26-0 ]
YieldReaction ConditionsOperation in experiment
In acetonitrile; The compound N-[4'-(4-guanidinocarbonylphenoxymethyl)biphenyl-4-carbcnyl]guanidine is obtained analogously. EXAMPLE 5 A solution of 7.0 g of <strong>[74204-00-5]3-bromo-5-methylphenol</strong> and 5.97 g of methyl bromoacetate and also 13 g of caesium carbonate in 100 ml of acetonitrile is stirred overnight at room temperature. After customary working up, 9.70 g of methyl 3-bromo-5-methylphenoxyacetate ("AB") are obtained.
  • 4
  • [ 4578-63-6 ]
  • [ 100-39-0 ]
  • [ 534-17-8 ]
  • [ 173336-07-7 ]
YieldReaction ConditionsOperation in experiment
With sodium iodide; In acetone; n) 2-Benzyloxy-4-tert-butyl-benzoic acid benzyl ester A mixture of 5 g of <strong>[4578-63-6]2-hydroxy-4-tert-butyl-benzoic acid</strong>, 9.1 ml of benzyl bromide, 17 g of caesium carbonate, 0.3 g of sodium iodide and 500 ml of acetone is stirred for 20 hours under reflux and then filtered and the filtrate is concentrated by evaporation. The residue is partitioned between diethyl ether and water, the organic phases are concentrated by evaporation and the residue is purified by means of FC (1000 g of silica gel, dichloromethane/hexane=1:1). Title compound: Rf (dichloromethane/hexane=1:1)=0.47.
  • 5
  • [ 940-07-8 ]
  • europium(III) oxide [ No CAS ]
  • [ 534-17-8 ]
  • Cs3[Eu(pyrazine-2,6-dicarboxylate)3]*7H2O [ No CAS ]
  • 6
  • [ 936247-35-7 ]
  • [ 85118-00-9 ]
  • [ 534-17-8 ]
  • [ 1609082-28-1 ]
YieldReaction ConditionsOperation in experiment
Example 8A 5-Chloro-3-[(2,6-difluorobenzyl)oxy]-2-nitropyridine 33 g of <strong>[936247-35-7]5-chloro-2-nitropyridin-3-ol</strong> (Example 7A; 189 mmol, 1 equivalent) and 61.6 g of caesium carbonate (189 mmol, 1 equivalent) were initially charged in 528 ml of DMF, 40.4 g of 2,6-difluorobenzyl bromide (189 mmol, 1 equivalent) were added and the mixture was stirred at RT overnight. The reaction mixture was stirred into water/1N aqueous hydrochloric acid. The solid was filtered off, washed with water and air-dried. This gave 54.9 g (97% of theory) of the title compound. 1H-NMR (400 MHz, DMSO-d6): delta=5.46 (s, 2H); 7.22 (t, 2H); 7.58 (q, 1H); 8.28 (d, 1H); 8.47 (d, 1H).
  • 7
  • [ 71-41-0 ]
  • [ 534-17-8 ]
  • [ 2050-94-4 ]
YieldReaction ConditionsOperation in experiment
70% With 3-butyl-1-methyl-1H-imidazol-3-ium hexafluorophosphate; at 70℃; for 18.0h;Sealed tube; General procedure: A mixture of cinnamyl alcohol (67.1 mg, 0.5mmol), Cs2CO3 (325.8 mg, 1 mmol) and 1-n-butyl-3-methylimidazolium hexafluorophosphate ([bmim][PF6]) (0.1 mL) in dibromomethane (1 mL) was equipped with a seal tube and stirred for 18 h at 70° C. The reaction mixture was evaporated and purified by flash column chromatography (silica gel) (2percent Ether/hexane) to obtain dicinnamyl carbonate (1a) 69.0 mg (94percent).
  • 8
  • [ 4265-25-2 ]
  • [ 534-17-8 ]
  • [ 73183-34-3 ]
  • C15H20BO3(1-)*Cs(1+) [ No CAS ]
 

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