基于天然产物salviadione和丹参酮IIA骨架杂合的新型衍生物设计、合成及其抗急性肺损伤活性研究

Acute lung injury (ALI) is one of the leading causes of morbidity and mortality in intensive care units worldwide, and currently no effective pharmacological treatment is available. Recently, the natural product Tan-IIA is attracting an increasing attention due to its dazzling in vitro and in vivo anti-inflammatory activity, and particularly demonstrates great clinical therapeutic potential for ALI. Nevertheless, further clinical development of Tan-IIA was seriously impaired by moderate potency and poor drug-like properties. In this proposal, to overcome these limitations arising from the problematic orth-quinone moiety, another natural product salvidione with the unique skeleton was merged into the Tan-IIA scaffold through a well-established biomimetic synthesis strategy, leading to a series of novel benzo[def]carbazole hybrids with the aims to improve drug-like properties while retain or strengthen the original anti-inflammatory activity and specific lung tissue distribution. Based on this unique hybrid scaffold, this project is also proposed to conduct a comprehensive medicinal chemistry campaign with the strategies of scaffold ring system shrinking, ring-opening, and bioisosteres. The structure-activity and -druggability relationships together with the action mechanism and target will be fully investigated to identify structurally novel drug candidates with improved potency and better drug-like properties for the prevention and treatment of ALI.

急性肺损伤是一种常见的致死率极高的危重病症，目前临床上仍然缺乏安全、有效的治疗靶点及药物。天然产物丹参酮IIA独特的抗炎活性在治疗急性肺损伤方面显示出极大潜力。然而，该天然产物在活性强度和成药性等方面仍然存在着诸多问题。为克服丹参酮IIA的邻醌片段所带来的一系列成药性问题，本项目运用仿生合成策略，将天然产物salviadione独特的苯并[def]咔唑结构与丹参酮IIA进行杂合，保留其原有的呋喃D环，破除邻醌，从而得到一类全新骨架的咔唑类衍生物，期望在改善丹参酮IIA水溶性、化学及代谢稳定性等成药性的同时，保持或增强其抗炎活性及肺组织分布特异性。并以此为基础，运用骨架环系收缩、去刚性开环和杂原子等排替换等策略, 进一步多方位结构改造，通过构-效关系等研究，同时探索作用机制与靶点，进而获得抗炎活性增强、成药性改善的新型候选化合物，为开发安全、有效的急性肺损伤预防和治疗新药奠定基础。

天然产物丹参酮IIA独特的抗炎活性在治疗急性肺损伤方面显示出极大潜力。然而，该天然产物在活性强度和成药性等方面仍然存在着诸多问题。为克服丹参酮IIA的邻醌片段所带来的一系列成药性问题，本项目运用仿生合成策略，将天然产物salviadione独特的苯并[def]咔唑结构与丹参酮IIA进行杂合，保留其原有的呋喃D环，破除邻醌，从而得到一类全新骨架的咔唑类衍生物。在此基础上，进一步运用骨架环系收缩、去刚性开环和杂原子等排替换等策略进行多方位结构改造，并通过系统结构-活性或成药性关系研究，获得抗炎活性显著增强、代谢稳定性以及PK性质显著改善的抗急性肺损伤候选化合物15a和15h。该类化合物可以特异性抑制肺组织炎症因子释放而对外周炎症因子无影响，有望避免系统性炎症因子抑制所带来的潜在安全风险。在此基础上，通过蛋白质微阵列技术，结合多种靶标验证实验，揭示细胞周期依赖蛋白9（CDK9）是候选化合物15a潜在作用靶标，并可能直接结合在CDK9的变构位点进而诱导其降解的抗急性肺损伤机制。上述研究结果为开发新型安全有效的急性肺损伤预防和治疗新药奠定基础。