benzofurans and episilvestrol

Four new cyclopenta[

Topics: Aglaia; Antineoplastic Agents, Phytogenic; Benzofurans; HT29 Cells; Humans; Magnetic Resonance Spectroscopy; PC-3 Cells; Plant Extracts; Plant Roots; Triterpenes

Four new 2,3-secodammarane triterpenoids, stellatonins A-D (3-6), together with a new 3,4-secodammarane triterpenoid, stellatonin E (7), and the known silvestrol (1), 5‴-episilvestrol (2), and β-sitosterol, were isolated from a methanol extract of the stems of Aglaia stellatopilosa through bioassay-guided fractionation. The structures of the new compounds were elucidated using spectroscopic and chemical methods. The compounds were evaluated for their cytotoxic activity against three human cancer cell lines and for their antimicrobial activity using a microtiter plate assay against a panel of Gram-positive and Gram-negative bacteria and fungi.

Topics: Aglaia; Antineoplastic Agents, Phytogenic; Benzofurans; Dammaranes; Drug Screening Assays, Antitumor; Female; Gram-Negative Bacteria; Gram-Positive Bacteria; HT29 Cells; Humans; Malaysia; Microbial Sensitivity Tests; Molecular Structure; Nuclear Magnetic Resonance, Biomolecular; Plant Stems; Saccharomyces cerevisiae; Sitosterols; Triterpenes

The first total synthesis of the low-abundance natural product 2''',5'''-diepisilvestrol (4) is described. The key step involved a Mitsunobu coupling between cyclopenta[b]benzofuran phenol 7 and dioxane lactol 6. Deprotection then gave a 1:2.6 ratio of natural product 2''',5'''-diepisilvestrol (4) and its C1 epimer 1''',2''',5'''-triepisilvestrol (15) in 50% overall yield. An in vitro protein translation inhibition assay showed that 2''',5'''-diepisilvestrol (4) was considerably less active than episilvestrol (2), while the unnatural isomer 1''',2''',5'''-triepisilvestrol (15) was essentially inactive, showing that the configuration at C1''' and C2''' has a large effect on the biological activity.

Topics: Benzofurans; Crystallography, X-Ray; Molecular Conformation; Molecular Structure; Nuclear Magnetic Resonance, Biomolecular; Stereoisomerism; Structure-Activity Relationship; Triterpenes

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.

Topics: Aglaia; Antineoplastic Agents, Phytogenic; Benzofurans; Cell Line, Tumor; Cell Proliferation; Humans; Magnetic Resonance Spectroscopy; Molecular Structure; Triterpenes

Topics: Benzofurans; Macrocyclic Compounds; Models, Chemical; Molecular Structure; Triterpenes