Ed ketone moiety of the A-ring in the -face followed by enolization or enol etherification top to the 3,20epoxy merchandise 13 and 14. Based on this assumption, to avoid the presence of an acid, we attempted to utilize the 7,14-diol derivative 11 with no a guarding group because the substrate to synthesize 12 through the sequential selenenylation and selenoxide elimination reactions in the identical style. To our surprise, the three,20-epoxy item 14 in place of 12 was obtained once more beneath these conditions, despite the fact that no acid was involved in this reaction. These resultsNIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author ManuscriptJ Med Chem. Author manuscript; obtainable in PMC 2014 November 14.Ding et al.Pagestrongly indicated that 12 endowed with both -formyl enone moiety and 7-hemiacetal group was unstable, and could automatically undergo three,7-rearrangement reaction without having the help of acid, presumably owing towards the improved electrophilicity of your -carbon inside the formyl enone JAK Inhibitor medchemexpress technique. Transposition of a functional group from 1 carbon to one more generally delivers a wide degree of diversity and flexibility in organic item synthesis and related drug design and style.30a We initially thought of the 1,3-enone transposition method inside the A-ring via direct Wharton carbonyl transposition30b of 6 to create 1-3-ketone (1-ene-3-ketone) analogues 19 and 20. Nonetheless, this method was not feasible because of the harsh reaction circumstances as well as the lack of regioselectivity in the enone formation. We therefore created an option and efficient synthetic method within a controlled regioselective manner (Scheme 3). The synthesis of analogues 19 and 20 began using the protection of your 7,14-dihydroxyl group of 1 as an acetonide. The 1-hydroxyl group in the acetonide was then selectively activated as a mesylate 16, which further underwent an elimination reaction31 inside the presence of Li2CO3 at 110 to supply the 1-ene analogue 17 in 84 yield.10b To introduce a hydroxyl group towards the 3-position with the A-ring, we initiated a crucial allylic oxidation by the therapy of 17 with selenium dioxide32 in refluxing 1,4-dioxane to stereoselectively generate the 1-ene-3hydroxyl analogue 18 in a fantastic yield;10b even so, prolonged reaction time failed to provide the enone product 19. Getting completed the synthesis of 18, our consideration was focused on the oxidation from the allylic alcohol. To our disappointment, neither activated MnO2 nor Dess-Martin reagent promoted this transformation. Ultimately, the goal was realized by utilizing pyridinium dichromate (PDC) to furnish the 1-ene-3-ketone analog 19 in 80 yield, followed by the removal from the defending group to supply the preferred analogue 20 bearing a 1-ene-3-ketone moiety within the A-ring. In Vitro Antiproliferative Activity With seven novel dienone analogues such as six, 7, ten, 13, 14, 19 and 20 in hand, their antiproliferative activities were evaluated against two breast cancer cell lines, MCF-7 (ERpositive) and MDA-MB-231 (triple-negative), together with the data summarized in Table 1. 1 was also tested for comparison. The results showed that five 7,20-epoxy dienone analogues (6, 7, ten, 19 and 20) not merely exhibited significantly improved antiproliferative activity ERK1 Activator Synonyms relative to 1 against ER-positive breast cancer MCF-7 cells with IC50 values varying from low micromolar to submicromolar range (0.56 0.31 M three.48 0.19 M), but additionally displayed superior growth inhibitory effects on triple-negative MDA-MB-231 cells with low micromolar IC50, for which 1.