Synthesis of Lanostane‐Type Triterpenoid N‐Glycosides and Their Cytotoxicity against Human Cancer Cell Lines

Abstract

Seventeen lanostane-type triterpenoid derivatives (2 - 18), including 11N-glycosides (8 - 18), were synthesized from the natural triterpenoid, lanosterol (1), and were evaluated for their cytotoxicity against the human cancer cell lines, HL-60, A549, and MKN45, as well as the normal human lung cells, WI-38. Among them, N-β-d-2-acetamido-2-deoxyglucoside (10) showed cytotoxicity against HL-60, A549, MKN45, and WI-38 cells (IC 0.0078 - 2.8 μm). However, N-β-d-galactoside (12) showed cytotoxicity against HL-60 and MKN45 cells (IC 0.0021 - 4.0 μm), but not the normal WI-38 cells. Furthermore, Western blot analysis suggested that 12 induces apoptosis by activation of caspases-3, 8, and 9. These results will be useful for the synthesis of other tetracyclic triterpenoids or steroid N-glycosides to increase their cytotoxicity and apoptosis-inducing activities.

Design, Synthesis and Biological Evaluation of Steroidal Glycoconjugates as Potential Antiproliferative Agents

“…Reaction progress was monitored by analytical TLC was per formed on 0.50 mm Silica Gel 60 F254 plates (Qingdao Ocean Chemical Factory, Shandong, China) and were visualized by spraying with sulphuric acid in 10 % EtOH. 1 H NMR and 13 C NMR spectra were recorded in CDCl 3 or C 5 D 5 N with Bruker AV-500 or Bruker AV-600 spectrometer (TMS as internal standard). Chemical shifts were expressed in δ values (ppm) and the coupling constants (J) in Hz.…”

“…Chemical shifts were expressed in δ values (ppm) and the coupling constants (J) in Hz. 1 H and 13 C NMR were assigned using 1D and 2D NMR experiments (HSQC, HMBC and NOESY). Multiplicities are indicated by s (singlet), d (doublet), t (triplet), q (quartet), and m (multiplet).…”

“…Specifically, methoxyamine 7 was reduced by NaCNBH 3 to give a separable 1 : 1 mixture of MeON-pregnenolone 8/9 (R/ S, 1 : 1; Scheme 2). The chemical shift of chiral center at C-20 for each diastereomer (8/9) was assigned based upon 1 H NMR, 13 C NMR and HSQC experiment, C-20 protons (20R: 3.01-2.93 ppm, multiplet; 20S: 2.86-2.79 ppm, multiplet) and carbons (20R: 58.6 ppm; 20S: 59.7 ppm). The stereochemical structure of 8 and 9 (EtOAc) was ultimately confirmed though a single crystal X-ray diffraction experiment by using Cu Kα radiation, and the absolute configuration as 20R (compound 8), 20S (compound 9), respectively (Cambridge Crystallographic Data Centre 2010171, 2010608; Figure 2).…”

“…1 H NMR (500 MHz, C 5 D 5 N): δ = 5.42-5.38 (m, 1H), 4.88-4.80 (m, 1H), 4.60 (dd, J = 14.6, 7.7 Hz, 1H), 3.65 (dd, J = 11.0, 2.9 Hz, 1H), 3.56 (t, J = 10.6 Hz, 1H), 2.12 (s, 3H) 1.20 (t, J = 6.3 Hz, 3H), 1.03 (s, 3H), 0.91 (d, J = 7.6 Hz, 3H), 0.75 (d, J = 5.7 Hz, 3H). 13…”

“…[9] It has been reported that neoglycosylation could dramatically altered their cytotoxicity and selectivity against cancer cell lines. [10] To date, a number of natural products and small molecules, such as cardenolide, [11] colchicine, [12] lanosterol, [13] and betulinic acid, [14] have been employed for the neoglycosylation and anticancer assay. In our previous work, we found that the neoglycosides of tigogenin could significantly enhance its anticancer activity, [15] and compound Tg29 ((3R)-N-methoxyamino-tigogenin-β-2-deoxy-d-galactoside) exhibited IC 50 values even reaching 2.7 and 4.6 μM against HepG2 and MCF-7 cells, respectively.…”