Stephacidin

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]

Conversion of dimer Stephacidin B to monomer Avrainvillamide
Conversion of dimer Stephacidin B to monomer Avrainvillamide
Structures of Stephacidin B and Stephacidin A

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 exhibit antimicrobial 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]

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