Selected Methodologies Convenient for the Synthesis of <i>N</i>,5‐Diaryloxazole‐2‐amine Pharmacophore

Lintnerová, Lucia; Kovacikova, Lucia; Hanquet, Gilles; Boháč, Andrej

doi:10.1002/jhet.2063

Cited by 7 publications

(2 citation statements)

References 26 publications

(42 reference statements)

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“…Ligand AAZ was prepared in five steps in a low overall 10% yield mostly due to the problematic oxazole-2-amine fragment formation [12]. Low yields of oxazole-2-amine formation (1e58 %) have been also described [13,14]. Moreover AAZ contains N-aryloxazol-2-amine part that uses to liberate from connection with oxazole by influence of nucleophilic reagent (e.g.…”

Section: Introductionmentioning

confidence: 99%

Ynamide Click chemistry in development of triazole VEGFR2 TK modulators

Vojtíčková

Dobiáš

Hanquet

et al. 2015

European Journal of Medicinal Chemistry

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Keywords:Oxazole/1,2,3-triazole isosteric replacement Ynamide CuACC Click chemistry VEGFR2 tyrosine kinase inhibition Cytotoxic activity in Huh-7 and Mahlavu hepatocellular carcinoma cell lines PI3K/Akt pathway a b s t r a c t Structure novelty, chemical stability and synthetic feasibility attracted us to design 1,2,3-triazole compounds as potential inhibitors of VEGFR2 tyrosine kinase. Novel triazoles T1eT7 were proposed by oxazole (AAZ from PDB: 1Y6A)/1,2,3-triazole isosteric replacement, molecular modelling and docking. In order to enable synthesis of T1eT7 we developed a methodology for preparation of ynamide 22. Compound 22 was used for all Click chemistry reactions leading to triazoles T1eT3 and T6eT7. Among the obtained products, T1, T3 and T7 specifically bind VEGFR2 TK and modulate its activity by concentration dependent manner. Moreover predicted binding poses of T1eT7 in VEGFR2 TK were similar to the one known for the oxazole inhibitor AAZ (PDB: 1Y6A). Unfortunately the VEGFR2 inhibition by triazoles e.g. T3 and T7 is lower than that determined for their oxazole bioisosters T3-ox and AAZ, resp. Different electronic properties of 1,2,3-triazole/oxazole heterocyclic rings were proposed to be the main reason for the diminished affinity of T1eT3, T6 and T7 to an oxazole AAZ inhibitor binding site in VEGFR2 TK (PDB: 1Y6A or 1Y6B). Moreover T1eT3 and T6 were screened on cytotoxic activity against two human hepatocellular carcinoma cell lines. Selective cytotoxic activity of T2 against aggressive Mahlavu cells has been discovered indicating possible affinity of T2 to Mahlavu constitutionally active PI3K/Akt pathway.

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Section: Introductionmentioning

confidence: 99%

Ynamide Click chemistry in development of triazole VEGFR2 TK modulators

Vojtíčková

Dobiáš

Hanquet

et al. 2015

European Journal of Medicinal Chemistry

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“…9 For example, researchers at AstraZeneca recently reported their difficulties in developing conditions for the palladium-catalyzed cross-coupling of 2-aminooxazoles. 10 The authors reported that only trace amounts of coupling product could be obtained in the case of the parent 2-aminooxazole ( 1 ), although a handful of 4- and 5-substituted derivatives could be coupled in low to moderate yield.…”

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Mechanistic Insight Leads to a Ligand Which Facilitates the Palladium‐Catalyzed Formation of 2‐(Hetero)Arylaminooxazoles and 4‐(Hetero)Arylaminothiazoles

2017

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Using mechanistic insight, a new ligand (EPhos) for the Pd-catalyzed C–N cross-coupling between primary amines and aryl halides has been developed. Employing an isopropoxy group at the C3-position favors the C-bound isomer of ligand-supported Pd(II) complexes and leads to significantly improved reactivity. The use of a catalyst system based on EPhos with NaOPh as a mild homogeneous base proved to be very effective in the formation of 4-arylaminothiazoles and highly functionalized 2-arylaminooxazoles. Previously, these were not readily accessible using Pd-catalyzed methodology.

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Mechanistic Insight Leads to a Ligand Which Facilitates the Palladium‐Catalyzed Formation of 2‐(Hetero)Arylaminooxazoles and 4‐(Hetero)Arylaminothiazoles

2017

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By using mechanistic insight, anew ligand (EPhos) for the palladium-catalyzed CÀNc ross-coupling between primary amines and aryl halides has been developed. Employing an isopropoxy group at the C3-position favors the C-bound isomer of the ligand-supported palladium(II) complexes and leads to significantly improved reactivity.The use of acatalyst system based on EPhos with NaOPh as am ild homogeneous base proved to be very effective in the formation of 4-arylaminothiazoles and highly functionalized2 -arylaminooxazoles.P reviously,t hese were not readily accessible using palladium catalysis.

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Selected Methodologies Convenient for the Synthesis of N,5‐Diaryloxazole‐2‐amine Pharmacophore

Cited by 7 publications

References 26 publications

Ynamide Click chemistry in development of triazole VEGFR2 TK modulators

Ynamide Click chemistry in development of triazole VEGFR2 TK modulators

Mechanistic Insight Leads to a Ligand Which Facilitates the Palladium‐Catalyzed Formation of 2‐(Hetero)Arylaminooxazoles and 4‐(Hetero)Arylaminothiazoles

Mechanistic Insight Leads to a Ligand Which Facilitates the Palladium‐Catalyzed Formation of 2‐(Hetero)Arylaminooxazoles and 4‐(Hetero)Arylaminothiazoles

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