RESUMO
For the construction of new combinatorial libraries, a lead compound was created by replacing the core structure of a hit compound discovered by screening for cytotoxic agents against a tumorigenic cell line. The newly designed compound maintained biological activity and allowed alternative library construction for antitumor drugs.
Assuntos
Antineoplásicos/síntese química , Benzofuranos/síntese química , Ácidos Carboxílicos/síntese química , Antineoplásicos/farmacologia , Benzofuranos/farmacologia , Ácidos Carboxílicos/farmacologia , Linhagem Celular Tumoral , Avaliação Pré-Clínica de Medicamentos/métodos , Ésteres , HumanosRESUMO
Based on 2-methyl-4-nitro-2H-pyrazole-3-carboxylic acid[2-(cyclohexanecarbonylamino)benzothiazol-6-yl]amide (1), which shows selective cytotoxicity against tumorigenic cell lines, 2,6-dichloro-N-[2-(cyclopropanecarbonylamino)benzothiazol-6-yl]benzamide (13b) was designed and synthesized as a biologically stable derivative containing no nitro group. The highly potent derivative 13b exhibited excellent in vivo inhibitory effect on tumor growth.
Assuntos
Antineoplásicos , Neoplasias Pulmonares/tratamento farmacológico , Tiazóis , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Benzamidas/síntese química , Benzamidas/farmacologia , Benzamidas/uso terapêutico , Benzotiazóis/síntese química , Benzotiazóis/farmacologia , Benzotiazóis/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Desenho de Fármacos , Feminino , Humanos , Camundongos , Estrutura Molecular , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/farmacologia , Tiazóis/uso terapêutico , Fatores de Tempo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Based on the structure of 4-hydroxy-3-methyl-6-phenylbenzofuran-2-carboxylic acid ethyl ester (1), which exhibits selective cytotoxicity against a tumorigenic cell line, (2,4-dimethoxyphenyl)-(4-hydroxy-3-methyl-6-phenylbenzofuran-2-yl)-methanone (18m) was designed and synthesized as a biologically stable derivative containing no ester group. Although the potency of 18m was almost the same as our initial hit compound 1, 18m is expected to last longer in the human body as an anticancer agent.
Assuntos
Antineoplásicos/síntese química , Benzofuranos/síntese química , Ácidos Carboxílicos/síntese química , Antineoplásicos/farmacologia , Benzofuranos/farmacologia , Ácidos Carboxílicos/farmacologia , Linhagem Celular Tumoral , Ésteres , HumanosRESUMO
As a result of a hit-to-lead program using a technique of solution-phase parallel synthesis, a highly potent (2,4-dimethoxyphenyl)-[6-(3-fluorophenyl)-4-hydroxy-3-methylbenzofuran-2-yl]methanone (15b) was synthesized as an optimized derivative of 4-hydroxy-3-methyl-6-phenylbenzofuran-2-carboxylic acid ethyl ester (1), which was discovered as a screening hit from small-molecule libraries and exhibited selective cytotoxicity against a tumorigenic cell line.
Assuntos
Antineoplásicos/síntese química , Benzofuranos/síntese química , Ácidos Carboxílicos/síntese química , Linhagem Celular Tumoral , Técnicas de Química Combinatória/métodos , HumanosRESUMO
(3-Amino-6-thiophen-2-yl-thieno[2,3-b]pyridin-2-yl)phenylmethanone (3) was discovered as a new type of cytotoxic agent selective against a tumorigenic cell line. The molecular structure of a previously reported compound, (4-hydroxy-3-methyl-6-phenylbenzofuran-2-yl)phenylmethanone (2), had remarkably similar bioisosteric substructures to that of compound 3. Although the relationship between the molecular structure and biological activity of each derivative synthesized from these two hit compounds (2 and 3) were studied, unexpectedly no correlation was observed. However, after further synthetic study from 3, one of the most potent derivative (10k) having a different SAR profile from 2, was discovered.