Stephacidin Explained

Stephacidin A and B are antitumor alkaloids isolated from the fungus Aspergillus ochraceus ^[1] that belong to a class of naturally occurring 2,5-diketopiperazines.^[2] This unusual family of fungal metabolites are complex bridged 2,5-diketopiperazine alkaloids that possess a unique bicyclo[2.2.2]diazaoctane core ring system and are constituted mainly from tryptophan, proline, and substituted proline derivatives where the olefinic unit of the isoprene moiety has been formally oxidatively cyclized across the α-carbon atoms of a 2,5-diketopiperazine ring.The molecular architecture of stephacidin B, formally a dimer ^[3] of avrainvillamide, reveals a complex dimeric prenylated N-hydroxyindole alkaloid that contains 15 rings and 9 stereogenic centers and is one of the most complex indole alkaloids isolated from fungi. Stephacidin B rapidly converts into the electrophilic monomer avrainvillamide in cell culture, and there is evidence that the monomer avrainvillamide interacts with intracellular thiol-containing proteins, most likely by covalent modification.^[4] Avrainvillamide, which contains a 3-alkylidene-3H-indole 1-oxide function, was identified in culture media from various strains of Aspergillus and is reported to exhibitantimicrobial activity against multidrug-resistant bacteria.^[5] The avrainvillamide and stephacidins family of structurally complex anticancer natural products are active against the human colon HCT 116 cell line.^[6] The signature bicyclo[2.2.2]diazaoctane ring system common to these alkaloids has inspired numerous synthetic approaches.^[7]

External links

• Stephacidin A and B: two structurally novel, selective inhibitors of the testosterone-dependent prostate LNCaP cells
• PubChem - Stephacidin A
• PubChem - C6-epi-Stephacidin A
• PubChem - Stephacidin B

Notes and References

1. Qian-Cutrone J, Huang S, Shu YZ, Vyas D, Fairchild C, Menendez A, Krampitz K, Dalterio R, Klohr SE, Gao Q . Stephacidin A and B: two structurally novel, selective inhibitors of the testosterone-dependent prostate LNCaP cells . Journal of the American Chemical Society . 124 . 49 . 14556–14557 . December 2002 . 12465964 . 10.1021/ja028538n .
2. 2,5-Diketopiperazines: Synthesis, Reactions, Medicinal Chemistry, and Bioactive Natural Products . Borthwick AD . Chemical Reviews . 2012 . 112 . 7 . 3641–3716 . 10.1021/cr200398y . 22575049.
3. Stephacidin B-A new stage of complexity within prenylated indole alkaloids from fungi . von Nussbaum F . Angewandte Chemie International Edition . 2003 . 42 . 27 . 3068–3071 . 10.1002/anie.200301646 . 12866092.
4. Wulff JE, Herzon SB, Siegrist R, Myers AG . Evidence for the rapid conversion of stephacidin B into the electrophilic monomer avrainvillamide in cell culture . Journal of the American Chemical Society . 129 . 16 . 4898–4899 . April 2007 . 17397160 . 10.1021/ja0690971 . 3175819.
5. Sugie Y, Hirai H, Inagaki T, Ishiguro M, Kim YJ, Kojima Y, Sakakibara T, Sakemi S, Sugiura A, Suzuki Y, Brennan L . A new antibiotic CJ-17,665 from Aspergillus ochraceus . The Journal of Antibiotics . 54 . 11 . 911–916 . 2001 . 11827033 . 10.7164/antibiotics.54.911 . free .
6. Baran PS, Hafensteiner BD, Ambhaikar NB, Guerrero CA, Gallagher JD . Enantioselective total synthesis of avrainvillamide and the stephacidins . Journal of the American Chemical Society . 128 . 26 . 8678–8693 . July 2006 . 16802835 . 10.1021/ja061660s .
7. Escolano C . Stephacidin B, the avrainvillamide dimer: A formidable synthetic challenge . Angewandte Chemie International Edition . 44 . 47 . 7670–7673 . December 2005 . 16252300 . 10.1002/anie.200502383 .