Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.3.1.21 (CPT)
 4,580 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A series of 6-arylamino-7-chloro-quinazoline-5,8-diones have been evaluated as novel human topoisomerase I (TOP1) inhibitors based on the antitumor activity of 1,4-naphthoquinone. Besides their in vitro cytotoxicity, their ability to inhibit human TOP1-DNA in vitro was tested with human TOP1 and a supercoiled (Form I) plasmid substrate DNA (Park et al., 2004). Using the flexible docking program, QXP, we have developed ternary complex models by docking camptothecin and ten 6-arylamino-7-chloro-quinazoline-5,8-dione analogs into the X-ray crystal structure of the human TOP1-DNA binary complex. The compound binding modes substantiated their potential inhibitory activities against TOP1 in the relaxation assay. Compounds whose templates the 6-arylamino-7-chloro-quinazoline-5,8-dione moiety intercalated between the -1 and +1 base pairs of the scissile strand showed good inhibitory activities. The template of compounds with poor inhibitory activities intercalated between the DNA base pairs of the nonscissile strand. The interaction of the compounds and the human TOP1-DNA binary complex were stabilized by an array of hydrogen bonds and hydrophobic interactions with the TOP1 residues, DNA bases, and water molecules. Docking results from the QXP program suggested potential binding modes of each non-CPT type compound in the human TOP1-DNA cleavable complex, which could provide a rational basis for future TOP1 inhibitor development.
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PMID:Binding mode analysis of topoisomerase inhibitors, 6-arylamino-7-chloro-quinazoline-5,8-diones, within the cleavable complex of human topoisomerase I and DNA. 1825 39

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.
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PMID:Phenylpyrazolo[1,5-a]quinazolin-5(4H)-one: a suitable scaffold for the development of noncamptothecin topoisomerase I (Top1) inhibitors. 2398 76