Design, Synthesis, and Anti-Cancer Activity Evaluation of a 3-methyleneisoindolin-
1-One Library
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Published:2023-08
Issue:9
Volume:26
Page:1775-1792
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ISSN:1386-2073
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Container-title:Combinatorial Chemistry & High Throughput Screening
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language:en
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Short-container-title:CCHTS
Author:
Mehta Saurabh1ORCID,
Mangyan Mangeram1,
Brahmchari Dhirendra1ORCID
Affiliation:
1. Department of Applied Chemistry, Delhi Technological University, Delhi, 110042, India
Abstract
Background:
Isoindolin-1-ones are medicinally privileged heterocyclic compounds. Due
to the interesting biological activities exhibited by these compounds, several synthetic and medicinal
research groups have developed numerous synthetic approaches for these compounds. We have
also previously reported two efficient approaches for the synthesis of the isoindolin-1-ones through
iodoaminocyclization of alkynyl amides using n-BuLi and phosphazene superbases.
Objective:
This study aimed to construct a medium-size library of multi-substituted 3-
methyleneisoindolin-1-ones and study its biological profile, specifically anti-cancer activity.
Methods:
Solution phase parallel synthesis was performed for the synthesis of the 3-
methyleneisoindolin-1-ones library through n-BuLi-mediated iodoaminocyclization of 2‑(1-
Alkynyl)benzamides. The iodocyclized products were further derivatized through palladiumcatalyzed
Sonogashira and Suzuki Miyaura couplings and N-alkylation reactions. In silico evaluation
of the physicochemical and ADMET properties was performed to examine the drug-likeness of
the library compounds. Selected isoindolin-1-one analogues were evaluated for in vitro antiproliferative
activity in various human cancer cell lines (MCF-7, A-549, and U-373 MG).
Results:
A library of 46 multisubstituted 3-methyleneisoindolin-1-ones has been synthesized. The
iodo-isoindolin-1-ones were synthesized in 66-76% yields through n-BuLi-mediated iodoaminocyclization
of 2‑(1-Alkynyl)benzamides. Further diversification afforded the diverse library members
in yields of 40–96%. Two of the library compounds exhibited GI50 values of < 10 μM in the human
breast cancer cell line (MCF-7).
Conclusion:
Isoindolin-1-one library was constructed through electrophilic cyclization. The diversification
was successfully performed through various C-C and C-N bond formation reactions. The
anti-proliferative activity of the library members appears to be arising from the interaction of the
compounds with the protein kinase drug targets.
Publisher
Bentham Science Publishers Ltd.
Subject
Organic Chemistry,Computer Science Applications,Drug Discovery,General Medicine
Cited by
1 articles.
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