Abstract：
In our previous study, a screening of a variety of lycotonine-type diterpenoid alkaloids were screened for cardiotonic activity revealed that lycoctonine had moderate cardiac effect. In this study, a series of structurally diverse of lycoctonine were synthesized by modifying on B-ring, D-ring, E-ring, F-ring, N-atom or salt formation on lycoctonine skeleton. We evaluated the cardiotonic activity of the derivatives by isolated frog heart, aiming to identify some compounds with significantly enhanced cardiac effects, among which compound 27 with a N-isobutyl group emerged as the most promising cardiotonic candidate. Furthermore, the cardiotonic mechanism of compound 27 was preliminarily investigated. The result suggested that the cardiotonic effect of compound 27 is related to calcium channels. Patch clamp technique confirmed that the compound 27 had inhibitory effects on CaV1.2 and CaV3.2, with inhibition rates of 78.52 % ± 2.26 % and 79.05 % ± 1.59 % at the concentration of 50 μM, respectively. Subsequently, the protective effect of 27 on H9c2 cells injury induced by cobalt chloride was tested. In addition, compound 27 can alleviate CoCl2-induced myocardial injury by alleviating calcium overload. These findings suggest that compound 27 was a new structural derived from lycoctonine, which may serve as a new lead compound for the treatment of heart failure.
摘要：
在我们之前的研究中,一项对多种lycotonine型二萜生物碱进行的强心活性筛选结果显示lycoactonine具有中等的心脏作用.在这项研究中,通过在B环上修饰合成了一系列结构多样的lycottonine，D形环,E形环,F形环,在lycottonine骨架上形成N原子或盐。我们通过分离的青蛙心脏评估了衍生物的强心活性，旨在鉴定一些具有显著增强心脏效应的化合物，其中具有N-异丁基的化合物27成为最有前途的强心候选化合物.此外，初步研究了化合物27的强心机制。结果表明，化合物27的强心作用与钙通道有关。膜片钳技术证实化合物27对CaV1.2和CaV3.2有抑制作用，在50μM浓度下抑制率为78.52%±2.26%和79.05%±1.59%，分别。随后，研究了27对氯化钴诱导的H9c2细胞损伤的保护作用。此外,化合物27可以通过减轻钙超载来减轻CoCl2诱导的心肌损伤。这些发现表明，化合物27是一种新的结构来源于lycoctonine，它可以作为治疗心力衰竭的一种新的先导化合物。
