Studies On The Synthesis And In Vivo Metabolism In Rats Of A Phenylnaphthalene-type Lignan Derivative VBE-6 As A Dual PI3K/Akt/mTOR And JNK Signaling Pathways Regulator

6-hydroxy-4-(4-hydroxy-3-methoxyphenyl)-3-hydroxymethyl-7-metho xy-3,4-dihydro-2-naphthaldehyde (VBE-1), a phenyldihydronaphthalene-type lignan from Vitex Negundo L., can inhibit the PI3K/Akt/mTOR pathway. VBE-1 exhibited different activities between in vitro and in vivo tests, which might due to its metabolic deactivation. Thus, regarding to the main deactivation site, VBE-1 was methylated to yield compound 6, 7-dimethoxy-4-(3,4-dimethoxyphenyl)-3-hydroxymethyl-3,4-dihydro-2-naphthaldehyde, named as VBE-6. VBE-6 presented a stronger inhibitory effect against breast cancer cells MCF-7 than VBE-1. In the previous study, VBE-6 showed to be a dual PI3K/Akt/mTOR and JNK signaling pathways regulator, by inhibiting Akt and activating JNK.This study has developed and optimized the semisynthesis route of VBE-6, which could contribute to the industrialization process of VBE-6 preparation. Then, the in vivo metabolism of VBE-6 has been evaluated in Spargue-Dawley rats. The primary route of metabolism of VBE-6 was O-dealkylation, which leads to three isomeric metabolites, M1, M2 and M3, in urine and feces. Based on MS and NMR spectra, the three metabolites were all new compounds, identified as 7-hydroxy-4-(3,4-dimethoxyphenyl)-6-methoxy-3-hydroxymethyl-3,4-di hydro-2-naphthaldehyde,6-hydroxy-4-(3,4-dimethoxyphenyl)-7-methoxy -3-hydroxylmethyl-3,4-dihydro-2-naphthaldehyde and 6,7-dimethoxy-4-(4-hydroxy-3-methoxyphenyl)-3-hydroxymethyl-3,4-dihydro-2-naphthald ehyde, respectively. In the metabolite quantification test, three major metabolites account for 48.8% in urine and 4.38% excreted in feces, respectively. There was trace amount of VBE-6 excreting via feces for 0.34%.The in vitro anticancer assay showed that three major metabolites M1, M2 and M3 were similarly potent against human breast cancer cell line MCF-7, compared with the parent drug VBE-6.Thus, this project has accomplished the synthesis and metabolism of VBE-6. Compared with that of VBE-1, VBE-6 does not undergo a metabolic deactivation in vivo after oral administration of VBE-6 to SD rats. The anticancer activities of metabolites of VBE-6 in rats were retained against human breast cancer MCF-7 in vitro. The metabolic data of VBE-6 might contribute to complement the toxicological and pharmacological evaluations in preclinical trials. Importantly, it could be of great use for the further mechanism study of VBE-6 as a promising anticancer candidate.