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Cyclization of substitued 2-(2-fluorophenylazo)azines to azino[1,2-c]benzo[d][1,2,4]triazinium derivatives.

ABSTRACT: Light-induced cyclization of several substituted 2-(2-fluorophenylazo)azines in the presence of Ca(2+) ions to the corresponding triazinium derivatives is investigated experimentally and computationally. The azo derivatives of 4-methylpyridine 4 undergo facile cyclization to the corresponding triazinium 1, and the rate of cyclization increases with increasing number of fluorine atoms at the benzene ring. No triazinium ions were obtained from azo derivatives of 4-cyanopyridine, pyrazine and pyrimidine, presumably due to their instability under the reaction conditions. The experimental results and mechanism are discussed with the aid of DFT computational results.

SUBMITTER: Jankowiak A

PROVIDER: S-EPMC3778383 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Cyclization of substitued 2-(2-fluorophenylazo)azines to azino[1,2-c]benzo[d][1,2,4]triazinium derivatives.

Jankowiak Aleksandra A Obijalska Emilia E Kaszynski Piotr P

Beilstein journal of organic chemistry 20130916

Light-induced cyclization of several substituted 2-(2-fluorophenylazo)azines in the presence of Ca(2+) ions to the corresponding triazinium derivatives is investigated experimentally and computationally. The azo derivatives of 4-methylpyridine 4 undergo facile cyclization to the corresponding triazinium 1, and the rate of cyclization increases with increasing number of fluorine atoms at the benzene ring. No triazinium ions were obtained from azo derivatives of 4-cyanopyridine, pyrazine and pyrim ...[more]

PMID: 24062855

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Project description:In previous work, we applied the rotation-limiting strategy and introduced a substituent at the 3-position of the pyrazolo [3,4-d]pyrimidin-4-amine as the affinity element to interact with the deeper hydrophobic pocket, discovered a series of novel quinazolinones as potent PI3K? inhibitors. Among them, the indole derivative 3 is one of the most selective PI3K? inhibitors and the 3,4-dimethoxyphenyl derivative 4 is a potent and selective dual PI3K?/? inhibitor. In this study, we replaced the carbonyl group in the quinazolinone core with a sulfonyl group, designed a series of novel 2H-benzo[e][1,2,4]thiadiazine 1,1-dioxide derivatives as PI3K? inhibitors. After the reduction of nitro group in N-(2,6-dimethylphenyl)-2-nitrobenzenesulfonamide 5 and N-(2,6-dimethylphenyl)-2-nitro-5-fluorobenzenesulfonamide 6, the resulting 2-aminobenzenesulfonamides were reacted with trimethyl orthoacetate to give the 3-methyl-2H-benzo[e][1,2,4]thiadiazine 1,1-dioxide derivatives. After bromination of the 3-methyl group, the nucleophilic substitution with the 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine provided the respective iodide derivatives, which were further reacted with a series of arylboronic acids via Suzuki coupling to furnish the 2H-benzo[e][1,2,4]thiadiazine 1,1-dioxide derivatives 15a-J and 16a-d. In agreement with the quinazolinone derivatives, the introduction of a 5-indolyl or 3,4-dimethoxyphenyl at the affinity pocket generated the most potent analogues 15a and 15b with the IC50 values of 217 to 266 nM, respectively. In comparison with the quinazolinone lead compounds 3 and 4, these 2H-benzo[e][1,2,4]thiadiazine 1,1-dioxide derivatives exhibited much decreased PI3K? inhibitory potency, but maintained the high selectivity over other PI3K isoforms. Unlike the quinazolinone lead compound 4 that was a dual PI3K?/? inhibitor, the benzthiadiazine 1,1-dioxide 15b with the same 3,4-dimethoxyphenyl moiety was more than 21-fold selective over PI3K?. Moreover, the introducing of a fluorine atom at the 7-position of the 2H-benzo[e][1,2,4]thiadiazine 1,1-dioxide core, in general, was not favored for the PI3K? inhibitory activity. In agreement with their high PI3K? selectivity, 15a and 15b significantly inhibited the SU-DHL-6 cell proliferation.

Dataset Information

Cyclization of substitued 2-(2-fluorophenylazo)azines to azino[1,2-c]benzo[d][1,2,4]triazinium derivatives.

Publications

Cyclization of substitued 2-(2-fluorophenylazo)azines to azino[1,2-c]benzo[d][1,2,4]triazinium derivatives.

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