Synthesis and biological activities of petrosiols B and D

Abstract

A divergent total synthesis of natural diacetylenic tetraols, petrosiol B and petrosiol D, was accomplished by taking advantage of a carbohydrate chiral template. In particular, petrosiol B, which is the first total synthesis so far, was achieved in 13 linear steps with a 10% overall yield applying Ohira-Bestmann homologation, NaH-mediated dehydrobromination, and Cu(i)-catalyzed Cadiot-Chodkiewicz coupling as the key reaction steps. The synthetic petrosiols B and D were subjected to the study on differentiation activities toward neuronal progenitor PC12 cells. Our results suggested that both petrosiol B and petrosiol D could induce the differentiation of neuronal progenitor PC12 cells via the enhancement of Nrf2 activity. By comparing petrosiols B, D and their natural homologue E, petrosiol B displayed the most intensive cell differentiation activity and the highest Nrf2 activity enhancement as well.

Fig. 1. Structures of petrosiols A–E (1–5).

Scheme 1. Retrosynthetic analysis of petrosiols B and D.

Scheme 2. Synthesis of the C5–C16 fragment.

Scheme 3. Total synthesis of petrosiols B and D.

Fig. 2. Screening of sub-lethal concentrations of petrosiols B (A) and D (B) on PC12 cells. Cell viability was determined through CCK-8 assay at different concentrations of petrosiols B and D for 1, 3, and 5 d. ^#P < 0.001, relative to untreated control.

Fig. 3. Petrosiols B and D promoted neurite outgrowth and activity of Nrf2 in PC12 cells. Petrosiol B, D and E promoted neurite outgrowth in PC12 cells on day 1 (A), 3 (B), and 5 (C). *P < 0.05, relative to control. ^#P < 0.001, relative to control.

Fig. 4. The morphology changes of PC12 cells after petrosiols B, D, and E induction at 2.5 μg mL⁻¹ at day 3 and day 5.

Fig. 5. Petrosiols upregulated Nrf2 protein level in nuclear. (A) Protein levels in PC12 cell nuclear were determined via western blot. (B) Quantitative analysis of Nrf2 protein abundance was conducted with ImageJ software. Lamin A + C served as loading control. (C) The mRNA levels of HO-1 expression upon various concentrations of petrosiols B, D and E for 24 h. *P < 0.05, relative to control. ^#P < 0.001, relative to control.