A Cytotoxic Fellutamide Analogue from the Sponge-Derived Fungus Aspergillus versicolor

Total synthesis of fellutamides, lipopeptide proteasome inhibitors. More sustainable peptide bond formation

“…3 Unfortunately, two different compounds have were named fellutamide C in the literature around the same time-frame. To resolve ambiguity between them, Singh’s fellutamide C structure 1c has been renamed in this work fellutamide E, an approach consistent with others. 1e Fellutamide C is described as a potent cytotoxin vs. human cancer cells, which is a bit surprising as it is the only fellutamide that is not a C -terminal aldehyde.…”

“…To resolve ambiguity between them, Singh’s fellutamide C structure 1c has been renamed in this work fellutamide E, an approach consistent with others. 1e Fellutamide C is described as a potent cytotoxin vs. human cancer cells, which is a bit surprising as it is the only fellutamide that is not a C -terminal aldehyde. Fellutamides D and E have antifungal activity and inhibit the fungal proteasome.…”

“…Fellutamides A and B were originally discovered from a marine fungus found in fish, and newer representatives come from a range of fungi. 1 Peptide aldehydes like the fellutamides typically inhibit proteolytic enzymes, and the fellutamides expressly drew attention as proteasome inhibitors. 2 Fellutamide B stimulates transcription of the nerve growth factor (NGF) gene via proteasome inhibition and thereby promotes neurite outgrowth.…”

Synthesis of Fellutamide C and its Diastereomer

“…3-Hydroxydodecanoic Acid (9): To a solution of methyl 3-oxododecanoate (8) in methanol at 0°C, NaBH 4 (1 equiv) was added and stirred at room temperature for 3 h. Subsequently, a solution of NaOH (1.2 equiv) in water was added and the mixture was stirred for 12 h at room temperature. The reaction was neutralized with 1 N HCl, extracted with EtOAc, washed with H 2 O, dried over MgSO 4 , and evaporated to give a crude product, which was purified by RP HPLC 80% to afford 3-hydroxydodecanoic acid (9).…”

“…Furthermore, fellutamide F was found to be cytotoxic to XF498 cells (a human CNS cancer cell line) and HCT15 cells (a human colon cancer cell line) and to have potencies comparable to those of doxorubicin. 8 Our interest in bioactive sponge lipopeptides prompted us to establish a simple synthetic pathway for fellutamide C and for its analogs in order to explore their biological activities and structure-activity relationships. To establish a simple, synthetic route, we used a classical solution phase method based on the efficient and well-established Bocchemistry 9 rather than the more expensive Fmoc-chemistry 10 to synthesize fellutamide B (compound 3).…”