Small Molecules That Mimic the Thiol-Triggered Alkylating Properties Seen in the Natural Product Leinamycin

Abstract

Reaction of the antitumor agent leinamycin with cellular thiols results in conversion of the natural product to a DNA-alkylating episulfonium alkylating agent via an intriguing sequence of chemical reactions. To establish whether the chemistry first seen in leinamycin represents a general motif that can function in various molecular frameworks, construction of greatly simplified analogues containing only the "core" funcional groups anticipated to be necessary for thiol-triggered generation of an alkylating agent was undertaken. For this purpose, the "stripped-down" leinamycin analogue 7-(3-methyl-but-2-enyl)-1-oxo-1H-lambda4-benzo[1,2]dithiol-3-one (4) was synthesized. Treatment of 4 with thiol under several different conditions results in efficient conversion of the compound to cyclized 2,3-dihydro-benzo[b]thiophene-7-carboxylic acid products (13) that are envisioned to arise from Markovnikov addition of solvent to an intermediate episulfonium ion (14). Thus, the relatively simple molecule 4 is able to mimic the thiol-triggered alkylating properties displayed by the natural product leinamycin. This work helps define why the core functional groups required thiol-accelerated generation of an alkylating intermediate from leinamycin and indicates that substantially altered analogues of the natural product may retain alkylating properties. In a broader context, the results provide evidence that the unique cascade of chemical reactions first seen in the context of leinamycin represents a general motif that can operate in a variety of molecular frameworks.

Entering the leinamycin rearrangement via 2-(trimethylsilyl)ethyl sulfoxides

“…The known 15 carboxylic acid 11 was activated with DCC/DMAP and converted to the thioester 12a by reaction with thiophenol. In addition, we prepared ester derivatives 12b and c by analogous reactions.…”

“…To a stirred solution of 11 15 (200 mg, 0.62 mmol) in dry, distilled THF (2 mL) under nitrogen, dicyclohexyl carbodiimide (153 mg, 0.74 mmol) and a catalytic amount of 4-dimethylaminopyridine (7.6 mg, 0.06 mmol) were added. After about 30 min of stirring, p- -but-2-enyl)-2-[2-(trimethylsilanyl)-ethylsulfanyl]-benzoic acid phenyl ester 12c To a stirred solution of 11 15 (200 mg, 0.62 mmol) in dry, distilled THF (2 mL) under nitrogen, dicyclohexyl carbodiimide (153 mg, 0.74 mmol) and a catalytic amount of 4-dimethylaminopyridine (7.6 mg, 0.06 mmol) were added.…”

“…After about 30 min of stirring, p- -but-2-enyl)-2-[2-(trimethylsilanyl)-ethylsulfanyl]-benzoic acid phenyl ester 12c To a stirred solution of 11 15 (200 mg, 0.62 mmol) in dry, distilled THF (2 mL) under nitrogen, dicyclohexyl carbodiimide (153 mg, 0.74 mmol) and a catalytic amount of 4-dimethylaminopyridine (7.6 mg, 0.06 mmol) were added. After about 30 min of stirring, phenol (69.64 mg, 0.74 mmol) in dry THF (1 mL) was added and stirring was continued for 48 h. At the end of the reaction, the dicyclohexylurea precipitate was removed by filtration and the filtrate evaporated under reduced pressure to give a pale yellow oil.…”

“…All spectral data for this compound matched that reported previously. 15 Trapping by methyl iodide of the sulfenate intermediate 14a generated from 13a…”

“…For this task, we employed small synthetic molecules containing just the "core" functional groups involved in the leinamycin rearrangement. This approach builds upon our recent finding 15 that strippeddown leinamycin analogues such as 6 smoothly undergo a thiol-triggered, leinamycin-type rearrangement to generate the episulfonium alkylating agent 9 (Scheme 2).…”