The proposed studies in this application are aimed at developing new synthetic strategies toward an important class of naturally occurring antitumor agents, as well as their synthetic analogs. The compounds of interest are members of the Illudin family of sesquiterpenes, the most prominent members of which, in terms of cytotoxicity are Illudin S and Illudin M. Despite their promise as potent anticancer agents, the natural products are also highly cytotoxic with low therapeutic index, especially in solid tumor systems. One semisynthetic derivative of Illudin S in particular, known as hydroxymethylacylfulvene (HMAF) has generated a great deal of excitement, since it has a much higher therapeutic index than its natural counterparts and is currently in phase II clinical trials against a wide spectrum of cancer types, including ovarian, prostate, gastrointestinal and lung cancers. There are only a handful of syntheses of this class of compounds, and currently only three conceptually different routes to the most prominent member, HMAF. One approach employs the Padwa carbonly ylide cycloaddition methodology (used by at least three different groups), the other utilizes an intramolecular allenic Pauson-Khand cyclization method, and a very recent synthesis features a ring-closing methatesis reaction as the key step. There is a continuing need for improved methods for the synthesis of this very important class of compounds. The methodologies proposed here are novel in that they represent the only routes to acylfulvenes that are based on classical fulvene syntheses via condensation between a cyclopentadiene unit and a carbonyl group. The synthetic strategies are practical, allow for structural variations in the starting materials and should not only deliver the desired acylfulvenes but also a number of analogs that might possess more favorable therapeutic properties. The intramolecular tandem acylation-condensation pathway figures prominently in several of the strategies. The chemistry presented in each of the synthetic scheme has the potential to uncover a new facet of fulvenes, a class of compounds that has been known for over 100 years. Moreover, all previously unknown derivatives will be subjected to preliminary biological screening in collaboration with our colleagues at the University of Halle, Germany, before they are submitted to the NCI Drug Development program.

Public Health Relevance

The target molecules in this proposal are related to the naturally occurring sesquiterpenes illudin M and S that have been isolated from the toxic mushroom Omphalotus illudens. These compounds have been shown by the National Cancer Institute to possess antitumor activity, albeit with poor index. The semisynthetic illudin analog, hydroxymethylfulvene (HMAF) and some of its analogs are currently being used in Phase II clinical trials supported by the NCI and MGI Pharma. The series of Phase II trials include studies in breast, colon, renal, ovarian, non-small cell lung, and cervical cancer. MGI Pharma, Inc has also started to enroll patients in a Phase II study in prostate, pancreatic and ovarian cancers. The ovarian cancer study involves women with tumors who are no longer responding to a chemotherapy regimen that includes Taxol and platinum-based reagents.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Enhancement Award (SC1)
Project #
Application #
Study Section
Special Emphasis Panel (ZGM1-MBRS-X (CH))
Program Officer
Fabian, Miles
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
San Francisco State University
Schools of Arts and Sciences
San Francisco
United States
Zip Code
Erden, Ihsan; Gleason, Cindy J (2018) C12H12 interconversions: two non-pyrolytic syntheses of tricyclo[,8]dodeca-2,5,9,11-tetraene. Tetrahedron Lett 59:284-286
Eyilcim, Oznur; Issever, Sezin; Ocal, Nuket et al. (2018) Imidazolidin-4-ones via (3+2) cycloadditions of aza-oxyallyl cations onto (E)-Narylideneanilines. Tetrahedron Lett 59:3674-3677
Tang, Khanh G; Kent, Greggory T; Erden, Ihsan et al. (2017) cis-?-Bromostyrene derivatives from cinnamic acids via a tandem substitutive bromination-decarboxylation sequence. Tetrahedron Lett 58:3894-3896
Erden, Ihsan; Gärtner, Christian; Ma, Jingxiang et al. (2017) Cyclopentadienones via a tandem C-cyclopropylnitrone cyclization-cycloreversion sequence. European J Org Chem 2017:5147-5153
Erden, Ihsan; Gronert, Scott; Cabrera, Gabriel et al. (2017) Diverse modes of reactivity of 6-(chloromethyl)-6-methylfulvene. European J Org Chem 2017:2925-2931
McGraw, Kristen M; Kent, Greggory T; Gonzalez, Joseph R et al. (2017) Competitive, substrate-dependent reductive debromination/dehydrobromination of 1,2-dibromides with triethylamine. Tetrahedron Lett 58:1973-1975
McGraw, Kristen M; Bowler, Jeannette T; Ly, Vy T et al. (2016) Reductive debromination of 1,2-dibromides with anisidines. Tetrahedron Lett 57:285-287
Erden, Ihsan; Watson, Samuel E (2016) First ketene cycloaddition approach to (±)-junionone. Tetrahedron Lett 57:237-238
Erden, Ihsan; Basada, John; Poli, Daniela et al. (2016) Unusual hydroxyl effect on fulvene endoperoxide decompositions. Tetrahedron Lett 57:2190-2193
Coskun, Necdet; Çetin, Meliha; Gronert, Scott et al. (2015) Pyrrolidine catalyzed reactions of cyclopentadiene with ?,?-unsaturated carbonyl compounds: 1,2- versus 1,4-additions. Tetrahedron 71:2636-2642

Showing the most recent 10 out of 15 publications