Characterization of undescribed melanoma inhibitors from Euphorbia mauritanica L. cultivated in Egypt targeting BRAF V600E and MEK 1 kinases via in-silico study and ADME prediction

• Published in: Phytochemistry (Oxford) Vol. 198; p. 113154
• Main Authors: Essa, Ahmed F, El-Hawary, Seham S, Emam, Sherif E, Kubacy, Tahia M, El-Khrisy, Ezz El-Din A M, Younis, Inas Y, Elshamy, Abdelsamed I
• Format: Journal Article
• Language: English
• Published: England 01.06.2022
• Subjects: Animals; Caco-2 Cells; Diterpenes - chemistry; Diterpenes - pharmacology; Egypt; Euphorbia - chemistry; Hep G2 Cells; Humans; MAP Kinase Kinase 1 - metabolism; Melanoma - drug therapy; Melanoma - enzymology; Melanoma, Experimental - drug therapy; Melanoma, Experimental - enzymology; Mice; Molecular Docking Simulation; Molecular Structure; Proto-Oncogene Proteins B-raf - metabolism; Spectroscopy, Fourier Transform Infrared; Egypt; Euphorbia mauritanica L; Melanoma; Euphorbiaceae; Jatrophane; Molecular docking; Ent-abietane
• ISSN: 1873-3700

Three undescribed diterpenes including two ent-abietanes, euphomauritanol A, and euphomauritanol B, and one jatrophane, euphomauritanophane A, in addition to eight previously described metabolites were isolated from the MeOH-CH Cl (1:1) extract of the Euphorbia mauritanica. The chemical structures of isolates were established based on the spectroscopic means including FT-IR, HRMS, 1D and 2D NMR. The absolute stereochemistry of the undescribed diterpenes was deduced by experimental and calculated TDDFT-electronic circular dichroism (ECD). The anti-proliferative effects of the isolated diterpenes were evaluated against B16-BL6, Hep G2, and Caco-2. The euphomauritanol A, euphomauritanol B, and euphomauritanophane A significantly inhibited the growth of murine melanoma B16-BL6 cell lines with IC 10.28, 20.22, and 38.81 μM, respectively with no responses against the other cells. These activities were rationalized by molecular docking of the active compounds in BRAF and MEK1 active sites. Moreover, the in-silico pharmacokinetics predictions by Swiss ADME revealed that the active compounds possessed favorable oral bioavailability and drug-likeness properties.