Inhibitor SourceBook™ Second Edition

Cell Division/Cell Cycle/Cell Adhesion
Topoisomerase Related Inhibitors
DNA topoisomerases are nuclear enzymes that regulate
the conformational changes in DNA topology by
catalyzing the breakage and rejoining of DNA strands
during the normal cell cycle. They relieve torsional
stress during replication and transcription. The catalytic
cycle of the enzyme consists of DNA cleavage to form a
covalent enzyme-DNA intermediate, DNA relaxation,
and re-ligation of the phosphate backbone to restore
the continuity of the DNA. Three different types of
topoisomerases have been reported in humans; Type I
(91-kDa monomer), Type IIa (170-kDa dimer), and Type
IIb (180-kDa dimer). Simpler organisms possess only
topoisomerase I; however, higher organisms have all
three types of topoisomerases. While topoisomerase
IIa is present in all eukaryotes, IIb is present only in
vertebrates and appears to be closely associated with cell
differentiation, but not proliferation. Topoisomerases
act by catalyzing the breakdown and rejoining reactions
in the phosphodiester backbone of DNA. Topoisomerase
I reversibly cleaves a single strand in duplex DNA
molecule, whereas topoisomerase II breaks and rejoins
both DNA strands.
During the past few years topoisomerases have
become important chemotherapeutic targets for
cancer treatment. Several novel compounds have been
Topoisomerase Related Inhibitors
developed that can target either topoisomerase I or
topoisomerase IIa-/IIb- isoforms, or all three types
of topoisomerases. Inhibition of topoisomerase II is
considered to be more challenging due to the complexity
of interactions. Most inhibitors of topoisomerase II
block the ligation step, leading to stabilized “cleavable
complexes” between DNA and the enzyme. Most enzyme
inhibitors function by docking into the enzyme active
site or nearby allosteric site to block the reaction of
the normal substrate. Inhibition of topoisomerase II
involves two parts: the aromatic part of the inhibitor
molecule intercalates between DNA base pairs and
another more polar portion interacts with topoisomerase.
Because topoisomerase II inhibitors (e.g., doxorubicin
and etoposide) act as poisons rather than as classical
competitive inhibitors, their action is dependent upon the
level of the enzyme in cells. Rapidly proliferating cells,
which contain relatively higher levels of topoisomerase II,
appear to be more sensitive to these agents.
References:
Leppard, J. B., and Champoux, J. J. 2005. Chromosoma 114, 75.
Topcu, Z. 200 . J. Clin. Pharm. Ther. 26, 405.
Felix, C.A. 200 . Med. Pediatr. Oncol. 36, 525.
Bakshi, R.P., et al. 200 . Crit. Rev. Biochem. Mol. Biol. 36, .
Champoux, J.J. 2000. Ann. N. Y. Acad. Sci. 922, 56.
Fortune, J.M., and Osheroff, N. 2000. Prog. Nucleic Acid Res. Mol. Biol. 64, 22 .
Product Cat. No. Comments Size Price
N Acetyl- -keto-b-
Boswellic Acid,
Boswellia serrata
110123 (3-O-Acetyl-11-keto-b-Boswellic Acid; AKBA; AKbBA)
Reported to inhibit calf thymus topoisomerase I ( ≥ 0 mM).
AG 387 658520 [AG 555, 5-Iodo; a-Cyano-(3,4-dihydroxy)-5-iodo-N-(3-phenylpropyl)cinnamide; 2-
Cyano-3-(3,4-dihydroxy-5-iodo-phenyl)-N-(3-phenylpropyl)acrylamide]
Aurintricarboxylic Acid 189400 (ATA)
Camptothecin,
Camptotheca
acuminata
Camptothecin, 0-
Hydroxy-, Camptotheca
acuminata
Daunorubicin,
Hydrochloride
An analog of tyrphostin AG 555 (Cat. No. 658404) that acts as an inhibitor of EGFR
tyrosine kinase and of DNA topoisomerase I.
A polyanionic, polyaromatic compound that inhibits apoptotic cell death in various
cell types induced by a variety of factors. A potent inhibitor of DNA topoisomerase II.
208925 {4-Ethyl-4-hydroxy-1H-pyrano[3´,4´:6,7]indolizino[1,2-b]quinoline-
3,14(4H,12H)dione}
More online... www.calbiochem.com/inhibitors/topoisomerase
A reversible DNA topoisomerase I inhibitor that binds to and stabilizes the
topoisomerase-DNA covalent complex.
390238 (HCPT; 10-Hydroxycamptothecin)
A powerful DNA topoisomerase I inhibitor that reduces DNA synthesis in murine
hepatoma cells. Has a selective inhibitory effect on the phosphorylation of
histones H and H3, but is less effective on other histones.
251800 (Daunomycin, HCl)
Potent anticancer agent that inhibits RNA and DNA synthesis by intercalating into
DNA. Inhibits eukaryotic topoisomerase I and II.
5 mg $ 68
5 mg $87
00 mg $34
50 mg $62
25 mg $92
5 mg $6
82 Orders Phone 800 854 34 7
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