RESUMO
Novel 2,4-diaminoquinazoline derivatives originating from a virtual screening approach were designed, synthesized and their biological activities as heat shock protein 90 (Hsp90) inhibitors were evaluated. The prepared compounds exhibited significant anti-proliferative activities against DU-145, HT-29, HCT-116, A375P and MCF-7 cancer cell lines. The selected compounds were tested against Her2, a client protein of Hsp90, and showed significant reduction in Her2 protein expression. Compound 6b was found the most potent, reduced Her2 protein expression levels and induced Hsp70 protein expression levels significantly.
Assuntos
Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Quinazolinas/síntese química , Quinazolinas/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Humanos , Quinazolinas/químicaRESUMO
Structure based drug design (SBDD) was used to discover heat shock protein 90 (HSP90) inhibitors useful in the treatment of cancer. By using the crystal structure of HSP90-ligand complex (1uyi), a docking model was prepared and was validated by external dataset containing known HSP90 inhibitors. This validated model was then used to virtually screen commercial databases, selected hits of which were bought and sent for real biological evaluation. Further as an alternative method, pharmacophores were generated using crystal structure conformations of ligands in HSP90 complexes (1uyi and 2bz5) and where used for virtual screening. Both cases yielded several hits containing novel scaffolds, particularly compound KHSP8 showed an IC(50) value of 0.902 µM in case of colon cancer (HT29), which is comparable to doxorubicin (0.828 µM). These compounds were being now used as leads for constructing small molecular libraries to get compounds with favourable pharmacokinetics and drug like properties.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Desenho de Fármacos , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Modelos Moleculares , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/patologia , Humanos , Concentração Inibidora 50 , Estrutura MolecularRESUMO
A series of aryloxazole, thiazole, and isoxazole derivatives was synthesized as vascular-targeting anticancer agents. Antiproliferative activity and tumor vascular-disrupting activity of all of the synthesized compounds were tested in vitro using various human cancer cell lines and HUVECs (human umbilical vein endothelial cells). Several compounds with an arylpiperazinyl oxazole core showed excellent cytotoxicity and metabolic stability in vitro. Among this series, two representative compounds (6-48 and 6-51) were selected and tested for the evaluation of anticancer effects in vivo using tumor-bearing mice. Compound 6-48 effectively reduced tumor growth (42.3% reduction in size) at the dose of 100 mg/kg. We believe that compound 6-48 will serve as a good lead compound for antimitotic and vascular-disrupting agents; further investigation to improve the in vivo efficacy of this series is underway.