Isolation, Identification and Synthesis of Neolignans from Phoebe Declinata Leaves: Molecular Modeling and Anticancer Evaluation

Two series of neolignans, aristoligol (R1) and aristoligone (R2), had been isolated from P. declinata Nees (Lauraceae) plant leaves. Dichloromethane (D.C.M.) was used to isolate R1 and R2 using flask silica column chromatography as a stationary phase. Meanwhile, n-hexane, dichloromethane, and methanol were used as mobile phases. Moreover, the synthesis of compound R2 to produce acetyl aristoligol (R3) was also done in this study. Compound R2 was synthesized with a reducing agent in methanol (NaBH4/MeOH) to result in a transition compound, the reduced-aristoligol. The transition compound was acetylated with acetic anhydride and catalyzed by D.M.A.P. to produce compound R3. The molecular structure identification of all neolignans and their molecular weights was validated by 1H-NMR, 13C-NMR, 2D-NMR, and LC-MS. Further determination of their structure-activity relationship, including molecular modeling and in vitro antiproliferative activity against MCF-7 breast cancer cell lines, showed that compound R2 has the best binding affinity towards human estrogen receptor-1 (∆G = -6.7 kcal/mol, Ki = 1.21 x 10-5 M). The ADME properties showed that compound R2 is the best one but still less active compared to the standard cancer drug, doxorubicin (∆G = -8.1 kcal/mol and Ki = 1.14 x 10-6 M). Meanwhile, compound R1 has the highest activity to inhibit the MCF-7 cell proliferation, with a 25 µg/mL concentration, and the highest cytotoxic activity with IC50 was 35 µg/mL.