Reaction of antitumor hydroxymethylacylfulvene (HMAF) with thiols

Covalent Modifiers: A Chemical Perspective on the Reactivity of α,β-Unsaturated Carbonyls with Thiols via Hetero-Michael Addition Reactions

“…158 These thiol additions occur at acidic and neutral pH, with the ideal pH ranging from 4.8-6.1 depending on the substrate and thiol, which is in contrast to most hetero-Michael additions that are normally faster at more basic pH (mechanism for thiol addition shown in Scheme 30). 158a, 158c Dick et al showed that at a more biologically relevant pH of 7.4, HMAF ( 460 , also called irofulven) is unreactive with GSH while illudin M ( 457 ) reacts readily. 159 Under more acidic conditions, 460 has been shown to react with other thiols such as those mentioned above, as well as 4-hydroxythiophenol, thioglycerol, thiocresol, and benzylmercaptan.…”

“…159 Under more acidic conditions, 460 has been shown to react with other thiols such as those mentioned above, as well as 4-hydroxythiophenol, thioglycerol, thiocresol, and benzylmercaptan. 158e McMorris et al found that strongly acidic conditions (dilute H 2 SO 4 , pH = 0) favored thiol additions via substitution of the allylic alcohol to give adducts such as 463 in high yields (70-80%, Scheme 31). 158e Moderately acidic to neutral conditions (pH = 4-7) favored hetero-Michael addition (0.24 M 460 , acetone/water) to give 464-466 or suspected radical addition (0.011 M, THF/water) to give 467 .…”

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

“…Subsequently, nucleophilic attack opens the cyclopropane ring with concomitant loss of OH from the adjacent Catom; if the second nucleophile is H 2 O, the second reaction is equivalent to a rearrangement with aromatization. A potential link between illudin toxicity and reactivity toward thiols in the cell has been established by McMorris et al [14] [15], who explicitly demonstrated that illudins are more toxic to cells that have low levels of glutathione [15].…”

“…McMorris et al have synthesized multiple derivatives of these illudins in attempts to find candidates that retain toxicity but exhibit increased selectivity towards tumor cells [4 ± 7] [14]. In particular, the third-generation derivative 4 is now in clinical trials.…”

“…± In experimental studies involving illudin analogues, their cell toxicity was attributed in part to electrophilicity [4] [6] [7] [14]. Two highly toxic compounds, 1 and 2, inhibit cell growth at an IC 50 of 4 AE 1 nm ( Table 4).…”