<i>Ab Initio</i> Structure/Reactivity Investigations of Illudin‐Based Antitumor Agents: A Model for Reaction <i>in vivo</i>

Gregerson, Laura N.; McMorris, Trevor C.; Siegel, Jay S.; Baldridge, Kim K.

doi:10.1002/hlca.200390341

Cited by 4 publications

(2 citation statements)

References 53 publications

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“…As an alkylating agent, irofulvene's toxicity stems from its electrophilic character: once the a,b-unsaturated ketone has been activated by reduction, the cyclopropane ring is attacked by cellular nucleophiles, such as DNA or proteins [56], [57]. Adducts formed in this reaction lead to inhibition of DNA synthesis, cell cycle arrest, DNA strand breaks, and induce apoptosis.…”

Section: Antitumourmentioning

confidence: 99%

Fungal Genetics, Genomics, and Secondary Metabolites in Pharmaceutical Sciences

Misiek

Hoffmeister

2007

Planta Med

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Natural products represent the traditional source of new drug candidates [1]. A global overview on the metabolic wealth of fungal secondary metabolites ± prominent and less prominent ones ± is provided in diverse compilations [2], [3]. From the systematic viewpoint, the most prolific producers of pharmaceutically relevant molecules are the ascomycetes. Their evolutionary counterpart, the basidiomycetes, are equally rich and often unique in their secondary metabolism, however, they cannot compare for significance in terms of clinically used compounds. We open our review with spotlights in the history of pharmacy to underline the Janus-faced nature of fungal metabolites.The Eleusinian Mysteries, initiation ceremonies in the ancient Greek culture that have been established about 1500 BC, climaxed when the initiates reached a visionary state. Their revelatory state of mind was mediated by a drink called ªkykeonº. Today's research attributes this preparation to rye, parasitised by the ergot fungus Claviceps ± a classic in the history of pharmacy. Ergot fungi are known to produce hallucinogenic lysergic acid amides [4]. In the medieval Europe, the sclerotia of the same fungus posed a severe threat to human health when continued ingestion of contaminated bread caused horrible symptoms, like gangrene of the extremities. The order of St. Anthony, in particular, cared for those who were ailing from these symptoms colloquially referred to as ªholy fireº or ªSt. Anthony's fireº. Created in 1515 for an Antonitarian monastery, one painting of the Isenheim Altar symbolises the suffering and the pain of those affected by the toxic metabolites of the ergot fungus. The Isenheim Altar is one of the most outstanding pieces of art ever and marked the onset of the Renaissance. Starting in the 18 th centuryClaviceps sclerotia were pharmaceutically used to induce contractions of the uterus. In the 1930 s, the ergot alkaloids served as a molecular template for the synthesis of the lysergic acid diethylamide (LSD) by Albert Hofmann and co-workers at the San- AbstractFilamentous fungi produce a plethora of bioactive natural products. These metabolites display a broad range of useful activities for pharmaceutical purposes, exemplified best by the antibiotic penicillin. Yet, many more have been isolated, characterised, and tested, and some have made their way in clinical trials and into pharmaceutical practice. Through genomics, we become increasingly aware that the biosynthetic abilities for natural products are much richer than expected. The first part of our review highlights selected metabolites that filamentous fungi offer to pharmacists for drug development. This is followed by a summary on the potential of fungal genetics and genomics for pharmaceutical sciences and natural product research.

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Section: Antitumourmentioning

confidence: 99%

Fungal Genetics, Genomics, and Secondary Metabolites in Pharmaceutical Sciences

Misiek

Hoffmeister

2007

Planta Med

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“…Despite their high cytotoxicity, these illudins exhibit low therapeutic indices in solid-tumor systems . Consequently, several analogues of the natural illudins have been prepared and evaluated for the treatment of various cancers . One such semisynthetic derivative, irofulven ( 2 ), was prepared from illudin S through treatment with excess acid and formaldehyde and has demonstrated greatly enhanced therapeutic potential against several solid tumor systems .…”

Section: Introductionmentioning

confidence: 99%

Enantioselective Total Synthesis of (−)-Acylfulvene and (−)-Irofulven

et al. 2009

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We report our full account of the enantioselective total synthesis of (−)-acylfulvene (1) and (−)-irofulven (2), which features metathesis reactions for the rapid assembly of the molecular framework of these antitumor agents. We discuss (1) the application of an Evans’ Cu-catalyzed aldol addition reaction using a strained cyclopropyl ketenethioacetal, (2) an efficient enyne ring-closing metathesis (EYRCM) cascade reaction in a challenging setting, (3) the reagent IPNBSH for a late stage reductive allylic transposition reaction, and (4) the final RCM/dehydrogenation sequence for the formation of (−)-acylfulvene (1) and (−)-irofulven (2).

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Cobalt(I)‐Mediated Intramolecular [2+2+2] Cocyclizations of (Methylenecyclopropyl)diynes as an Easy Access to Cyclopropanated Oligocycles

et al. 2005

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Enediynes with methylenecyclopropane moieties attached either through the three-membered ring or the double bond smoothly underwent cobalt-mediated [2+2+2] cocyclizations to give cyclopropane-fused and spirocyclopropanated cobaltcomplexed tricyclo[7.3.0.0 2,6 ]dodeca-1,6-dienes (1,2,3,3a,4, 6,7,8-octahydro-as-indacenes) under relatively mild conditions in yields ranging from 31 to 94 % (6 examples). Electron-withdrawing substituents at the acetylenic terminus of

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Ab Initio Structure/Reactivity Investigations of Illudin‐Based Antitumor Agents: A Model for Reaction in vivo

Cited by 4 publications

References 53 publications

Fungal Genetics, Genomics, and Secondary Metabolites in Pharmaceutical Sciences

Fungal Genetics, Genomics, and Secondary Metabolites in Pharmaceutical Sciences

Enantioselective Total Synthesis of (−)-Acylfulvene and (−)-Irofulven

Cobalt(I)‐Mediated Intramolecular [2+2+2] Cocyclizations of (Methylenecyclopropyl)diynes as an Easy Access to Cyclopropanated Oligocycles

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