Ab initio structure/reactivity investigations of illudin-based antitumor agents: A model for reaction in vivo

(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), Hartree-Fock (HF), and Moller-Plesset second-order perturbation theory (MP2). Solvent effects have been explored by means of the new continuum-solvation method, COSab, presented in an accompanying paper.