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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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Related in: MedlinePlus

Synthesis of compounds 1–26.See Fig. 2 for R specification.
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f3: Synthesis of compounds 1–26.See Fig. 2 for R specification.

Mentions: Compounds 1–7 and 8–12 were obtained starting from 4,6-dichloropyrimidine 28 (Fig. 3a). In case of unsymmetrical compounds (1–7), compound 28 was first condensed with a slight excess of aniline in i-PrOH in the presence of triethylamine (TEA) and then with the appropriate aniline derivatives in i-PrOH, in both cases taking advantage from the Microwave Assisted Organic Synthesis (MAOS). Diarylurea derivative 7 was obtained by the reaction of aminoderivative 6 with phenyl isocyanate in dichloromethane.


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 compounds 1–26.See Fig. 2 for R specification.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f3: Synthesis of compounds 1–26.See Fig. 2 for R specification.
Mentions: Compounds 1–7 and 8–12 were obtained starting from 4,6-dichloropyrimidine 28 (Fig. 3a). In case of unsymmetrical compounds (1–7), compound 28 was first condensed with a slight excess of aniline in i-PrOH in the presence of triethylamine (TEA) and then with the appropriate aniline derivatives in i-PrOH, in both cases taking advantage from the Microwave Assisted Organic Synthesis (MAOS). Diarylurea derivative 7 was obtained by the reaction of aminoderivative 6 with phenyl isocyanate in dichloromethane.

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