| Identification | Back Directory | [Name]
YHO-13177 | [CAS]
912287-56-0 | [Synonyms]
CS-2881
YHO-13177
Benzeneacetonitrile, α-[[5-(4-hydroxy-1-piperidinyl)-2-thienyl]methylene]-3,4-dimethoxy-, (αZ)- | [Molecular Formula]
C20H22N2O3S | [MDL Number]
MFCD28900680 | [MOL File]
912287-56-0.mol | [Molecular Weight]
370.47 |
| Chemical Properties | Back Directory | [Boiling point ]
577.4±50.0 °C(Predicted) | [density ]
1.266±0.06 g/cm3(Predicted) | [storage temp. ]
2-8°C | [solubility ]
DMSO: 100mg/mL | [form ]
Solid | [pka]
14.78±0.20(Predicted) | [color ]
Light yellow to yellow |
| Hazard Information | Back Directory | [Uses]
YHO-13177, a acrylonitrile derivative, is an orally active, potent and specific inhibitor of breast cancer resistance protein (BCRP) and ABCG2 with an IC50 value of 10 nM. YHO-13177 potentiates the cytotoxicity of SN-38 in HCT116 and A549 cells that express BCRP. YHO-13177 combined with Irinotecan (HY-16562) significantly suppresses the tumor growth in an HCT116/BCRP xenograft model[1][2][3]. | [Synthesis]
GENERAL STEPS: 5-(4-hydroxypiperidin-1-yl)-2-thiophenecarboxaldehyde and 3,4-dimethoxybenzeneacetonitrile were placed in a reactor and dissolved in ethanol. After addition of sodium ethoxide, the mixture was stirred under reflux conditions. After completion of the reaction, the reaction mixture was cooled with flowing water for tens of minutes. Water was added to the cooled mixture and stirring was continued for tens of minutes. The precipitated crystals were collected by filtration, washed sequentially with water, ethanol and hexane, and then dried under reduced pressure to give (Z)-2-(3,4-dimethoxyphenyl)-3-[5-(4-hydroxypiperidin-1-yl)thiophen-2-yl]acrylonitrile. Using 5-bromothiophene-2-carbaldehyde (42.30 g) and 4-hydroxypiperidine (67.30 g), an amination reaction was carried out according to Preparation Step 1 to obtain 5-(4-hydroxypiperidin-1-yl)-2-thiophenecarboxaldehyde (yield: 33.00 g, 71%). The prepared 5-(4-hydroxypiperidin-1-yl)-2-thiophenecarboxaldehyde (10.56 g) was subjected to condensation reaction with 3,4-dimethoxyphenylacetonitrile (8.86 g) according to the preparation step 2 to obtain (Z)-2-(3,4-dimethoxyphenyl)-3-[5-(4-hydroxypiperidin-1-yl)thiophen-2-yl]acrylonitrile (yield: 13.50 g, 73%). The obtained (Z)-2-(3,4-dimethoxyphenyl)-3-[5-(4-hydroxypiperidin-1-yl)thiophen-2-yl]acrylonitrile (20.00 g) was dissolved in chloroform (650 mL), and reacted with pyridine (6.41 g) and bromoacetyl bromide (14.13 g) according to Preparation Step 3 (Method A) to obtain bromoacetic acid 1-[5-[(Z)-2- cyano-2 -(3,4-dimethoxyphenyl)vinyl]thiophen-2-yl]piperidin-4-yl ester (yield: 23.00 g, 87%). The prepared 1-[5-[(Z)-2-cyano-2-(3,4-dimethoxyphenyl)vinyl]thiophen-2-yl]piperidin-4-yl ester of bromoacetic acid (2.30 g) was dissolved in chloroform (100 mL), and was reacted with piperidine (533 mg) and triethylamine (658 mg) according to Preparation Step 4 to give (Z)-2-(3,4-dimethoxyphenyl)-3-(5 -(4-hydroxypiperidin-1-yl)thiophen-2-yl)acrylonitrile (Yield: 1.40 g, 60%). | [in vivo]
YHO-13177 (19.7μM, i.v., or 27.3μM, p.o., a single dose for 25 days) is converted by YHO-13351, increases the survival time of mice inoculated with BCRP-transduced murine leukemia P388 cells and suppresses the tumor growth in an HCT116/BCRP xenograft mouse model[1].
| Animal Model: | HCT116/BCRP xenograft mouse model[1] | | Dosage: | 19.7 μM or 27.3 μM | | Administration: | 19.7 μM, i.v., or 27.3 μM, p.o., a single dose for 25 days | | Result: | Was maintained for at least 8 hours in plasma. |
| [References]
[1] Yamazaki R, et al. Novel acrylonitrile derivatives, YHO-13177 and YHO-13351, reverse BCRP/ABCG2-mediated drug resistance in vitro and in vivo. Mol Cancer Ther. 2011 Jul;10(7):1252-63. DOI:10.1158/1535-7163.MCT-10-0874
[2] Shishido Y, et al. ABCG2 inhibitor YHO-13351 sensitizes cancer stem/initiating-like side population cells to irinotecan. Anticancer Res. 2013 Apr;33(4):1379-86. PMID:23564776
[3] Yu S, et al. The mechanisms of multidrug resistance of breast cancer and research progress on related reversal agents. Bioorg Med Chem. 2023 Nov 15;95:117486. DOI:10.1016/j.bmc.2023.117486 |
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