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Structure-Activity Relationship of Indole-Tethered Pyrimidine Derivatives that Concurrently Inhibit Epidermal Growth Factor Receptor and Other Angiokinases.

Song J, Yoo J, Kwon A, Kim D, Nguyen HK, Lee BY, Suh W, Min KH - PLoS ONE (2015)

Bottom Line: MKP101 inhibited not only the epidermal growth factor receptor with an IC50 value of 43 nM but also inhibited angiokinases as potently as pazopanib.A docking model of MKP101 and the kinase domain of the epidermal growth factor receptor was generated to predict its binding mode, and validated by synthesizing and evaluating MKP101 derivatives.We believe that this study could provide a basis for developing angiokinase inhibitors having high affinity for the epidermal growth factor receptor, from the pyrimidine scaffold.

View Article: PubMed Central - PubMed

Affiliation: College of Pharmacy, Chung-Ang University, Seoul, Republic of Korea.

ABSTRACT
Antiangiogenic agents have been widely investigated in combination with standard chemotherapy or targeted cancer agents for better management of advanced cancers. Therapeutic agents that concurrently inhibit epidermal growth factor receptor and other angiokinases could be useful alternatives to combination therapies for epidermal growth factor receptor-dependent cancers. Here, we report the synthesis of an indole derivative of pazopanib using a bioisosteric replacement strategy, which was designated MKP101. MKP101 inhibited not only the epidermal growth factor receptor with an IC50 value of 43 nM but also inhibited angiokinases as potently as pazopanib. In addition, MKP101 effectively inhibited vascular endothelial growth factor-induced endothelial proliferation, tube formation, migration of human umbilical vein endothelial cells and proliferation of HCC827, an epidermal growth factor receptor-addicted cancer cell line. A docking model of MKP101 and the kinase domain of the epidermal growth factor receptor was generated to predict its binding mode, and validated by synthesizing and evaluating MKP101 derivatives. Additionally, a study of structure-activity relationships of indolylamino or indolyloxy pyrimidine analogues derived from MKP101 demonstrated that selectivity for epidermal growth factor receptor and other angiokinases, especially vascular endothelial growth factor receptor 2 depends on the position of substituents on pyrimidine and the type of link between pyrimidine and the indole moiety. We believe that this study could provide a basis for developing angiokinase inhibitors having high affinity for the epidermal growth factor receptor, from the pyrimidine scaffold.

No MeSH data available.


Related in: MedlinePlus

Synthesis of MKP101-123.Reagents and conditions: (A) Synthesis of MKP101-104, MKP106-117, MKP122: (a) 5-Aminoindoles (0.8–1.0 equiv.), Et3N (0.8–3.0 equiv.), isopropanol, rt, 1–10 h, or 5-hydroxyindole (0.77 equiv.), DBU (1.54 equiv.), MeCN, rt, 1 h; (b) CH3I (1.0–1.5 equiv.), NaH (or Cs2CO3) (1.0–1.2 equiv.), DMF, 0°C (or rt), 1 h; (c) ArNH2 (0.9–1.1 equiv.), 1-butanol, microwave irradiation, 200°C, 30 min. (B) Synthesis of MKP105: (a) 6-Aminoindole (1.5 equiv.), MeOH / H2O (1:3), rt, overnight; (b). CH3I (1.0 equiv.), NaH (1.0 equiv.), DMF, -10°C, 2h; (c) 5-Amino-2-methylbenzenesulfonamide (0.9–1.1 equiv.), 1-butanol, microwave 200°C, 30min. (C) Synthesis of MKP118-121, MKP123: (a) 5-Aminoindole (1.0 equiv.), Et3N (1.0 equiv.), isopropanol, rt, 2 h or 5-hydroxyindole (1.2 equiv.), DBU (2.0 equiv.), MeCN, rt, 1 h; (b) CH3I (1.1 equiv.), NaH (1.1 equiv.), DMF, 0°C rt, 1h; (c) ArNH2 (0.9–1.1 equiv.), 1-butanol, microwave irradiation 200°C, 30 min.
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pone.0138823.g001: Synthesis of MKP101-123.Reagents and conditions: (A) Synthesis of MKP101-104, MKP106-117, MKP122: (a) 5-Aminoindoles (0.8–1.0 equiv.), Et3N (0.8–3.0 equiv.), isopropanol, rt, 1–10 h, or 5-hydroxyindole (0.77 equiv.), DBU (1.54 equiv.), MeCN, rt, 1 h; (b) CH3I (1.0–1.5 equiv.), NaH (or Cs2CO3) (1.0–1.2 equiv.), DMF, 0°C (or rt), 1 h; (c) ArNH2 (0.9–1.1 equiv.), 1-butanol, microwave irradiation, 200°C, 30 min. (B) Synthesis of MKP105: (a) 6-Aminoindole (1.5 equiv.), MeOH / H2O (1:3), rt, overnight; (b). CH3I (1.0 equiv.), NaH (1.0 equiv.), DMF, -10°C, 2h; (c) 5-Amino-2-methylbenzenesulfonamide (0.9–1.1 equiv.), 1-butanol, microwave 200°C, 30min. (C) Synthesis of MKP118-121, MKP123: (a) 5-Aminoindole (1.0 equiv.), Et3N (1.0 equiv.), isopropanol, rt, 2 h or 5-hydroxyindole (1.2 equiv.), DBU (2.0 equiv.), MeCN, rt, 1 h; (b) CH3I (1.1 equiv.), NaH (1.1 equiv.), DMF, 0°C rt, 1h; (c) ArNH2 (0.9–1.1 equiv.), 1-butanol, microwave irradiation 200°C, 30 min.

Mentions: All indole-tethered pyrimidine derivatives were synthesized as shown in Fig 1. Commercially available 2,4-dichloropyrimidine was condensed with various 5-aminoindoles under basic condition to afford 1a-d. N-methylation of 1a-d using iodomethane yielded 2a-d. Finally, condensation of intermediates 1 or 2 with a variety of anilines provided the corresponding disubstituted pyrimidines, MKP101-104, 106–117 and MKP122 (Fig 1A). The synthesis of MKP105 was accomplished by condensation of 6-aminoindole with 2,4-dichloropyrimidine and N-methylation, followed by reaction with 5-amino-2-methylbenzenesulfonamide (Fig 1B). MKP118-121 and MKP123 were prepared using a procedure similar to that used for the synthesis of MKP106-117. Condensation of 4,6-dichloropyrimidine with 5-aminoindole or 5-hydroxyindole yielded 5a-b. N-methylation of 5a provided compound 6. MKP118-121 and MKP123 were obtained from condensation of various anilines with 5a-b, and 6 (Fig 1C).


Structure-Activity Relationship of Indole-Tethered Pyrimidine Derivatives that Concurrently Inhibit Epidermal Growth Factor Receptor and Other Angiokinases.

Song J, Yoo J, Kwon A, Kim D, Nguyen HK, Lee BY, Suh W, Min KH - PLoS ONE (2015)

Synthesis of MKP101-123.Reagents and conditions: (A) Synthesis of MKP101-104, MKP106-117, MKP122: (a) 5-Aminoindoles (0.8–1.0 equiv.), Et3N (0.8–3.0 equiv.), isopropanol, rt, 1–10 h, or 5-hydroxyindole (0.77 equiv.), DBU (1.54 equiv.), MeCN, rt, 1 h; (b) CH3I (1.0–1.5 equiv.), NaH (or Cs2CO3) (1.0–1.2 equiv.), DMF, 0°C (or rt), 1 h; (c) ArNH2 (0.9–1.1 equiv.), 1-butanol, microwave irradiation, 200°C, 30 min. (B) Synthesis of MKP105: (a) 6-Aminoindole (1.5 equiv.), MeOH / H2O (1:3), rt, overnight; (b). CH3I (1.0 equiv.), NaH (1.0 equiv.), DMF, -10°C, 2h; (c) 5-Amino-2-methylbenzenesulfonamide (0.9–1.1 equiv.), 1-butanol, microwave 200°C, 30min. (C) Synthesis of MKP118-121, MKP123: (a) 5-Aminoindole (1.0 equiv.), Et3N (1.0 equiv.), isopropanol, rt, 2 h or 5-hydroxyindole (1.2 equiv.), DBU (2.0 equiv.), MeCN, rt, 1 h; (b) CH3I (1.1 equiv.), NaH (1.1 equiv.), DMF, 0°C rt, 1h; (c) ArNH2 (0.9–1.1 equiv.), 1-butanol, microwave irradiation 200°C, 30 min.
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Related In: Results  -  Collection

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pone.0138823.g001: Synthesis of MKP101-123.Reagents and conditions: (A) Synthesis of MKP101-104, MKP106-117, MKP122: (a) 5-Aminoindoles (0.8–1.0 equiv.), Et3N (0.8–3.0 equiv.), isopropanol, rt, 1–10 h, or 5-hydroxyindole (0.77 equiv.), DBU (1.54 equiv.), MeCN, rt, 1 h; (b) CH3I (1.0–1.5 equiv.), NaH (or Cs2CO3) (1.0–1.2 equiv.), DMF, 0°C (or rt), 1 h; (c) ArNH2 (0.9–1.1 equiv.), 1-butanol, microwave irradiation, 200°C, 30 min. (B) Synthesis of MKP105: (a) 6-Aminoindole (1.5 equiv.), MeOH / H2O (1:3), rt, overnight; (b). CH3I (1.0 equiv.), NaH (1.0 equiv.), DMF, -10°C, 2h; (c) 5-Amino-2-methylbenzenesulfonamide (0.9–1.1 equiv.), 1-butanol, microwave 200°C, 30min. (C) Synthesis of MKP118-121, MKP123: (a) 5-Aminoindole (1.0 equiv.), Et3N (1.0 equiv.), isopropanol, rt, 2 h or 5-hydroxyindole (1.2 equiv.), DBU (2.0 equiv.), MeCN, rt, 1 h; (b) CH3I (1.1 equiv.), NaH (1.1 equiv.), DMF, 0°C rt, 1h; (c) ArNH2 (0.9–1.1 equiv.), 1-butanol, microwave irradiation 200°C, 30 min.
Mentions: All indole-tethered pyrimidine derivatives were synthesized as shown in Fig 1. Commercially available 2,4-dichloropyrimidine was condensed with various 5-aminoindoles under basic condition to afford 1a-d. N-methylation of 1a-d using iodomethane yielded 2a-d. Finally, condensation of intermediates 1 or 2 with a variety of anilines provided the corresponding disubstituted pyrimidines, MKP101-104, 106–117 and MKP122 (Fig 1A). The synthesis of MKP105 was accomplished by condensation of 6-aminoindole with 2,4-dichloropyrimidine and N-methylation, followed by reaction with 5-amino-2-methylbenzenesulfonamide (Fig 1B). MKP118-121 and MKP123 were prepared using a procedure similar to that used for the synthesis of MKP106-117. Condensation of 4,6-dichloropyrimidine with 5-aminoindole or 5-hydroxyindole yielded 5a-b. N-methylation of 5a provided compound 6. MKP118-121 and MKP123 were obtained from condensation of various anilines with 5a-b, and 6 (Fig 1C).

Bottom Line: MKP101 inhibited not only the epidermal growth factor receptor with an IC50 value of 43 nM but also inhibited angiokinases as potently as pazopanib.A docking model of MKP101 and the kinase domain of the epidermal growth factor receptor was generated to predict its binding mode, and validated by synthesizing and evaluating MKP101 derivatives.We believe that this study could provide a basis for developing angiokinase inhibitors having high affinity for the epidermal growth factor receptor, from the pyrimidine scaffold.

View Article: PubMed Central - PubMed

Affiliation: College of Pharmacy, Chung-Ang University, Seoul, Republic of Korea.

ABSTRACT
Antiangiogenic agents have been widely investigated in combination with standard chemotherapy or targeted cancer agents for better management of advanced cancers. Therapeutic agents that concurrently inhibit epidermal growth factor receptor and other angiokinases could be useful alternatives to combination therapies for epidermal growth factor receptor-dependent cancers. Here, we report the synthesis of an indole derivative of pazopanib using a bioisosteric replacement strategy, which was designated MKP101. MKP101 inhibited not only the epidermal growth factor receptor with an IC50 value of 43 nM but also inhibited angiokinases as potently as pazopanib. In addition, MKP101 effectively inhibited vascular endothelial growth factor-induced endothelial proliferation, tube formation, migration of human umbilical vein endothelial cells and proliferation of HCC827, an epidermal growth factor receptor-addicted cancer cell line. A docking model of MKP101 and the kinase domain of the epidermal growth factor receptor was generated to predict its binding mode, and validated by synthesizing and evaluating MKP101 derivatives. Additionally, a study of structure-activity relationships of indolylamino or indolyloxy pyrimidine analogues derived from MKP101 demonstrated that selectivity for epidermal growth factor receptor and other angiokinases, especially vascular endothelial growth factor receptor 2 depends on the position of substituents on pyrimidine and the type of link between pyrimidine and the indole moiety. We believe that this study could provide a basis for developing angiokinase inhibitors having high affinity for the epidermal growth factor receptor, from the pyrimidine scaffold.

No MeSH data available.


Related in: MedlinePlus