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 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
^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.
PMID12465964.
^Borthwick AD (2012). "2,5-Diketopiperazines: Synthesis, Reactions, Medicinal Chemistry, and Bioactive Natural Products". Chemical Reviews. 112 (7): 3641–3716.
doi:
10.1021/cr200398y.
PMID22575049.
^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.
PMID12866092.
^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.
PMID16802835.
^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.
PMID16252300.