Abstract
In search for a novel chemotype to develop topoisomerase I (Top1) inhibitors, the pyrazolo[1,5-a]quinazoline nucleus, structurally related to the indenoisoquinoline system precursor of well-known Top1 poisons, was variously decorated (i.e., a substituted phenyl ring at 2- or 3-position, a protonable side chain at 4- or 5-position), affording a number of Top1 inhibitors with cleavage patterns common to CPT and MJ-III-65. SARs data were rationalized by means of an advanced docking protocol.
Publication types
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Research Support, N.I.H., Intramural
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Research Support, Non-U.S. Gov't
MeSH terms
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DNA Topoisomerases, Type I / chemistry
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DNA Topoisomerases, Type I / metabolism*
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Drug Discovery*
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Heterocyclic Compounds, 3-Ring / chemistry
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Heterocyclic Compounds, 3-Ring / metabolism
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Heterocyclic Compounds, 3-Ring / pharmacology*
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Humans
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Molecular Docking Simulation
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Protein Conformation
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Pyrroles / chemistry*
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Pyrroles / metabolism
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Pyrroles / pharmacology*
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Quinazolines / chemistry*
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Quinazolines / metabolism
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Quinazolines / pharmacology*
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Topoisomerase I Inhibitors / chemistry*
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Topoisomerase I Inhibitors / metabolism
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Topoisomerase I Inhibitors / pharmacology*
Substances
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Heterocyclic Compounds, 3-Ring
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Pyrroles
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Quinazolines
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Topoisomerase I Inhibitors
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DNA Topoisomerases, Type I