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Targeting kinases with anilinopyrimidines: discovery of N-phenyl-N'-[4-(pyrimidin-4-ylamino)phenyl]urea derivatives as selective inhibitors of class III receptor tyrosine kinase subfamily.

Gandin V, Ferrarese A, Dalla Via M, Marzano C, Chilin A, Marzaro G - Sci Rep (2015)

Bottom Line: Among the synthesized compounds, the N-phenyl-N'-[4-(pyrimidin-4-ylamino)phenyl]urea derivatives selectively targeted some members of class III receptor tyrosine kinase family.Starting from the structure of hit compound 19 we synthesized a further compound with an improved affinity toward the class III receptor tyrosine kinase members and endowed with a promising antitumor activity both in vitro and in vivo in a murine solid tumor model.Molecular modeling simulations were used in order to rationalize the behavior of the title compounds.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical and Pharmacological Sciences, University of Padova, via Marzolo, I-35131, Padova (Italy).

ABSTRACT
Kinase inhibitors are attractive drugs/drug candidates for the treatment of cancer. The most recent literature has highlighted the importance of multi target kinase inhibitors, although a correct balance between specificity and non-specificity is required. In this view, the discovery of multi-tyrosine kinase inhibitors with subfamily selectivity is a challenging goal. Herein we present the synthesis and the preliminary kinase profiling of a set of novel 4-anilinopyrimidines. Among the synthesized compounds, the N-phenyl-N'-[4-(pyrimidin-4-ylamino)phenyl]urea derivatives selectively targeted some members of class III receptor tyrosine kinase family. Starting from the structure of hit compound 19 we synthesized a further compound with an improved affinity toward the class III receptor tyrosine kinase members and endowed with a promising antitumor activity both in vitro and in vivo in a murine solid tumor model. Molecular modeling simulations were used in order to rationalize the behavior of the title compounds.

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Synthesis of compound 27.
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f6: Synthesis of compound 27.

Mentions: Based on the kinases screening results and on the IC50 and the SI values, we selected derivative 19 as our “hit compound”. As mentioned above, the 6-phenyl ring was designed to occupy the hydrophobic pocket II (Fig. 1g), which is next to the hydrophilic ribose binding region of the kinases (Fig. 1c). Hence, we tried to improve the ability of the hit compound to interact with class III RTK members through the insertion of a small hydrophilic moiety, intended to occupy the sugar pocket of the kinases, thus obtaining compound 27 (Fig. 6; see also Supplementary Information for details on synthetic procedures).


Targeting kinases with anilinopyrimidines: discovery of N-phenyl-N'-[4-(pyrimidin-4-ylamino)phenyl]urea derivatives as selective inhibitors of class III receptor tyrosine kinase subfamily.

Gandin V, Ferrarese A, Dalla Via M, Marzano C, Chilin A, Marzaro G - Sci Rep (2015)

Synthesis of compound 27.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4645160&req=5

f6: Synthesis of compound 27.
Mentions: Based on the kinases screening results and on the IC50 and the SI values, we selected derivative 19 as our “hit compound”. As mentioned above, the 6-phenyl ring was designed to occupy the hydrophobic pocket II (Fig. 1g), which is next to the hydrophilic ribose binding region of the kinases (Fig. 1c). Hence, we tried to improve the ability of the hit compound to interact with class III RTK members through the insertion of a small hydrophilic moiety, intended to occupy the sugar pocket of the kinases, thus obtaining compound 27 (Fig. 6; see also Supplementary Information for details on synthetic procedures).

Bottom Line: Among the synthesized compounds, the N-phenyl-N'-[4-(pyrimidin-4-ylamino)phenyl]urea derivatives selectively targeted some members of class III receptor tyrosine kinase family.Starting from the structure of hit compound 19 we synthesized a further compound with an improved affinity toward the class III receptor tyrosine kinase members and endowed with a promising antitumor activity both in vitro and in vivo in a murine solid tumor model.Molecular modeling simulations were used in order to rationalize the behavior of the title compounds.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical and Pharmacological Sciences, University of Padova, via Marzolo, I-35131, Padova (Italy).

ABSTRACT
Kinase inhibitors are attractive drugs/drug candidates for the treatment of cancer. The most recent literature has highlighted the importance of multi target kinase inhibitors, although a correct balance between specificity and non-specificity is required. In this view, the discovery of multi-tyrosine kinase inhibitors with subfamily selectivity is a challenging goal. Herein we present the synthesis and the preliminary kinase profiling of a set of novel 4-anilinopyrimidines. Among the synthesized compounds, the N-phenyl-N'-[4-(pyrimidin-4-ylamino)phenyl]urea derivatives selectively targeted some members of class III receptor tyrosine kinase family. Starting from the structure of hit compound 19 we synthesized a further compound with an improved affinity toward the class III receptor tyrosine kinase members and endowed with a promising antitumor activity both in vitro and in vivo in a murine solid tumor model. Molecular modeling simulations were used in order to rationalize the behavior of the title compounds.

No MeSH data available.


Related in: MedlinePlus