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Chemical Structure| 3945-69-5 Chemical Structure| 3945-69-5

Structure of DMTMM
CAS No.: 3945-69-5

Chemical Structure| 3945-69-5

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Rabinowitz, Zachary ; Deutsch‐Williams, Riley J ; Weissleder, Ralph ;

Abstract: Fluorescence-guided surgery is an emerging clinical field that aims to improve cancer detection in real-time, enabling spot-on therapeutic decisions. The use of fluorescent affinity probes has primarily involved systemically injected probes and, more recently, “spray-on probes”. A current challenge has been to develop “turn-off” probes that can be inactivated by a UV light pulse and reduce background noise during iterative decision-making. Here, we report on the first development of a FAP-targeted erasable spray-on probe (ESOP). The probe consists of three components: (i) a highly bright, yellow light-emitting rhodamine dye, (ii) a photo-responsive linear triazene linker, and (iii) a FAP affinity ligand. We demonstrate that this probe could enable highly sensitive tumor-specific margin visualization within minutes after a spray-on application. Moreover, we show that the fluorescent signals could be fully erased with a 2-min UV-light pulse in tissue, permitting iterative staining applications with consistently high tumor-to-background ratios (TBRs). ESOP targeted against cancer or host tissue is feasible and is likely to yield transformative impacts on next-generation cancer surgeries, ultimately improving patient care.

Keywords: cancer ; FAP ; fibroblast ; fluorescence ; rhodamines ; surgery

Purchased from AmBeed: ;

Wolfer, Jamison D ; Minkoff, Benjamin B ; Burch, Heather L ; Sussman, Michael R ;

Abstract: Protein footprinting is a useful method for studying protein higher order structure and conformational changes induced by interactions with various ligands via addition of covalent modifications onto the protein. Compared to other methods that provide single amino acid-level structural resolution, such as cryo-EM, X-ray diffraction, and NMR, mass spectrometry (MS)-based methods can be advantageous as they require lower protein amounts and purity. As with other MS-based proteomic methods, such as post-translational modification analysis, enrichment techniques have proven necessary for both optimal sensitivity and sequence coverage when analyzing highly complex proteomes. Currently used reagents for footprinting via covalent labeling, such as hydroxyl radicals and carbodiimide-based methods, do not yet have a suitable enrichment method, limiting their applicability to whole proteome analysis. Here, we report a method for enrichable covalent labeling built upon the GEE/EDC system commonly used to covalently label aspartic acid and glutamic acid residues. Novel labeling reagents containing alkynyl functionality can be "clicked" to any azido-containing molecule with copper-catalyzed azide−alkyne cycloaddition (CuAAC), allowing for enrichment or further labeling. Multiple azide- and alkyne-containing GEE-like molecules were tested, and the most efficient method was determined to be the EDC-facilitated coupling of glycine propargyl amide (GPA) to proteins. The pipeline we report includes clicking via CuAAC to a commercially available biotin-azide containing a photocleavable linker, followed by enrichment using a streptavidin resin and subsequent cleavage under ultraviolet light. The enrichment process was optimized through the screening of clickable amines, coupling reagents, and enrichment scaffolds and methods with pure model proteins and has also been applied to complex mixtures of proteins isolated from the model plant, Arabidopsis thaliana, suggesting that our method may ultimately be used to measure protein conformation on a proteomic scale.

Gardner, Eric D. ; Dimas, Dustin A. ; Finneran, Matthew C. ; Brown, Sara M. ; Burgett, Anthony W. ; Singh, Shanteri

Abstract: Tryprostatin A and B are prenylated, tryptophan-containing, diketopiperazine natural products, displaying cytotoxic activity through different mechanisms of action. The presence of the 6-methoxy substituent on the indole moiety of tryprostatin A was shown to be essential for the dual inhibition of topoisomerase II and tubulin polymerization However, the inability to perform late-stage modification of the indole ring has limited the structure-activity relationship studies of this class of natural products. Herein, we describe an efficient chemoenzymic approach for the late-stage modification of tryprostatin B using a cyclic dipeptide N-prenyltransferase (CdpNPT) from Aspergillus fumigatus, which generates novel analogs functionalized with allylic, benzylic, heterocyclic, and diene moieties. Notably, this biocatalytic functionalizational study revealed high selectivity for the indole C6 position. Seven of the 11 structurally characterized analogs were exclusively C6-alkylated, and the remaining four contained predominant C6-regioisomers. Of the 24 accepted substrates, 10 provided >50% conversion and eight provided 20-50% conversion, with the remaining six giving <20% conversion under standard conditions. This study demonstrates that prenyltransferase-based late-stage diversification enables direct access to previously inaccessible natural product analogs.

Keywords: biocatalysts ; chemoenzymatic synthesis ; late-stage functionalization ; prenyltransferase ; tryprostatin

Purchased from AmBeed: ; ; ; ;

Alternative Products

Product Details of [ 3945-69-5 ]

CAS No. :3945-69-5
Formula : C10H17ClN4O3
M.W : 276.72
SMILES Code : C[N+]1(C2=NC(OC)=NC(OC)=N2)CCOCC1.[Cl-]
English Name :4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium chloride
MDL No. :MFCD03613550
InChI Key :BMTZEAOGFDXDAD-UHFFFAOYSA-M
Pubchem ID :2734059

Safety of [ 3945-69-5 ]

Computational Chemistry of [ 3945-69-5 ] Show Less

Physicochemical Properties

Num. heavy atoms 18
Num. arom. heavy atoms 6
Fraction Csp3 0.7
Num. rotatable bonds 3
Num. H-bond acceptors 7.0
Num. H-bond donors 0.0
Molar Refractivity 70.25
TPSA ?

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

66.36 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

-3.17
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

1.26
Log Po/w (WLOGP)?

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

-3.52
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.

-3.56
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

0.37
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

-1.72

Water Solubility

Log S (ESOL):?

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

-2.4
Solubility 1.11 mg/ml ; 0.004 mol/l
Class?

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

Soluble
Log S (Ali)?

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

-2.25
Solubility 1.55 mg/ml ; 0.00559 mol/l
Class?

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

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

-2.83
Solubility 0.406 mg/ml ; 0.00147 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.

-7.09 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

0.0
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

1.0 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)

3.0

Application In Synthesis of [ 3945-69-5 ]

* 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 [ 3945-69-5 ]

[ 3945-69-5 ] Synthesis Path-Downstream   1~10

  • 1
  • [ 3945-69-5 ]
  • [ 241483-00-1 ]
YieldReaction ConditionsOperation in experiment
96% In dichloromethane at 20℃; for 3h;
96% In dichloromethane at 20℃; for 3h;
96% In dichloromethane at 20℃; for 3h;
In ethyl acetate at 23 - 29℃; for 0.5h; 35.A.B Example 35; Generation of DMT-MM Generation of DMT-MM To a solution OF 2-CI-4, 6-DIMEO-1, 3,5-triazene (CDMT) (6.2 mg, 35 mmol; 1.5 eq. ) in 70 mL of EtOAc kept in a room temperature water bath were added 4 mL (36.38 mmol) of neat N-methylmorpholine (MM). Solid 4- (4, 6-DIMETHOXY-1, 3,5- triazin-2-yl) -4-methylmorpholinium chloride (DMT-MM) started to precipitate out. The suspension containing DMT-MM was stirred for 30 min at room temperature at which time it became a thick paste. The temperature rose from 23 to 28-29C during the reaction. The temperature of the reaction is kept down to minimize competing demethylation to form di-MeO-N morfolino-triazene (DMMT).

  • 2
  • [ 109-02-4 ]
  • [ 3140-73-6 ]
  • [ 241483-00-1 ]
  • [ 3945-69-5 ]
YieldReaction ConditionsOperation in experiment
1: 95% 2: 2% In dichloromethane at 20℃; for 17h;
1: 78% 2: 21% In dichloromethane at 20℃; for 0.5h;
  • 3
  • [ 64-04-0 ]
  • [ 3945-69-5 ]
  • [ 501-52-0 ]
  • [ 10264-31-0 ]
  • [ 241483-00-1 ]
  • [ 906212-16-6 ]
YieldReaction ConditionsOperation in experiment
1: 47% 2: 18% 3: 22%
  • 4
  • 3-(methoxycarbonyl)amino-4-methoxy-isoxazole-5-carboxylic acid [ No CAS ]
  • [ 57478-19-0 ]
  • [ 144-55-8 ]
  • [ 3945-69-5 ]
  • 3-[(Methoxycarbonyl)amino]-N-para-[4-(trifluoromethyl)phenoxy]phenyl-isoxazole-5-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
37% With hydrogenchloride; In ethanol; water; ethyl acetate; 3-[(Methoxycarbonyl)amino]-N-para-[4-(trifluoromethyl)phenoxy]phenyl-isoxazole-5-carboxamide (44) A mixture of 0.162g (0.75mmol) of 3-(methoxycarbonyl)amino-4-methoxy-isoxazole-5-carboxylic acid, 0.172g (0.68mmol) of 4-[4-(trifluoromethyl) phenoxy]aniline and 0.212g (0.75mmol) of 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride in 5ml of ethanol is heated at 70C for 6 hours, and then stirred at room temperature for 16 hours. After evaporation of the ethanol, the residue is taken up in ethyl acetate and the resulting solution is washed successively with a saturated solution of sodium hydrogenocarbonate, water, 2% solution of hydrochloric acid, and water. After drying and concentrating, the residue is chromatographed (ethyl acetate/heptane, 2:8) to give 0,122g (37% yield) of a cream solid (M+1 = 452).
  • 5
  • [ 82834-12-6 ]
  • [ 3945-69-5 ]
  • [ 945033-04-5 ]
YieldReaction ConditionsOperation in experiment
In tetrahydrofuran at 20 - 25℃; for 0.166667h; 1 Into a round bottom flask, tetrahydrofuran (25 ml), N-I(S)- carboxyethylbutyl-(S)-alanine (1.Og) and 4-(4,6-dimethoxy-l,3,5-triazin-2-yl)-4- methylmorpholinium chloride (1.274 g) were added. The reaction mass was stirred for about 10 minutes at a temperature ranging from about 200C to about 25°C under nitrogen. The resulting solution contained the complex of Formula II.
  • 6
  • [ 3945-69-5 ]
  • [ CAS Unavailable ]
  • [ 241483-00-1 ]
YieldReaction ConditionsOperation in experiment
In N,N-dimethyl-formamide at 20℃;
  • 7
  • [ 3945-69-5 ]
  • [ 106261-49-8 ]
  • [ 1166872-12-3 ]
YieldReaction ConditionsOperation in experiment
In acetonitrile for 0.166667h; 1 5 g of 4-(4-methylpiperazinyl-methyl) benzoic acid dihydrochloride hemihydrate were added to the reaction mixture. All solid material was completely dissolved after10 minutes forming slightly yellow clear solution.;
In water; acetonitrile at 20 - 25℃; for 0.75h; 2 1O g of 4-(4-methylpiperazinyl-methyl) benzoic acid dihydrochloride hemihydrate dissolved in50 ml of water were subsequently added to the reaction mixture at 20-25 0C. Suspension turned to a clear homogeneous solution after 15 minutes of vigorous stirring. Reaction mixture was stirred for 0.5 h
  • 8
  • [ 3945-69-5 ]
  • [ 179162-55-1 ]
  • [ 1896685-52-1 ]
YieldReaction ConditionsOperation in experiment
Stage #1: 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride; 4-{5-[4-(pentyloxy)phenyl]-1,2-oxazol-3-yl}benzoic acid at 20℃; for 0.25h; Inert atmosphere; Stage #2: With N-ethyl-N,N-diisopropylamine at 10 - 20℃; 1 Method-IT: To a stirred solution of PPIB in THFDMF (40 vol.) under N2 atmosphere, was charged 4-(4,6-Dimethoxy- 1,3,5 -triazin-2-yl)-4- methylmorpholin-4-ium chloride (DMTMM) (1.5 eq.) and stir for 15 mm at room temperature. Reaction mixture was cooled to 10-15°C and DIPEA charged slowly. Reaction mixture was allowed to stir for overnight at room temperature and workup and purification was carried as described in method I.
  • 9
  • [ 1466-83-7 ]
  • [ 3945-69-5 ]
  • [ 1403558-90-6 ]
YieldReaction ConditionsOperation in experiment
With 4-methyl-morpholine In 1,4-dioxane; water for 3h; General procedure for the preparataion of (3aa): General procedure: To a solution of benzoic acid 1a (2.2 g, 18.0 mmol) and N-methylmorpholine (396 µL, 3.60 mmol) in 1,4-dioxane/H2O(100 mL:50 mL) was added DMT-MM (5.23 g, 18.9 mmol) at room temperature. After stirring for 15 min, a solution ofalanine 2a (1.76 g, 19.8 mmol) and aq 1 M NaOH (19.8 mL, 19.8 mmol) was added. After the reaction was completed(monitored by TLC), N-methylmorpholine (3.96 mL, 36.0 mmol) and DMT-MM (14.9 g, 54 mmol) were added in order.After stirring for 3 h, the reaction mixture was diluted in EtOAc (100 mL) and washed with aq 1 M HCl (40 mL), sat. aqNaHCO3 (40 mL), and brine (30 mL). The organic layer was dried over Na2SO4, filtered, and evaporated under reducedpressure. The residue was purified by column chromatography (EtOAc:hexane = 7:3) to give oxazole 3aa in 78% yield.
  • 10
  • [ 10290-61-6 ]
  • [ 3945-69-5 ]
  • [ 2154430-32-5 ]
YieldReaction ConditionsOperation in experiment
With 4-methyl-morpholine In 1,4-dioxane; water for 3h; General procedure for the preparataion of (3aa): General procedure: To a solution of benzoic acid 1a (2.2 g, 18.0 mmol) and N-methylmorpholine (396 µL, 3.60 mmol) in 1,4-dioxane/H2O(100 mL:50 mL) was added DMT-MM (5.23 g, 18.9 mmol) at room temperature. After stirring for 15 min, a solution ofalanine 2a (1.76 g, 19.8 mmol) and aq 1 M NaOH (19.8 mL, 19.8 mmol) was added. After the reaction was completed(monitored by TLC), N-methylmorpholine (3.96 mL, 36.0 mmol) and DMT-MM (14.9 g, 54 mmol) were added in order.After stirring for 3 h, the reaction mixture was diluted in EtOAc (100 mL) and washed with aq 1 M HCl (40 mL), sat. aqNaHCO3 (40 mL), and brine (30 mL). The organic layer was dried over Na2SO4, filtered, and evaporated under reducedpressure. The residue was purified by column chromatography (EtOAc:hexane = 7:3) to give oxazole 3aa in 78% yield.
 

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