Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China.
Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China; Laboratory of Xinjiang Native Medicinal and Edible Plant Resource Chemistry, College of Chemistry and Environmental Science, Kashi University, Kashgar 844007, People's Republic of China.
Bioorg Chem. 2023 Mar;132:106374. doi: 10.1016/j.bioorg.2023.106374. Epub 2023 Jan 16.
Twenty-eight grayanane diterpenoids (1-28) including 13 new ones, named daublossomins A-M (1-13), and two new natural products, 3-O-acetylgrayanotoxin II (14) and 10-epi-grayanotoxin III (15), were isolated from the flowers of Rhododendron dauricum L. (Ericaceae). Their structures were elucidated by means of comprehensive spectroscopic methods and quantum chemical calculations (C NMR-DP4+ analysis and calculated ECD), and the absolute configurations of ten grayanane diterpenoids 1, 4, 5, 7, 8, 22, 23, 25, 27, and 28 were determined by X-ray crystallographic analysis. Daublossomin A (1) represents the first example of an 11,16-epoxygrayan-6-one diterpenoid. Daublossomins B (2) and C (3) are the first examples of 9β,10β-epoxygrayanane diterpenoids, and daublossomin I (9) is the second conjugated grayan-1(5),6(7),9(10)-triene diterpenoid. Compounds 1-11 and 13-27 were evaluated for their analgesic activities in the HOAc-induced writhing test in mice, and 1-8, 10, 11, 13, 15, 17, 18, 22-24, and 26 exhibited significant analgesic effects at a dose of 5.0 mg/kg (inhibition rates > 50%). Among them, daublossomins A (1) and F (6) still showed potent analgesic activity even at a lower dose of 0.2 mg/kg with the inhibition rates of 54.4% and 55.2%, respectively. Grayanotoxin III (20) showed more potent analgesic activities than the positive control, morphine, at a dose of 0.04 mg/kg. A preliminary structure-activity relationship for the analgesic grayanane diterpenoids was discussed, providing some useful clues to design and develop structurally novel potent analgesics.
二十八种灰叶烷二萜类化合物（1-28），包括 13 种新化合物，命名为 daublossomins A-M（1-13），以及两种新的天然产物，3-O-乙酰基格雷诺毒素 II（14）和 10-表格雷诺毒素 III（15），从杜鹃花花中分离得到。通过综合光谱方法和量子化学计算（C NMR-DP4+分析和计算 ECD）阐明了它们的结构，并通过 X 射线晶体学分析确定了 10 种灰叶烷二萜类化合物 1、4、5、7、8、22、23、25、27 和 28 的绝对构型。Daublossomin A（1）代表了第一个 11,16-环氧灰叶烷-6-酮二萜类化合物。Daublossomins B（2）和 C（3）是第一个 9β,10β-环氧灰叶烷二萜类化合物，而 daublossomin I（9）是第二个共轭灰烷-1(5),6(7),9(10)-三烯二萜类化合物。对化合物 1-11 和 13-27 进行了 HOAc 诱导的小鼠扭体试验中的镇痛活性评估，化合物 1-8、10、11、13、15、17、18、22-24 和 26 在 5.0 mg/kg 剂量下显示出显著的镇痛作用（抑制率>50%）。其中，daublossomins A（1）和 F（6）即使在较低剂量 0.2 mg/kg 时仍表现出较强的镇痛活性，抑制率分别为 54.4%和 55.2%。格雷诺毒素 III（20）在 0.04 mg/kg 剂量下的镇痛活性强于阳性对照吗啡。对镇痛灰叶烷二萜类化合物进行了初步的结构-活性关系讨论，为设计和开发结构新颖的强效镇痛药提供了一些有用的线索。
