Small molecules that mimic the thiol-triggered alkylating properties seen in the natural product leinamycin.
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.
Chatterji
Tonika
T
Department of Chemistry, University of Missouri, Columbia, Missouri 65211, USA.
Kizil
Murat
M
Keerthi
Kripa
K
Chowdhury
Goutam
G
Pospísil
Tomás
T
Gates
Kent S
KS
D000477:Alkylating Agents / Q000138:chemical synthesis / Q000737:chemistry*; D000903:Antibiotics, Antineoplastic / Q000737:chemistry*; D040761:Biomimetic Materials / Q000138:chemical synthesis / Q000737:chemistry*; D007769:Lactams; D018942:Macrolides; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds / Q000138:chemical synthesis / Q000737:chemistry*; D013844:Thiazoles; D013871:Thiones
D000477:Alkylating Agents; D000903:Antibiotics, Antineoplastic; D007769:Lactams; D018942:Macrolides; D013438:Sulfhydryl Compounds; D013844:Thiazoles; D013871:Thiones; C059000:leinamycin