RESUMEN
As a result of our continuous research, new 3,4-dihydroquinazoline derivative containing ureido group, KCP10043F was synthesized and evaluated for T-type Ca(2+) channel (Cav3.1) blockade, cytotoxicity, and cell cycle arrest against human non-small cell lung (A549) cells. KCP10043F showed both weaker T-type Ca(2+) channel blocking activity and less cytotoxicity against A549 cells than parent compound KYS05090S [4-(benzylcarbamoylmethyl)-3-(4-biphenylyl)-2-(N,N',N'-trimethyl-1,5-pentanediamino)-3,4-dihydroquinazoline 2 hydrochloride], but it exhibited more potent G1-phase arrest than KYS05090S in A549 cells. This was found to be accompanied by the downregulations of cyclin-dependent kinase (CDK) 2, CDK4, CDK6, cyclin D2, cyclin D3, and cyclin E at the protein levels. However, p27(KIP1) as a CDK inhibitor was gradually upregulated at the protein levels and increased recruitment to CDK2, CDK4 and CDK6 after KCP10043F treatment. Based on the strong G1-phase cell cycle arrest of KCP10043F in A549 cells, the combination of KCP10043F with etoposide (or cisplatin) resulted in a synergistic cell death (combination index=0.2-0.8) via the induction of apoptosis compared with either agent alone. Taken together with these overall results and the favorable in vitro ADME (absorption, distribution, metabolism, and excretion) profiles of KCP10043F, therefore, it could be used as a potential agent for the combination therapy on human lung cancer.
Asunto(s)
Antineoplásicos/química , Bloqueadores de los Canales de Calcio/química , Canales de Calcio Tipo T/química , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Bloqueadores de los Canales de Calcio/farmacocinética , Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio Tipo T/metabolismo , Línea Celular Tumoral , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/metabolismo , Quinasas Ciclina-Dependientes/metabolismo , Ciclinas/metabolismo , Perros , Regulación hacia Abajo/efectos de los fármacos , Puntos de Control de la Fase G1 del Ciclo Celular/efectos de los fármacos , Semivida , Humanos , Ratones , Microsomas Hepáticos/metabolismo , Quinazolinas/química , Quinazolinas/farmacocinética , Quinazolinas/farmacología , Ratas , Regulación hacia Arriba/efectos de los fármacosRESUMEN
Four positively charged compounds, previously shown to produce analgesic activity by interacting with prokineticin receptor or T-type calcium channels, were tested for their ability to inhibit capsaicin-induced elevation of intracellular Ca(2+) in HEK-293 cells stably transfected with the human recombinant TRPV1, with the goal of identifying novel TRPV1 open-pore inhibitors. KYS-05090 showed the highest potency as a TRPV1 antagonist, even higher than that of the open-pore triazine inhibitor 8aA. The latter showed quite remarkable agonist/desensitizer activity at the rat recombinant TRPM8 channel. The activity of KYS-05090 and the other compounds was selective because none of these compounds was able to modulate the rat TRPA1 channel. Open-pore inhibitors of TRPV1 may be a new class of multi-target analgesics with lesser side effects, such as loss of acute pain sensitivity and hyperthermia, than most TRPV1 antagonists developed so far.