RESUMO
Checkpoint kinase 1 (Chk1) is a key mediator of the DNA damage response that regulates cell cycle progression, DNA damage repair, and DNA replication. Small-molecule Chk1 inhibitors sensitize cancer cells to genotoxic agents and have shown preclinical activity as single agents in cancers characterized by high levels of replication stress. However, the underlying genetic determinants of Chk1-inhibitor sensitivity remain unclear. Although treatment options for advanced colorectal cancer are limited, radiotherapy is effective. Here, we report that exposure to a novel amidine derivative, K1586, leads to an initial reduction in the proliferative potential of colorectal cancer cells. Cell cycle analysis revealed that the length of the G2/M phase increased with K1586 exposure as a result of Chk1 instability. Exposure to K1586 enhanced the degradation of Chk1 in a time- and dose-dependent manner, increasing replication stress and sensitizing colorectal cancer cells to radiation. Taken together, the results suggest that a novel amidine derivative may have potential as a radiotherapy-sensitization agent that targets Chk1.
Assuntos
Amidinas , Quinase 1 do Ponto de Checagem , Neoplasias Colorretais , Quinase 1 do Ponto de Checagem/metabolismo , Quinase 1 do Ponto de Checagem/antagonistas & inibidores , Humanos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Neoplasias Colorretais/radioterapia , Amidinas/farmacologia , Linhagem Celular Tumoral , Radiação Ionizante , Radiossensibilizantes/farmacologia , Replicação do DNA/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacosRESUMO
PPO herbicides emerge to be widely use in the agricultural field and a focus of research to many scientists due to its environmentally-friendly properties. In lieu with this, this study presents acrylate and acrylamide substituted pyrimidinediones as PPO herbicide candidates. Most synthesized compounds exhibits herbicidal activities against both monocot and dicot weeds, especially, compound 5a which showed non-selective superior activity against the commercialized, Saflufenacil. Compound 5a was further tested for residual effect and showed promising results as shorter period is needed to cultivate the next crops. The synthesized acrylate and acrylamide substituted pyrimidinediones, especially, 5a could potentially be utilized in the development of commercial protoporphyrinogen oxidase inhibitors with further tests and studies.