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Published on: March 6, 2019
Thiocolchicine-podophyllotoxin conjugates: dynamic libraries based on disulfide exchange reaction
Bruno Danieli1, Alessandra Giardini, Giordano Lesma
1Dipartimento di Chimica Organica e Industriale, Università degli Studi di Milano, Via Venezian 21, 20133 Milan, Italy.
The Journal of Organic Chemistry
|March 25, 2006
Summary
A novel dynamic combinatorial library using disulfide bond exchange was created. Divalent compounds showed unique biological activity, not just additive effects, highlighting target-specific interactions.
Area of Science:
- Medicinal Chemistry
- Chemical Biology
- Drug Discovery
Background:
- Dynamic combinatorial chemistry (DCC) enables the creation of diverse molecular libraries.
- Thiocolchicine and podophyllotoxin are known cytotoxic agents.
- Disulfide bond exchange is a reversible reaction suitable for library synthesis.
Purpose of the Study:
- To develop a dynamic combinatorial library of thiocolchicine-podophyllotoxin derivatives.
- To investigate the influence of a biological target on library composition.
- To evaluate the biological activity of the synthesized divalent compounds.
Main Methods:
- Synthesis of a dynamic combinatorial library via disulfide bond exchange.
- High-resolution electrospray ionization mass spectrometry (ESI-MS) for mixture analysis.
- Biological evaluation of synthesized compounds against a relevant target.
Main Results:
- Successful construction of a dynamic combinatorial library based on disulfide exchange.
- Demonstration of biological target-induced modulation of library composition.
- Identification of divalent compounds with novel biological activity profiles.
- ESI-MS proved effective for assessing library composition and evolution.
Conclusions:
- Dynamic combinatorial libraries offer a powerful platform for drug discovery.
- Divalent compounds exhibit unique biological activities distinct from their individual components.
- Target-influenced library formation provides insights into drug-target interactions.
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