Abstract：
The chemical transformation of lathyrane nucleus through reduction and oxidation reactions using Euphorbia Factor L1 (EFL1) and Euphorbia Factor L1 (EFL3) as examples were investigated, along with a co-modification strategy of lathyrane nucleus and its side ester chain. A total of 38 lathyrane derivatives (5-42) including 34 new compounds were obtained, which greatly enriched the structural diversity of the lathyrane-type diterpenoids. Cytotoxicity against drug-sensitive and drug (adriamycin, ADM) resistant MCF-7 cells showed that 23 out of 38 transformed derivatives possessed obvious cytotoxic activity with IC50 values ranging from 7.0 to 41.1 μM and 3.2 to 45.5 μM, respectively, against both cells, compared to the noncytotoxic EFL1 and EFL3. The multidrug resistance (MDR) reversing activities of these lathyrane derivatives were further evaluated in MCF-7/ADM. Three transformed compounds (reversal fold, RF = 151.33, 62.94 and 47.3 for 27, 37 and 42) showed markedly higher activity than EFL1 (RF = 32.92) and EFL3 (RF = 39.68). Structure-activity relationship study revealed an essential role of C-6/17 and C-12/13 double bonds on lathyrane nucleus for exerting MDR reversal activity. Western blotting analysis showed that 42 could reduce the expression level of P-glycoprotein (P-gp) in MCF-7/ADM cells; however, the most active compound 27 with an unnatural 5/7/7/4 fused-ring diterpenoid skeleton, had no inhibitory effect on P-gp expression.
摘要：
以大黄因子L1(EFL1)和大黄因子L1(EFL3)为例,研究了通过还原和氧化反应对小黄核的化学转化,同时还提出了龙脑核及其侧酯链的共修饰策略。共获得38个lathrane衍生物（5-42个），包括34个新化合物，极大丰富了龙舌兰型二萜的结构多样性。对药物敏感和药物的细胞毒性（阿霉素，ADM）抗性MCF-7细胞显示，38种转化衍生物中有23种具有明显的细胞毒活性，IC50值在7.0至41.1μM和3.2至45.5μM之间，分别,对抗两个细胞，与非细胞毒性EFL1和EFL3相比。在MCF-7/ADM中进一步评估了这些lathrane衍生物的多药耐药性（MDR）逆转活性。三种转化的化合物(反转折叠，27、37和42的RF=151.33、62.94和47.3）显示出明显高于EFL1（RF=32.92）和EFL3（RF=39.68）的活性。构效关系研究揭示了C-6/17和C-12/13双键在lathyrane核上发挥MDR逆转活性的重要作用。Westernblotting分析表明,42可以降低MCF-7/ADM细胞中P-糖蛋白(P-gp)的表达水平;最具活性的化合物27具有非天然的5/7/7/4稠环二萜骨架，对P-gp表达无抑制作用。
