33781-60-1

Usage

Chemical Properties

Thick Orange Oil

Uses

Antitumor agent derived from Illudin S.

Upstream product

• 1149-99-1 illudin S 
• 652134-50-4 (1S,2R)-8,9-dihydroxy-3,6,8-trimethyl-7-spiro-cyclopropylbicyclo[4.3.0]nona-1,3,5-triene 
• 203390-34-5 C₁₄H₁₈O₂ 

Downstream Products

• 158440-71-2 [14C]-Irofulven 
• 187277-46-9 (+/-)-hydroxymethylacylfulvene 

Relevant academic research and scientific papers

ILLUDIN ANALOGS, USES THEREOF, AND METHODS FOR SYNTHESIZING THE SAME

This invention provides illudin derivatives, intermediates, preparation methods, pharmaceutical compositions and uses thereof. Specific examples include novel synthetic routes to prepare illudin derivatives and an illudin derivative having a positive optical rotation, which has therapeutic value.

Chemical and enzymatic reductive activation of acylfulvene to isomeric cytotoxic reactive intermediates

Acylfulvenes (AFs), a class of semisynthetic analogues of the sesquiterpene natural product illudin S, are cytotoxic toward cancer cells. The minor structural changes between illudin S and AFs translate to an improved therapeutic window in preclinical cell-based assays and xenograft models. AFs are, therefore, unique tools for addressing the chemical and biochemical basis of cytotoxic selectivity. AFs elicit cytotoxic responses by alkylation of biological targets, including DNA. While AFs are capable of direct alkylation, cytosolic reductive bioactivation to an electrophilic intermediate is correlated with enhanced cytotoxicity. Data obtained in this study illustrate chemical aspects of the process of AF activation. By tracking reaction mechanisms with stable isotope-labeled reagents, enzymatic versus chemical activation pathways for AF were compared for reactions involving the NADPH-dependent enzyme prostaglandin reductase 1 (PTGR1) or sodium borohydride, respectively. These two processes resulted in isomeric products that appear to give rise to similar patterns of DNA modification. The chemically activated isomer has been newly isolated and chemically characterized in this study, including an assessment of its relative stereochemistry and stability at varying pH and under bioassay conditions. In mammalian cancer cells, this chemically activated analogue was shown to not rely on further cellular activation to significantly enhance cytotoxic potency, in contrast to the requirements of AF. On the basis of this study, we anticipate that the chemically activated form of AF will serve as a useful chemical probe for evaluating biomolecular interactions independent of enzyme-mediated activation.

Enantioselective total synthesis of (-)-acylfulvene and (-)-irofulven

(Chemical Equation Presented) 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 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).

Enantioselective total synthesis of (-)-acylfulvene and (-)-irofulven

(Chemical Equation Presented) Antitumor agents (-)-acylfulvene and (-)-irofulven are prepared in an approach that employs the powerful enyne ring-closing metathesis reaction to secure the spiro-bicyclic AB rings. Other key features of this synthesis include an efficient aldol-based introduction of the stereocenter at C2, a diazene-mediated reductive allylic transposition, and a ring-closing metathesis/oxidation sequence.

Investigating the role of stereochemistry in the activity of anticancer acylfulvenes: Synthesis, reductase-mediated bioactivation, and cellular toxicity

Acylfulvenes comprise a family of semisynthetic natural product derivatives with potent antitumor activities. Previous studies indicated that acylfulvenes are bioactivated by NADPH-dependent alkenal/one reductase (AOR), presumably generating intermediates

Synthesis and Biological Activity of Enantiomers of Antitumor Irofulven

Stereoselective synthesis of (-)-irofulven has been achieved by cycloaddition of (R)-5-chloro-5-methyl-2-cyclopentenone to the 1,3-dipolar intermediate from 1-acetyl-1-(diazoacetyl)cyclopropane. The enantiomer, (+)-irofulven, was prepared in a similar way starting with (S)-5-chloro-5-methyl-2-cyclopentenone. (+)-Irofulven was 5 to 6 times less toxic than (-)-irofulven to adenocarcinoma (MV 522) cells.

A rapid synthesis of hydroxymethylacylfulvene (HMAF) using the allenic Pauson-Khand reaction. A synthetic approach to either enantiomer of this illudane structure

An allenic Pauson-Khand reaction has been employed in the preparation of (±)-hydroxymethylacylfulvene (HMAF), an anticancer agent that is currently in Phase II clinical trials for a variety of solid tumor types. The synthesis is effected in 11 steps from commercially available starting materials. In addition, an asymmetric route to the title compound has been established by intersecting the racemic synthesis with an enantiomerically pure intermediate. The preparation of the enantiomerically pure intermediate involved the Sharpless asymmetric dihydroxylation (AD) of a trisubstituted olefin of an enyne system. This approach provides access to both enantiomers of HMAF simply by changing the ligands in the Sharpless AD reaction. Optimized conditions for the stereospecific synthesis of E or Z trisubstituted enynes from an aliphatic ketone using either Peterson olefination or Horner-Wadsworth-Emmons protocols are reported. Finally, a better understanding of the stereoelectronic requirements of the allenic P-K reaction is recognized.

Synthesis of [3H]-illudin S, [3H]-acylfulvene, [3H]and[14C]- hydroxymethylacylfulvene (MGI 114)

Tritiated derivatives of the toxic sesquiterpene illudin S (1) have been prepared by fermentation of Omphalotus illudens in the presence of [3H]- sodium acetate. [3H]-illudin S was converted to antitumor [3H]-acylfulvene (4) by treatment with dilute sulfuric acid. Antitumor [14C]- hydroxymethylacylfulvene (5) was best prepared by reacting acylfulvene with [14C]-paraformaldehyde in dilute sulfuric acid.

Total synthesis of hydroxymethylacylfulvene, an antitumour derivative of illudin S

(±)-Hydroxymethylacylfulvene is synthesized in 14 steps from 4-hydroxy-5-methyl-2-cyclopenten-1-one and 1-acetyl-1-(diazoacetyl)cyclopropane in 15% overall yield.