Total Synthesis of the Potent Anticancer Aglaia Metabolites (−)-Silvestrol and (−)-Episilvestrol and the Active Analogue (−)-4′-Desmethoxyepisilvestrol

Abstract

Total synthesis of the anticancer 1,4-dioxane containing natural products silvestrol (1) and episilvestrol (2) is described by an approach based on the proposed biosynthesis of these novel compounds. The key steps included an oxidative rearrangement of the protected d-glucose derivative 11 to afford the 1,4-dioxane 12, which could be elaborated to the coupling partner 5 and a photochemical [3 + 2]-cycloadditon between the 3-hydroxyflavone 27 and methyl cinnamate followed by base-induced alpha-ketol rearrangement and reduction to give the cyclopentabenzofuran core 33. The core (-)-6 and 1,4-dioxane fragment 5 were united by a highly stereoselective Mitsunobu coupling with the modified azodicarboxylate DMEAD to afford the axial coupled product 36. Deprotection then gave episilvestrol (2). Silvestrol (1) was synthesized by a coupling between core (-)-6 and the dioxane 44 followed by deprotection. Compound 1 was also synthesized from episilvestrol (2) by a Mitsunobu inversion. In addition, the analogue 4'-desmethoxyepisilvestrol (46) was synthesized via the same route. It was found that 46 and episilvestrol 2 displayed an unexpected concentration-dependent chemical shift variation for the nonexchangeable dioxane protons. Synthetic compounds 1, 2, 38, 46, and 54 were tested against cancer cells lines, and it was found that the stereochemistry of the core was critical for activity. Synthetic analogue 4'-desmethoxyepisilvestrol (46) was also active against lung and colon cancer cell lines.

Discovery of Anticancer Agents of Diverse Natural Origin

“…More specifically, this group demonstrated that silvestrol promotes aberrant interaction of mRNA with the RNA helicase eukaryotic initiation factor (eIF) 4A to prevent its productive association with eIF4F, thus inhibiting the initiation step of translation (86, 87). The structure of silvestrol was confirmed though total synthesis by two groups independently, namely, Porco, Jr. and co-workers at Boston University (88), and Rizzacasa and colleagues at the University of Melbourne in Australia (89, 90). The Rizzacasa group also prepared a biotinylated derivative of episilvestrol [the C-5"' epimer of silvestrol (81)], and showed this to be highly selective in binding eIF4A, further supporting this factor as the principal cellular target of silvestrol (79, 90).…”

Chemistry and Biology of Rocaglamides (= Flavaglines) and Related Derivatives from Aglaia Species (Meliaceae)

“…(−)-Silvestrol ( 35 ) was then achieved through a selective “double Mitsunobu ” reaction of (−)- epi -silvestrol ( 36 ). Future studies by Rizzacasa and coworkers disclosed a method to resolve racemic 191 using (−)-menthol, as well as an improved Mitsunobu coupling of 191 and 199 using (di-2-methoxyethyl azodicarboxylate) (137). …”

“…Aside from their complexity and synthetic challenge, silvestrol and epi -silvestrol displayed potent anticancer activity in A549 lung cancer proliferation assays with IC 50 values of 33 n M and 30 n M (137). The synthetic analogue 4′-desmethoxy- epi -silvestrol was also found to be highly potent against LIM1215 colon cancer cells proliferation with an IC 50 of 10 n M , foreshadowing the development of cytotoxic flavagline analogues that are more potent than their parent counterparts.…”

The novel plant-derived agent silvestrol has B-cell selective activity in chronic lymphocytic leukemia and acute lymphoblastic leukemia in vitro and in vivo

“…57 provided key advice and expertise in the preclinical evaluation strategy of silvestrol; J.C.B. assisted in experimental design and interpretation as well as critical reading of the paper, provided CLL patient samples, and is the co-principal investigator of the laboratory in which work was conducted; A.D.K.…”