Design, Synthesis And Antitumor Activity Of Narciclasine Derivatives

Narciclasine is a polyhydroxy alkaloid compound isolated from narcissus. Data from the National Cancer Institute (NCI) show the IC50 values range between 50 and 63nM in 60 tumor cell lines,87 and 97nM in normal endothelial cells. This indicates narciclasine has excellent anti-tumor activity with a narrow therapeutic window.Structure-activity relationship studies showed that only the modification of hydroxyl at C-2 position by esterification was expected to enhance the antitumor activity. Therefore, based on the principle of split we introduced the pharmacophore of Maytansine and Taxol to the C-2 position of narciclasine and synthesized compounds 2-28 and 2-31 in yields of 33.6% and 31.9% in 3 steps. The structure was confirmed by MS,1H NMR and 13C NMR. Preliminary anti-tumor activity in vitro showed the IC50 of compounds 2-28 and 2-31 in 7 tumor cell lines (A549, HCT116, MDA-MB-231, HepG2, DU145, A375 and Ishikawa) ranged between 5.01-34.00μM,1.02-8.65μM respectively, which was weaker than narciclasine (IC50 between 0.05-0.73μM). Compound 2-31 was worthy of further study with IC50 values of 1.02μM in HepG2 cell line. The antitumor activity of compound 2-31 was superior to compound 2-28, which may be attributed to the π-π hydrophobic effect between the aromatic ring structure and the target enzyme.Further research found that the security dose of narciclasine in vivo yielded significant therapeutic benefits in various models of human brain cancers xenografted into the brains of immunocompromised mice. The predictive LogP of Narciclasine is only-1.005, far below the required range of 2-5. Therefore, this study designed and introduced the thiamine to narciclasine at C-2 position to improve its LogP values and adjust the cyclization rate, which could be regulated by varying their substituents in disulfide bonds. By predicting several physicochemical properties of the designed compounds, we synthesized 5 thiamine derivatives of Narciclasine. All intermediates and target compounds were identified by MS, MS,’H NMR and 13C NMR, and we optimized the conditions of the key steps. In the vitro anti-tumor test in nine tumor cell lines, all the five narciclasine derivatives exhibit excellent anti-tumor activity, especially in HCT116, MDA-MB-231, DU145 and A375, which IC50 values are less than 1μM. The antitumor activity of these 5 derivatives was better than Adriamycin in MDA-MB-231. The IC50 values of compound 3-20 in HCT116, MDA-MB-231 and DU145 cell lines are 0.03μM,0.25μM and 0.002μM, better than that of narciclasine. The inhibitory activity of the five derivatives was slightly weaker than narciclasine on two glioma cell lines. Meanwhile, the IC50 values of compounds 3-20,3-22 and 3-23 are 0.225μM 0.256μM and 0.265μM in U87MG glioma cell line,0.333μM,0.441μM and 0.374μM in LN229 glioma cell line. These 3 analogues exhibit good inhibitory activity of neurons glioma and are worthy of further study. The vivo activity test, selectivity and brain targeting of these narciclasine derivatives are still under exploration.