Structure and reactivity of illudins

McMorris, Trevor C.; Kelner, Michael J.; Chadha, Raj K.; Siegel, Jay S.; Moon, Surk-sik; Moya, Medgar M.

doi:10.1016/s0040-4020(01)89489-8

Cited by 45 publications

(50 citation statements)

References 7 publications

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“…± Preliminary quantum-mechanical computations on 1 ± 7 at a variety of levels of theory established a reliable level of theory for the prediction of structure and properties. Of 1 ± 7, the structures 1 and 4 have been solved crystallographically [6] [7]. The calculated structures for 1 and 4 are in overall good agreement with the experimental X-ray structures ( Table 1).…”

supporting

confidence: 65%

“…The axial configuration of the Me on C(2) in this envelope configuration favors overlap of the MeÀC(2) s-orbital with the p*-orbital of the carbonyl at C(1). Such an arrangement of orbitals facilitates the migration of the Me group from C(2) to C(1), which would lead to the formation of isoilludin [6]. The X-ray and calculated structures show a rather compressed moiety across the C(2)ÀC(3) region, with particularly short distances between the substituents at C(2) and C(3).…”

mentioning

confidence: 96%

“…Several analogues with slightly modified structures (1 ± 7) that offer a range of therapeutic indices [4 ± 6], a few of which have drawn considerable attention as potential drug candidates [5] [7 ± 13], have been synthesized. All derivatives bear common structural features and undergo a nucleophile-triggered addition/rearrangement cascade to a stable aromatic metabolite [6] [14 ± 17]. The details of this structural commonality and the mechanism of the addition/rearrangement process are key components in our understanding of the design of these therapeutic agents.…”

mentioning

confidence: 99%

“…The reactivity of the illudins has been studied in vitro [6] [14 ± 17]. At physiological pH, illudins do not react with common intracellular nitrogen-, oxygen-or halogenbased nucleophiles.…”

mentioning

confidence: 99%

“…The proximity of the cyclopropyl ring (C(9) and C(10)) to the two substituents at C(2) (tertiary OH and CH 3 (8) groups) correlates to the reactivity of 1 [6]. As noted in early crystal structure work [6], the six-membered ring is in an envelope configuration with C(2) above the plane, and the other ring C-atoms are approximately planar with those of the five-membered ring. The extent of the C(2) out- of-plane angle in this envelope configuration also correlates with the extent of bondalternation seen across C(3)ÀC(4) and C(4)ÀC(5).…”

mentioning

confidence: 99%

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

Gregerson¹,

McMorris²,

Siegel³

et al. 2003

Helvetica Chimica Acta

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This and the companion paper are dedicated to Professor Duilio Arigoni on the occasion of his 75th birthday.His work on the structures of natural products and the mechanisms and stereochemistry of biochemical processes strongly influences our course of study. Non scholae sed vitae discumus.(Hydroxymethyl)acylfulvene (HMAF, irofulven; 4), a third-generation derivative of a natural product extracted from the mushroom Omphalotus illudens, is selectively toxic towards certain forms of malignant tumors. Conversion of HMAF and cognates to stable aromatic derivatives is triggered by thiol attack in vitro and in vivo. Quantum-chemical methods predict well the structure for several functionalized derivatives of irofulven as compared to known X-ray crystallographic structures. Computational reaction profiles for thiol attack and aromatic rearrangement of irofulven and illudin S, a toxin from which irofulven is derived, provide insight into HMAF×s selectivity and toxicity. Methods used include hybrid density-functional theory (HDFT), HartreeÀFock (HF), and M˘llerÀPlesset second-order perturbation theory (MP2). Solvent effects have been explored by means of the new continuum-solvation method, COSab, presented in an accompanying paper.

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confidence: 65%

mentioning

confidence: 96%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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

Gregerson¹,

McMorris²,

Siegel³

et al. 2003

Helvetica Chimica Acta

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Convenient Synthesis of Heterobicycles by Domino Heck−Diels−Alder Reactions

et al. 2001

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Keywords: Heck reaction, intramolecular / DielsϪAlder reaction / Tetrahydroisoindolines / Tetrahydroisoindolin-1-ones / Hexahydrobenzo[c]furans / Hexahydro-1H-[2]pyrindines Palladium(0)-catalyzed intramolecular cross coupling of bromodialkenylamines, bromoalkenylalkenamides and bromodialkenyl ethers followed by in situ [4+2] cycloaddition with suitable dienophiles gave tetrahydroisoindolines (31−73%

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A Chemical Proteomic Analysis of Illudin‐Interacting Proteins

Nodwell

Eirich

et al. 2019

Chemistry A European J

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The illudin natural product family are fungal secondary metabolites with a characteristic spirocyclopropyl‐substituted fused 6,5‐bicyclic ring system. They have been extensively studied for their cytotoxicity in various tumor cell types, and semisynthetic derivatives with improved therapeutic characteristics have progressed to clinical trials. Although it is believed that this potent alkylating compound class acts mainly through DNA modification, little is known about its binding to protein sites in a cellular context. To reveal putative protein targets of the illudin family in live cancer cells, we employed a semisynthetic strategy to access a series of illudin‐based probes for activity‐based protein profiling (ABPP). While the probes largely retained potent cytotoxicity, proteomic profiling studies unraveled multiple protein hits, suggesting that illudins exert their mode of action not from addressing a specific protein target but rather from DNA modification and unselective protein binding.

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Structure and reactivity of illudins

Cited by 45 publications

References 7 publications

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

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

Convenient Synthesis of Heterobicycles by Domino Heck−Diels−Alder Reactions

A Chemical Proteomic Analysis of Illudin‐Interacting Proteins

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