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Bioluminescence Imaging to Detect Late Stage Infection of African Trypanosomiasis
Published on: May 18, 2016
Podophyllotoxin analogues active versus Trypanosoma brucei
Md Jashim Uddin1, David C Smithson, Kristin M Brown
1Department of Biochemistry, Chemistry and Pharmacology, Vanderbilt Institute of Chemical Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Bioorganic & Medicinal Chemistry Letters
|February 5, 2010
Summary
Novel anti-trypanosomal compounds were developed by coupling non-steroidal anti-inflammatory drugs (NSAIDs) to podophyllotoxin. These conjugates showed significantly enhanced potency against Trypanosoma brucei, acting via tubulin de-polymerization.
Area of Science:
- Medicinal Chemistry
- Parasitology
- Drug Discovery
Background:
- Trypanosoma brucei causes human African trypanosomiasis, a neglected tropical disease.
- Podophyllotoxin is a known cytotoxic agent, but its clinical use is limited.
- Non-steroidal anti-inflammatory drugs (NSAIDs) have diverse biological activities.
Purpose of the Study:
- To synthesize novel podophyllotoxin-NSAID conjugates.
- To evaluate the anti-trypanosomal activity of these compounds.
- To investigate the mechanism of action and structure-activity relationships.
Main Methods:
- Chemical synthesis of podophyllotoxin analogues conjugated with various NSAIDs.
- In vitro evaluation of anti-trypanosomal activity against Trypanosoma brucei.
- Cytotoxicity assessment against a panel of human cell lines.
- Tubulin polymerization assays.
- Determination of LogP values.
Main Results:
- Several conjugates exhibited potent anti-trypanosomal activity with low nanomolar IC50 values.
- Potency was increased over 1300-fold compared to parent compounds.
- Compounds demonstrated cytostatic effects.
- Mechanism of action involves tubulin de-polymerization.
- Activity correlated with LogP values, suggesting enhanced cellular uptake.
Conclusions:
- Podophyllotoxin-NSAID conjugates represent a promising new class of anti-trypanosomal agents.
- The observed synergy enhances potency and potentially improves pharmacokinetic properties.
- Hydrophobic interactions mediated by NSAID moiety likely facilitate cellular entry of podophyllotoxin.
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