OBJECTIVES: Naphthalimides have shown potent antitumour activity against a variety of murine and human cancer cells. However, most of them have been abandoned because of a poor therapeutic index and haematotoxicity, such as amonafide. To overcome these disadvantages, many novel naphthalimide derivatives have been designed and synthesized as antitumour agents. METHODS: The cytotoxicity of 6,6-(propane-1,3-diylbis(azanediyl)bis(2-(2-(dimethylamino)ethyl)-1H-benzo[de]isoquinoline-1-3(2H)-dione) (BND-12) was evaluated using multiparameter cytotoxicity 2 kit by High Content Screening (HCS). The antiproliferative ability of BND-12 was evaluated using MTT assay. BND-12-mediated cell apoptosis was evaluated using HCS. Antitumor effects and systemic toxicity of BND-12 were evaluated in vivo using Kunming male mice. KEY FINDINGS: After screening, we found BND-12, a novel naphthalimide derivative, exerted favourable antitumour activity in vitro and in vivo. Our data demonstrated that the cytotoxicity of BND-12 was due to cell apoptosis via the mitochondrial pathway. Interestingly, we demonstrated that BND-12 exerted more potent antitumour activity in subcutaneous xenograft tumour growth, survival time and lung metastasis than amonafide in vivo. Encouragingly, preliminary toxicological evaluation demonstrated that BND-12 had no obvious systemic toxicity at the therapeutic dose, especially haematotoxicity. CONCLUSIONS: BND-12 exerted potent effects against HCC in vivo and in vitro, importantly, it had no obvious systemic toxicity at the therapeutic dose.
OBJECTIVES:Naphthalimides have shown potent antitumour activity against a variety of murine and humancancer cells. However, most of them have been abandoned because of a poor therapeutic index and haematotoxicity, such as amonafide. To overcome these disadvantages, many novel naphthalimide derivatives have been designed and synthesized as antitumour agents. METHODS: The cytotoxicity of 6,6-(propane-1,3-diylbis(azanediyl)bis(2-(2-(dimethylamino)ethyl)-1H-benzo[de]isoquinoline-1-3(2H)-dione) (BND-12) was evaluated using multiparameter cytotoxicity 2 kit by High Content Screening (HCS). The antiproliferative ability of BND-12 was evaluated using MTT assay. BND-12-mediated cell apoptosis was evaluated using HCS. Antitumor effects and systemic toxicity of BND-12 were evaluated in vivo using Kunming male mice. KEY FINDINGS: After screening, we found BND-12, a novel naphthalimide derivative, exerted favourable antitumour activity in vitro and in vivo. Our data demonstrated that the cytotoxicity of BND-12 was due to cell apoptosis via the mitochondrial pathway. Interestingly, we demonstrated that BND-12 exerted more potent antitumour activity in subcutaneous xenograft tumour growth, survival time and lung metastasis than amonafide in vivo. Encouragingly, preliminary toxicological evaluation demonstrated that BND-12 had no obvious systemic toxicity at the therapeutic dose, especially haematotoxicity. CONCLUSIONS:BND-12 exerted potent effects against HCC in vivo and in vitro, importantly, it had no obvious systemic toxicity at the therapeutic dose.