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[ CAS No. 16867-03-1 ] {[proInfo.proName]}

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Chemical Structure| 16867-03-1
Chemical Structure| 16867-03-1
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Product Citations

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Ingraham, Charles H. IV ; Stalinska, Joanna ; Carson, Sean C. , et al. DOI: PubMed ID:

Abstract: Glioblastomas are highly aggressive brain tumors for which therapeutic options are very limited. In a quest for new anti-glioblastoma drugs, we focused on specific structural modifications to the benzoyl-phenoxy-acetamide (BPA) structure present in a common lipid-lowering drug, fenofibrate, and in our first prototype glioblastoma drug, PP1. Here, we propose extensive computational analyses to improve the selection of the most effective glioblastoma drug candidates. Initially, over 100 structural BPA variations were analyzed and their physicochemical properties, such as water solubility (- logS), calculated partition coefficient (ClogP), probability for BBB crossing (BBB_SCORE), probability for CNS penetration (CNS-MPO) and calculated cardiotoxicity (hERG), were evaluated. This integrated approach allowed us to select pyridine variants of BPA that show improved BBB penetration, water solubility, and low cardiotoxicity. Herein the top 24 compounds were synthesized and analyzed in cell culture. Six of them demonstrated glioblastoma toxicity with IC50 ranging from 0.59 to 3.24 μM. Importantly, one of the compounds, HR68, accumulated in the brain tumor tissue at 3.7 ± 0.5 μM, which exceeds its glioblastoma IC50 (1.17 μM) by over threefold.

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Product Details of [ 16867-03-1 ]

CAS No. :16867-03-1 MDL No. :MFCD00006317
Formula : C5H6N2O Boiling Point : -
Linear Structure Formula :C5H3N(NH2)(OH) InChI Key :BMTSZVZQNMNPCT-UHFFFAOYSA-N
M.W : 110.11 Pubchem ID :28114
Synonyms :

Calculated chemistry of [ 16867-03-1 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 8
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.0
Num. rotatable bonds : 0
Num. H-bond acceptors : 2.0
Num. H-bond donors : 2.0
Molar Refractivity : 30.66
TPSA : 59.14 ?2

Pharmacokinetics

GI absorption : High
BBB permeant : No
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.87 cm/s

Lipophilicity

Log Po/w (iLOGP) : 0.7
Log Po/w (XLOGP3) : 0.15
Log Po/w (WLOGP) : 0.38
Log Po/w (MLOGP) : -0.45
Log Po/w (SILICOS-IT) : 0.25
Consensus Log Po/w : 0.21

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 1.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -1.17
Solubility : 7.41 mg/ml ; 0.0673 mol/l
Class : Very soluble
Log S (Ali) : -0.95
Solubility : 12.4 mg/ml ; 0.113 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -1.03
Solubility : 10.3 mg/ml ; 0.0938 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.31

Safety of [ 16867-03-1 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 16867-03-1 ]

* 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.

  • Upstream synthesis route of [ 16867-03-1 ]
  • Downstream synthetic route of [ 16867-03-1 ]

[ 16867-03-1 ] Synthesis Path-Upstream   1~8

  • 1
  • [ 16867-03-1 ]
  • [ 78-39-7 ]
  • [ 86467-39-2 ]
YieldReaction ConditionsOperation in experiment
65.8%
Stage #1: at 120℃; for 4 h;
Stage #2: Cooling
80 mL of ethyl orthoacetate was added to 15 g (136 mmol) of 2-amino-3-hydroxypyridine, followed by addition of p-toluenesulfonic acid in a catalytic amount, and the mixture was reacted at 120° C. for 4 hours. After the reaction solution was cooled, triethylamine was added to the solution, to neutralize p-toluenesulfonic acid. Then, the solution was subjected to distillation under reduced pressure by using an evaporator, and then purified by silica gel column chromatography.Amount of the product: 12.0 g, Yield: 65.8percent.
Reference: [1] Monatshefte fur Chemie, 2011, vol. 142, # 1, p. 87 - 91
[2] Heterocycles, 1995, vol. 41, # 3, p. 477 - 486
[3] Monatshefte fur Chemie, 2007, vol. 138, # 7, p. 663 - 667
[4] Patent: US2009/247736, 2009, A1, . Location in patent: Page/Page column 13
[5] Tetrahedron Letters, 1990, vol. 31, # 8, p. 1155 - 1156
[6] Synthetic Communications, 1992, vol. 22, # 20, p. 2891 - 2901
  • 2
  • [ 16867-03-1 ]
  • [ 123-54-6 ]
  • [ 86467-39-2 ]
Reference: [1] Journal of Organic Chemistry, 2014, vol. 79, # 13, p. 6310 - 6314
  • 3
  • [ 16867-03-1 ]
  • [ 64-19-7 ]
  • [ 86467-39-2 ]
Reference: [1] Tetrahedron Letters, 2007, vol. 48, # 13, p. 2295 - 2298
  • 4
  • [ 16867-03-1 ]
  • [ 32894-07-8 ]
  • [ 86467-39-2 ]
Reference: [1] Tetrahedron Letters, 1990, vol. 31, # 8, p. 1155 - 1156
  • 5
  • [ 16867-03-1 ]
  • [ 75-36-5 ]
  • [ 31354-48-0 ]
Reference: [1] Tetrahedron, 2006, vol. 62, # 10, p. 2405 - 2412
[2] Tetrahedron Letters, 2004, vol. 45, # 7, p. 1465 - 1468
  • 6
  • [ 16867-03-1 ]
  • [ 108-24-7 ]
  • [ 31354-48-0 ]
Reference: [1] Journal of Medicinal Chemistry, 2007, vol. 50, # 15, p. 3730 - 3742
  • 7
  • [ 16867-03-1 ]
  • [ 877399-47-8 ]
Reference: [1] Patent: CN108341802, 2018, A,
  • 8
  • [ 16867-03-1 ]
  • [ 24424-99-5 ]
  • [ 902835-93-2 ]
YieldReaction ConditionsOperation in experiment
95% With guanidine hydrochloride In ethanol at 35 - 40℃; for 2.5 h; General procedure: Amine (1 mmol) was added to a magnetically stirred solution of guanidine hydrochloride (15 molpercent) and di-tert-butyl dicarbonate (1.2 mmol) in EtOH (1 mL), at 35-40°C and stirred for appropriate time (Table 1). After completion of the reaction (followed by TLC or GC), EtOH was evaporated under vacuum and the residue either was washed with water to remove the catalyst or was dissolved in CH2Cl2 (or EtOAc) and filtered off to separate out the catalyst. Evaporation of the organic solvent (if used in work up) gives almost a pure product. In the cases of using an excess (Boc)2O the product was washed with petroleum ether or hexane to recover the residual (Boc)2O. If necessary, the product was further purified either by crystallization (hexane and dichloromethane, or diethyl ether and petroleum ether) or silica gel column chromatography using EtOAc-hexane (1: 6) as eluent.
Reference: [1] Tetrahedron Letters, 2011, vol. 52, # 12, p. 1260 - 1264
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