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Novel Betulin Derivatives as Antileishmanial Agents with Mode of Action Targeting Type IB DNA Topoisomerase

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Title Novel Betulin Derivatives as Antileishmanial Agents with Mode
of Action Targeting Type IB DNA Topoisomerase
 
Creator Chowdhury, Sayan
Mukherjee, Tulika
Sengupta, Souvik
Roy Chowdhury, Somenath
Mukhopadhyay, Sibabrata
Majumder, Hemanta K
 
Subject Chemistry
Infectious Diseases and Immunology
 
Description Toward developing antileishmanial agents with mode of action
targeted to DNA topoisomerases of Leishmania donovani, we
have synthesized a large number of derivatives of betulin. The
compound, a natural triterpene isolated from the cork layer of
Betula spp. plants exhibits several pharmacological properties.
Three compounds (disuccinyl betulin, diglutaryl dihydrobetulin,
and disuccinyl dihydrobetulin) inhibit growth of the parasite as well
as relaxation activity of the enzyme type IB topoisomerase [Leishmania
donovani topoisomerase I (LdTOP1LS)] of the parasite.
Mechanistic studies suggest that these compounds interact with
the enzyme in a reversible manner. The stoichiometry of these
compounds binding to LdTOP1LS is 1:1 (mole/mole) with a dissociation constant on the order of �10�6 M. Unlike CPT, these
compounds do not stabilize the cleavage complex; rather, they
abrogate the covalent complex formation. In processive mode of
relaxation assay condition, these compounds slow down the
strand rotation event, which ultimately affects the relaxation of
supercoiled DNA. It is noteworthy that these compounds reduce
the intracellular parasite burden in macrophages infected with
wild-type L. donovani as well as with sodium antimony gluconate
resistant parasite (GE1). Taken together, our data suggest that
these betulin derivatives can be exploited as potential drug candidates
against threatening drug resistant leishmaniasis.
 
Publisher American Society for Pharmacology and Experimental Therapeutics
 
Date 2011
 
Type Article
PeerReviewed
 
Format application/pdf
 
Identifier http://www.eprints.iicb.res.in/1310/1/MOLECULAR_PHARMACOLOGY__80_(_4_)__694%2D703;2011[33].pdf
Chowdhury, Sayan and Mukherjee, Tulika and Sengupta, Souvik and Roy Chowdhury, Somenath and Mukhopadhyay, Sibabrata and Majumder, Hemanta K (2011) Novel Betulin Derivatives as Antileishmanial Agents with Mode of Action Targeting Type IB DNA Topoisomerase. Molecular Pharmacology, 80 (4). pp. 694-703. ISSN 0026-895X
 
Relation http://dx.doi.org/10.1124/mol.111.072785
http://www.eprints.iicb.res.in/1310/