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Chemical Structure| 16265-04-6

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Abraha, Yuel W. ; Jacobs, Francois J. F. ; Brink, Alice ; Langner, Ernst H. G. ;

Abstract: Direct mixing (de novo) and Solvent Assisted Ligand Exchange (SALE) are the main methods used for the synthesis of Mixed-Linker Zeolitic Imidazolate Frameworks (ML-ZIFs). ML-ZIFs with combined -NO2 and -Br/-Cl functionalities were prepared via both synthetic routes. Thereafter the CO2 uptake of the ML-ZIFs were compared, as well as their abilities to fixate CO2 with epoxide substrates. The de novo synthesis resulted in ML-ZIFs with SOD topologies, 60: 40 (-NO2: -Br/-Cl) functionality ratios, higher porosities, better thermal stability and higher CO2 uptake than equivalent SALE products. SALE resulted in smaller ML-ZIF crystallites, only ∼ 10% incorporation of -Br/-Cl functionalized imidazolate linkers, and phase change during activation. ML-ZIF-7Cl, obtained from direct mixing, resulted in the highest CO2 uptake (90 cm3 g-1), in line with its higher porosity. ML-ZIF-7Cl, in combination with tetrabutylammonium bromide (TBAB), showed a high catalytic activity (TOF of 446 h-1) for the fixation of CO2 with propylene oxide and was reusable for up to 4 cycles without loss in activity.

Keywords: Zeolitic imidazolate frameworks (ZIFs) ; Solvent assisted ligand exchange (SALE) ; De Novo synthesis ; CO2 uptake ; CO2 fixation

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Park, Hyun Shin ;

Abstract: In chemical biology, reactive carbonyl species such as aldehydes and activated esters have been routinely utilized for modification biomolecules for various purposes such as imaging, enzyme profiling, drug delivery, and caging. This work herein presents a novel application of their chemistry to functionalize and control RNA and protein function through chemically reversible polyacylation. Also due to their reactive nature and propensity to form adducts with biomolecules and cause dysfunction, there has been continued interest in determining their concentration and composition to understand how they contribute to cancer, neurological disorders, and cardiovascular diseases. In furthering this endeavor, the second part of this work describes the development of fluorescent methods to measure and profile intracellular aldehydes. Chapter 1 describes the synthesis and RNA acylation activity of a series of minimalist azidoalkanoyl imidazole reagents, with the aim of functionalizing RNA at 2’-hydroxyl groups at stoichiometric to superstoichiometric levels. Due to their simple structure, they are prepared readily in high yields. Upon reaction with RNA, we find marked effects of small structural changes on their ability to acylate and be reductively removed. One compound in the series, a glycolic acid derivative, is shown to be highly active both in acylation of RNA and in phosphine-triggered deacylation, which enables reversible control of hybridization and folding. We also identify reagents that are ideal for long-term acylation of RNA, remaining stable even after azide reduction; this presents a novel and simple strategy for amine functionalization of RNA. Finally, an azidoacyl adduct on RNA was shown to react with a strained alkyne-containing fluorophore in a “cloak-click” strategy, suggesting a general approach to facile fluorescent labeling of RNAs. These simple azidoalkanoyl acylimidazole reagents serve as a set of molecular tools that can be employed easily for post-synthesis labeling and control of RNA irrespective of length.  Chapter 2 describes RNA 2’-OH polyacylation agents with improved reversibility based on quinone methide elimination. The rapidly reversible RNA caging method was utilized to control RNA folding and function, both in vitro and in cells. Previous uncloaking chemistry made use of azide reduction and subsequent amine cyclization, requiring 2 to 4 hours for completion. Aiming to improve reversal rates and yields, we designed novel acylating reagents that utilize quinone methide (QM) elimination for reversal. The QM uncloaking/de-acylation reactions were tested with two bioorthogonally cleavable motifs, azide and vinyl ether, and their acylation and reversal efficiencies were assessed with NMR and mass spectrometry on a model RNA substrate as well as on RNAs. Among the compounds tested, the azido-QM compound A-3 displayed excellent deacylation efficiency. To test its function in caging, A-3 was successfully applied to control EGFP mRNA translation in vitro and in cells. We envision that this compound will serve as a valuable tool for biological investigation and control of RNAs.  Chapter 3 discusses the potential application of chemically reversible acylating reagents to control protein function. Proteins are involved in all facets of cellular biology and have been harnessed for a wide range of technological and therapeutic purposes. To decipher their roles in complex biological systems and for additional spatiotemporal control in vitro, various caging strategies have been developed. However, simple methods applicable to native protein remain underexplored. In preliminary studies toward this goal, we examined whether NAI-N3, a chemically reversible acylating agent, could be used to control protein activity in a convenient manner. Polyacylation with NAI-N3 led to the inhibition of various proteins including trypsin, luciferase, horse radish peroxidase, and DNA polymerases. However, phosphine treatment and subsequent deacylation poorly recovered the original activity likely due to irreversible denaturation and aggregation and harsh reductive reversal conditions. Future efforts will investigate acylating reagents with enhanced reversibility such as the quinone methide probes in chapter 2 and reagents that maintain protein surface charge and with less denaturing properties.  Chapter 4 describes the application of fluorogenic probes to detect intracellular aldehydic load and progress toward the development of a method to profile intracellular aldehydes. Aldehydes are formed as metabolites in multiple cellular pathways and introduced from the environment. Due to their toxicity, their cellular levels are normally tightly regulated. Because they form adducts with DNA, aldehydes have been implicated in diseases with impaired DNA repair such as Fanconi anemia. Our lab has developed quenched hydrazone (“DarkZone”) dyes that output a fluorescent response to intracellular alkyl aldehydes. To analyze the aldehydic load in hematopoietic stem cells with DarkZone dyes, spectral overlap had to be minimized with fluorescent antibodies utilized for flow cytometry. To this end, novel DarkZone probes with various esterase cleavable motifs and fluorophores, Pacific Blue and V450, were explored. With the DarkZone probes, intracellular aldehydic loads in circulating human leukocytes were measured for the first time, and changes in cellular aldehyde concentration in the physiological range in response to aldehyde or ethanol challenge were detected. Additionally, we examined whether fluorophores with α-nucleophile reactive handles can be applied to determine cellular aldehyde composition. Utilization of these tools to investigate how deactivating aldehyde dehydrogenase 2 (ALDH2) mutants affect aldehyde content and whether ALDH activating molecules could be utilized to rescue cells from the genotoxicity of aldehydes is currently underway.

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Alternative Products

Product Details of [ 16265-04-6 ]

CAS No. :16265-04-6
Formula : C3H3ClN2
M.W : 102.52
SMILES Code : ClC1=NC=CN1
MDL No. :MFCD02179530
InChI Key :OCVXSFKKWXMYPF-UHFFFAOYSA-N
Pubchem ID :2773328

Safety of [ 16265-04-6 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H315-H319-H332-H335
Precautionary Statements:P280-P305+P351+P338-P310

Computational Chemistry of [ 16265-04-6 ] Show Less

Physicochemical Properties

Num. heavy atoms 6
Num. arom. heavy atoms 5
Fraction Csp3 0.0
Num. rotatable bonds 0
Num. H-bond acceptors 1.0
Num. H-bond donors 1.0
Molar Refractivity 23.6
TPSA ?

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

28.68 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

0.88
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

1.02
Log Po/w (WLOGP)?

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

1.06
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.

-0.2
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

1.91
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

0.93

Water Solubility

Log S (ESOL):?

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

-1.73
Solubility 1.89 mg/ml ; 0.0184 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.

-1.21
Solubility 6.29 mg/ml ; 0.0614 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

-1.78
Solubility 1.72 mg/ml ; 0.0167 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

High
BBB permeant?

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

Yes
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.

-6.2 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

2.0
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<1.0
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)

1.25

Application In Synthesis of [ 16265-04-6 ]

* 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 [ 16265-04-6 ]

[ 16265-04-6 ] Synthesis Path-Downstream   1~1

  • 1
  • [ 15469-97-3 ]
  • [ 16265-04-6 ]
YieldReaction ConditionsOperation in experiment
69% Example 1Synthesis of 2-chloroimidazole (2-cim)To a 300-mL, three-neck, round-bottom flask equipped with a magnetic stirrer and argon inlet, were added <strong>[15469-97-3]N-tritylimidazole</strong> (3.14 g, 0.01 mol) and anhydrous THF (140 mL).The stirrer was started, and the solution was cooled to -78° C. (acetone/dry ice).n-BuLi (2.5 M in hexanes, 8.0 mL, 0.02 mol) was added via syringe resulting in reddish solution.This solution was stirred for 60 min whereupon hexachloroethane (5.0 g, 0.021 mol) in THF (25 mL) was added in portions.The reaction mixture was stirred for 1 additional hour and then quenched with saturated aqueous ammonium chloride (100 mL).The cooling bath was removed, and when the reaction flask reached room temperature the contents were transferred to a 500 mL separatory funnel, and extracted with ethyl acetate (50 mL*2).The organic layer was separated, washed with water and brine, and dried over anhydrous sodium sulfate.After filtration, the solvents were evaporated under reduced pressure resulting in a slightly yellow solid.The solid was refluxed with 5percent acetic acid in methanol (75 mL) for 24 hours.Upon evaporation of the solvent, water was added to the residue.Extraction with hexanes effectively removed the triphenylmethane impurity.Evaporation of water in vacuo afforded off-white solid as pure 2-chloroimidazole (2-cim, 0.70 g, 69percent overall yield from N-triylimidazole).
 

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