Structure of 93919-56-3
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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
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Substituted benzylamino-2′-deoxyadenosine a modified nucleoside with radiosensitizing properties
Datta, Magdalena ; Szczyrba, Adrian ; Czaja, Anna ; Zdrowowicz, Magdalena ; Demkowicz, Sebastian ; Rak, Janusz
Abstract: To verify whether the recently synthesized nucleoside, 8-(4-Trifluoromethoxy)benzylamino-2′-deoxyadenosine, can sensitize tumorous cells to X-rays, radiolytic and in vitro studies have been conducted. Molecular modeling demonstrated that excess electrons should lead to efficient dissociative electron attachment (DEA) to dA-NHbenzylOCF3 resulting in a radical product that can potentially damage DNA. The computationally predicted DEA process was confirmed via stationary radiolysis of a dA-NHbenzylOCF3 water solution followed by LC-MS analysis of the obtained radiolytes. Moreover, dA-NHbenzylOCF3 was tested against its cytotoxicity and clonogenicity. We showed that the modified nucleoside is not cytotoxic to PC3, MCF-7, and HaCaT cell lines. Additionally, the clonogenic test exhibited a statistically significant radiosensitization of PC3 and MCF-7 cells to X-rays. On the other hand, flow cytometry assays demonstrated that the action of dA-NHbenzylOCF3 is related to its influence on the cell cycle rather than the level of DNA double-strand breaks induced by ionizing radiation. Our findings indicate that the compound enters the cell and predominantly localizes in the cytoplasm, with a notable amount also detected in the nucleus. Moreover, we established that the compound is not phosphorylated by cellular kinases nor integrated into genomic DNA by the replication machinery.
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Keywords: Radiosensitizing nucleosides ; Dissociative electron attachment ; Clonogenic assay ; MTT test ; Cell cycle
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CAS No. : | 93919-56-3 |
Formula : | C8H8F3NO |
M.W : | 191.15 |
SMILES Code : | NCC1=CC=C(OC(F)(F)F)C=C1 |
MDL No. : | MFCD00061237 |
InChI Key : | DBGROTRFYBSUTR-UHFFFAOYSA-N |
Pubchem ID : | 571846 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H227-H315-H319-H335 |
Precautionary Statements: | P305+P351+P338 |
Num. heavy atoms | 13 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.25 |
Num. rotatable bonds | 3 |
Num. H-bond acceptors | 5.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 40.8 |
TPSA ? Topological Polar Surface Area: Calculated from |
35.25 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.03 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.96 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
3.15 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.68 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.0 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
2.16 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.4 |
Solubility | 0.755 mg/ml ; 0.00395 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.33 |
Solubility | 0.904 mg/ml ; 0.00473 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-3.07 |
Solubility | 0.162 mg/ml ; 0.000845 mol/l |
Class? Solubility class: Log S scale |
Soluble |
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) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
No |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-6.07 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
1.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
0.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
1.15 |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
[000214] To a stirred solution of 6 (40 mg, 0.14 mmol) in DMF (3 mL) under argon atmosphere was added CDI (71.7 mg, 0.17 mmol) at 0 C; warmed to RT and stirred for 2 h. To this were added (4-(trifluoromethoxy) phenyl) methanamine 172 (33.8 mg, 0.17 mmol), and diisopropyl ethyl amine (0.05 mL, 0.29 mmol) and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mass was diluted with water (15 mL) and stirred for 1 h. The precipitate was filtered or extracted with EtOAc or CH2C12 and the obtained solid was dried in vacuo or purified by column chromatography or triturated to afford the desired product. |
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