Structure-activity relationships of illudins: analogs with improved therapeutic index.

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

“…Scheme 1). As previously noted [5], the product of thiol addition to 4 is highly reactive, readily attacked by an available nucleophile in solvent medium. In H 2 O, one would expect protonation of the enolate O-atom to form an enol, from which there are several mechanistic possibilities to consider for cyclopropane ring opening: i) direct nucleophilic attack on the cyclopropane ring, ii) internal OH migration/cyclopropane ring opening, iii) nucleopilic attack assisted by the OH at C(2), and iv) stabilization of the transition state for internal OH migration by an explicit H 2 O of solvation.…”

“…± Illudins are natural products isolated from the mushroom Omphalotus illudens [1 ± 3]. 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].…”

“…6 [5] [7] [15]. The Michael addition of thiol to the a,b-unsaturated carbonyl group produces a cyclohexadienol intermediate that is rapidly converted to a stable aromatic structure by opening of the cyclopropane ring and loss of the OH at C(2) (cf.…”

“…In reactions involving 3, a derivative related to an intermediate one might find along an internal OH reaction path has been isolated [5]. The structure of this tetrahydrofurano by-product 9 has been determined by X-ray crystallography [5].…”

“…The structure of this tetrahydrofurano by-product 9 has been determined by X-ray crystallography [5]. The Role of an Explicit H 2 O Molecule.…”