Abstract 751: Synthesis of irofulven analogs

Abstract

Abstract Irofulven (NSC 683863), a semi-synthetic analog of the fungal product illudin S, that has been evaluated in a variety of phase I and II clinical trials. Promising results were noted in clinical trials against a variety of solid cancers including colon, sarcoma, prostate, liver, ovarian and pancreas. Irofulven in a randomized phase IIB trial increased median overall lifespan in patients with metastatic taxane-refractory prostate cancer [HR = 0.69]. As irofulven was the first member of the acylfulvene class of agents to be created, we synthesized several hundred analogs for further testing. Modifications were specifically made to 7 sites of the irofulven molecule including the cyclopropane ring, the chiral center, the carbonyl group, the tertiary hydroxyl site, and several nucleophilic sites. Modifications at several sites completely eliminated both the cytotoxicity and antitumor activity of the analog. Analogs with modifications at one site retained cytotoxic activity, as well as in vivo toxicity in rodents, but surprisingly eliminated antitumor activity in xenograft models. Analogs in which the tertiary hydroxyl group of irofulven was replaced with specific functional groups were noted to have an increase in tumor selectivity as noted by both cell culture and xenograft studies. Specific functional groups noted to be favorable for increased activity included carbamate, sulfonamide, and urea moieties. Additional derivatives of each of these specific functional groups were synthesized and tested in a variety of cell culture and xenograft studies including multidrug resistant models. These studies identify molecular sites critical for the antitumor activity of acylfulvenes, as well as identify promising new analogs for further investigation. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 751.