Chongqing Research Center for Pharmaceutical Engineering, Chongqing Medical University, Chongqing 400016, China; Biochemistry and Molecular Biology Laboratory, Experimental Teaching and Management Center, Chongqing Medical University, Chongqing 401331, China.
Department of Thoracic Surgery, Daping Hospital, Army Medical University, PLA, Chongqing 400042, China.
Eur J Pharmacol. 2021 Sep 5;906:174215. doi: 10.1016/j.ejphar.2021.174215. Epub 2021 May 31.
Evodiamine (EVO) was derivatized to a C10-amino derivative (EVA) using a two-step method suitable for industrializing production. This method has advantages such as a short reaction time, high yield, few byproducts and simple purification. The AUC and C values of EVA were 7.02- and 4.62-fold, while the T and Cl values were one-half and one-eighth that of EVO, respectively. EVA markedly improved the bioavailability, which might be ascribed to the serum albumin deposit effect. EVA was bound to albumin in the same hydrophobic pocket as EVO, but one more hydrogen bond was formed between Asp323 and the amino group at the C10 position. The amino derivative of natural alkaloids showed a substantial increase in antitumor activity on small cell lung cancer (SCLC) cells. The role of the PI3K/AKT signaling pathway in alkaloid/derivative-induced apoptosis in tumor cells was thoroughly described. p-AKT, its downstream effectors Bcl-2, Bax, caspase-3 and its upstream regulator PTEN were regulated by EVA. The interaction between EVO/EVA and the upstream protein PI3K p110 was first investigated with molecular docking. The apoptosis induced by EVA was abrogated after the PI3K/AKT signaling pathway was reactivated by IGF-1. The interaction between EVO/EVA and P-gp was also first studied using docking method. Their binding forces were weak. But EVA might reduce much expression of P-gp than EVO, and ultimately led to reduction of EVA efflux. Our study provides novel insights into a feasible and productive amino derivative of natural alkaloids for SCLC therapy.
吴茱萸碱（EVO）通过两步法衍生为 C10-氨基衍生物（EVA），该方法适合工业化生产。该方法具有反应时间短、产率高、副产物少、纯化简单等优点。EVA 的 AUC 和 C 值分别是 EVO 的 7.02 倍和 4.62 倍，而 T 和 Cl 值分别是 EVO 的一半和八分之一。EVA 显著提高了生物利用度，这可能归因于血清白蛋白沉积效应。EVA 与 EVO 一样，结合在白蛋白的同一疏水口袋中，但在 C10 位的氨基与天冬氨酸 323 之间形成了一个额外的氢键。天然生物碱的氨基衍生物在小细胞肺癌（SCLC）细胞中表现出显著的抗肿瘤活性增加。PI3K/AKT 信号通路在生物碱/衍生物诱导肿瘤细胞凋亡中的作用得到了深入描述。EVA 调节 p-AKT、其下游效应物 Bcl-2、Bax、caspase-3 及其上游调节剂 PTEN。首次通过分子对接研究了 EVO/EVA 与上游蛋白 PI3K p110 的相互作用。用 IGF-1 重新激活 PI3K/AKT 信号通路后，EVA 诱导的细胞凋亡被阻断。首次使用对接方法研究了 EVO/EVA 与 P-糖蛋白（P-gp）的相互作用。它们的结合力较弱。但 EVA 可能比 EVO 减少 P-gp 的表达，最终导致 EVA 外流减少。我们的研究为 SCLC 治疗提供了一种可行且高产的天然生物碱氨基衍生物。
