RESUMO
An efficient palladium-catalyzed ortho-aroylation of O-arylmethyl and aryl-substituted acetoxime ethers has been developed; this method has high mono-site selectivity and does not require exogenous ligands. Under the direction of a simple exo-acetoxime auxiliary, a broad scope of masked arylmethyl alcohols and phenols as well as various aromatic aldehydes are compatible with this transformation, which probably follows a mechanistic pathway involving a six- or five-membered exo-cyclopalladated intermediate. The strategy can be expediently adopted to prepare synthetically valuable 1H-benzo[d][1,2]oxazines and benzo[d]isoxazoles. The directing group can be easily removed from the products to afford the functionalized diaryl ketones.
RESUMO
In an attempt to improve the antitumor activity of homocamptothecins (hCPTs), a series of novel 20-O-linked hCPT ester derivatives were first designed and synthesized based on a synthetic route, by which hCPTs are acylated with different substituted phenoxyacetic acid ester derivatives. Most of the derivatives were assayed for in vitro cytotoxicity against six human cancer cell lines KB, KB/VCR, A549, HCT-8, Bel7402, and A2780, and most of the assayed compounds exhibited good antiproliferative activity on these tumor cell lines especially on KB.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Camptotecina/análogos & derivados , Inibidores da Topoisomerase I/síntese química , Inibidores da Topoisomerase I/farmacologia , Antineoplásicos/química , Camptotecina/síntese química , Camptotecina/química , Camptotecina/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Ésteres , Humanos , Concentração Inibidora 50 , Células KB , Estrutura Molecular , Relação Estrutura-Atividade , Inibidores da Topoisomerase I/químicaRESUMO
A series of novel substituted uracil-1'(N)-acetic acid esters (6-20) of camptothecins (CPTs) were synthesized by the acylation method. These new compounds were evaluated for in vitro antitumor activity against tumor cell lines, A549, Bel7402, BGC-823, HCT-8 and A2780. In vitro results showed that most of the derivatives exhibited comparable or superior cytotoxicity compare to CPT (1) and topotecan (TPT, 2), with 12 and 13 possessing the best efficacy. Four compounds, 9, 12, 13 and 16, were selected to be evaluated for in vivo antitumor activity against H22, BGC-823 and Bel-7402 in mice. In vivo testing results indicated that 12 and 13 had antitumor activity against mouse liver carcinoma H22 close to Paclitaxel and cyclophosphamide. 12 had similar antitumor activity against human gastric carcinoma BGC-823 in nude mice compared to irinotecan (3) and possessed better antitumor activity against human hepatocarcinoma Bel-7402 in nude mice than 2. It is also discovered that 12 showed a similar mechanism but better inhibitory activity on topoisomerase I (Topo I) compared to 2. These findings indicate that 20(S)-O-fluorouracil-1'(N)-acetic acid ester derivative of CPTs, 12, could be developed as an antitumor drug candidate for clinical trial.
Assuntos
Antineoplásicos/química , Antineoplásicos/uso terapêutico , Camptotecina/análogos & derivados , Camptotecina/uso terapêutico , Neoplasias/tratamento farmacológico , Uracila/análogos & derivados , Uracila/uso terapêutico , Acetatos/síntese química , Acetatos/química , Acetatos/farmacologia , Acetatos/uso terapêutico , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Camptotecina/síntese química , Camptotecina/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , DNA Topoisomerases Tipo I/metabolismo , Humanos , Camundongos Nus , Neoplasias/metabolismo , Neoplasias/patologia , Inibidores da Topoisomerase I/síntese química , Inibidores da Topoisomerase I/química , Inibidores da Topoisomerase I/farmacologia , Inibidores da Topoisomerase I/uso terapêutico , Uracila/síntese química , Uracila/farmacologiaRESUMO
AIM: To improve the biological activity of A-ring modified analogues of camptothecin. METHODS: A-ring modified camptothecins were synthesized from 10-hydroxycamptothecin or 7-ethyl-10-hydroxycamptothecin (SN-38) in three or four steps. Their cytotoxicity was evaluated using MTY assay, and their in vivo antitumnor activity against mouse liver cancer H22 was tested. Results Five hexacyclic camptothecins (6a, 6b, 6c, 7a and 7b) are target compounds, and ten camptothecin derivatives are new compounds. CONCLUSION: The modification of a 1,4-oxazine-2-one ring fused with positions 9 and 10 of A-ring will reduce the antitumor activity of camptothecins.
Assuntos
Antineoplásicos/síntese química , Camptotecina/análogos & derivados , Camptotecina/síntese química , Compostos Policíclicos/síntese química , Animais , Antineoplásicos/farmacologia , Camptotecina/química , Camptotecina/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral/efeitos dos fármacos , Feminino , Humanos , Irinotecano , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Camundongos , Transplante de Neoplasias , Compostos Policíclicos/farmacologiaAssuntos
Antineoplásicos Fitogênicos/farmacologia , Camptotecina/farmacologia , Animais , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/uso terapêutico , Camptotecina/análogos & derivados , Camptotecina/química , Camptotecina/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Relação Estrutura-Atividade , Topotecan/química , Topotecan/uso terapêutico , Células Tumorais Cultivadas/efeitos dos fármacosRESUMO
A series of nitrogen-based 20S-hydroxyl camptothecin ester derivatives were prepared. 3-Aminopropionate of camptothecin was found more cytotoxic in vitro on several human tumor cell lines than 3-amidopropionate of camptothecin. Ester 16 showed best antitumor activity in vivo and in vitro in all esters we prepared.