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Small Molecules That Mimic The Thiol-triggered Alkylating Properties Seen In The Natural Product Leinamycin

drug design

Date : 24/05/2017

Author Information

Murat

Uploaded by : Murat
Uploaded on : 24/05/2017
Subject : Chemistry

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- -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.

This resource was uploaded by: Murat