Saintopin, a dual inhibitor of DNA topoisomerases I and II, as a probe for drug-enzyme interactions.

Leteurtre, François; Fujimori, A.; Tanizawa, Akihiko; Chhabra, Adhuna; Mazumder, Abhijit; Kohlhagen, Glenda; Nakano, Hirofumi; Pommier, ﻿Yves

doi:10.1016/s0021-9258(19)61962-9

Cited by 65 publications

(20 citation statements)

References 39 publications

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“…These cell lines possessed a 12to 44 -fold increase in resistance to saintopin compared to the resistance of the parent KB cells. Similar to the studies by Leteurtre et al, 89 both modified cell lines presented a strong cross -resistance to topo I ± directed agents irinotecan (CPT -11 ) and its active form (SN -38 ) . However, the cell lines showed only small reductions in sensitivity to etoposide.…”

Section: Saintopinsupporting

confidence: 77%

“…Saintopin ( Figure 8 ) is an antibiotic agent, which can induce DNA cleavage in vitro mediated by both types of topo by stabilizing the reversible enzyme ±DNA cleavable complex. 88 Leteurtre et al 89 further investigated the site of action of saintopin and showed that it directly interacts with guanine at the 5 H termini of the enzyme -induced DNA breaks (position + 1 ). A camptothecin -resistant topo I enzyme with a mutation next to the catalytic tyrosine was cross -resistant to saintopin, suggesting that both camptothecin and saintopin act on topo I near the catalytic tyrosine.…”

Section: Saintopinmentioning

confidence: 99%

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Dual topoisomerase I/II inhibitors

Gijn

Lendfers

Schellens

et al. 2000

J Oncol Pharm Pract

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Topoisomerase (topo) I and II are nuclear enzymes, which play a major role in the topological rearrangement of DNA during replication and transcription processes. In the course of years, many different agents have been found which can inhibit the topos and thereby exploit cytotoxicity, also against tumour cells. Selective inhibition of the topo I enzyme can, however, induce a reactive increase in topo II levels, and vice versa. This mechanism is associated with the development of drug resistance. Dual inhibition of both topo I and II may, theoretically, overcome this resistance problem. In this review, the most important and promising dual topo I/II inhibitors designed as anticancer agents will be discussed. Thus far, only the indolyl quinoline derivative TAS-103, the 7 H-benzo [ e] pyrido [4,3- b] indole derivative intoplicine, and the acridine derivative PZA have been shown to be dual topo inhibitors with high cytotoxicity.

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Section: Saintopinsupporting

confidence: 77%

Section: Saintopinmentioning

confidence: 99%

Dual topoisomerase I/II inhibitors

Gijn

Lendfers

Schellens

et al. 2000

J Oncol Pharm Pract

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“…Mutation of this residue to leucine results in a decrease of enzymatic activity, whereas its mutation to Ala leads to resistance to CPT and other topoisomerase poisons (Knab et al, 1993;Knab et al, 1995;Hann et al, 1998). Mutations to Ser, Asp, or His interfere with both enzyme activity and drug sensitivity (Leteurtre et al, 1994;Fertala et al, 2000). Crystal structures of topoisomerase-DNA covalent complexes indicate that this residue, depending on the experimental conditions, is able to form hydrogen bonds with the phosphate oxygen atoms of ÿ1 T (PDB id 1k4s), with the O5# oxygen of 11 G (PDB id 1nh3) or with the O4# and O5# oxygen atoms of 11 T (PDB id 1a31).…”

Section: Hydrogen Bonding At the Active Sitementioning

confidence: 99%

Role of the Linker Domain and the 203–214 N-Terminal Residues in the Human Topoisomerase I DNA Complex Dynamics

Chillemi

Redinbo

Bruselles

et al. 2004

Biophysical Journal

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The influence of the N-terminal residues 203-214 and the linker domain on motions in the human topoisomerase I-DNA complex has been investigated by comparing the molecular dynamics simulations of the system with (topo70) or without (topo58/6.3) these regions. Topo58/6.3 is found to fluctuate more than topo70, indicating that the presence of the N-terminal residues and the linker domain dampen the core and C-terminal fluctuations. The simulations also show that residues 203-207 and the linker domain participate in a network of correlated movements with key regions of the enzyme, involved in the human topoisomerase I catalytic cycle, providing a structural-dynamical explanation for the better DNA relaxation activity of topo70 when compared to topo58/6.3. The data have been examined in relation to a wealth of biochemical, site-directed mutagenesis and crystallographic data on human topoisomerase I. The simulations finally show the occurrence of a network of direct and water mediated hydrogen bonds in the proximity of the active site, and the presence of a water molecule in the appropriate position to accept a proton from the catalytic Tyr-723 residue, suggesting that water molecules have an important role in the stabilization and function of this enzyme.

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“…Mutation of yeast Asn726 (corresponding to Asn722 in human topoisomerase) in Leu results in a decrease of enzyme activity, whereas its mutation in Ala does not modify topoisomerase activity, but strongly enhances its resistance to CPT and other topoisomerase poisons (Knab et al, 1993(Knab et al, , 1995Hann et al, 1998b). Mutations of this residue in Ser, Asp or His interfere with both enzyme activity and drug sensitivity (Leteurtre et al, 1994, Fertala et al, 2000. Crystallographic data indicate that in the upstream DNA portion of the covalent complex, Asn722 forms a direct hydrogen bond with DNA, whereas Lys720 makes a direct hydrogen bond with DNA in the downstream portion of the non-covalent complex.…”

Section: Correlation Between MD Results and Site-directed Mutagenesis Experimentsmentioning

confidence: 99%

Structure and Hydration of the DNA-Human Topoisomerase I Covalent Complex

Chillemi

Castrignanò

Desideri

2001

Biophysical Journal

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The structure and hydration of reconstituted human topoisomerase I comprising the core and the carboxyl-terminal domains in covalent complex with 22-basepair DNA duplex has been investigated by molecular dynamics simulation. The structure and the intermolecular interactions were found to be well maintained over the simulation. The complex displays a high degree of flexibility of the contact area, confirmed by the presence of numerous water-mediated protein-DNA hydrogen bonds comparable in quantity and distribution to the direct ones. The interaction between the enzyme and the solvent also provides the key for interpreting the experimental reduction of activity or affinity observed upon single residue mutation. Finally, four long lasting water molecules are observed in the proximity of the active site, one of which in the appropriate position to accept a proton from the active Tyr723.

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Saintopin, a dual inhibitor of DNA topoisomerases I and II, as a probe for drug-enzyme interactions.

Cited by 65 publications

References 39 publications

Dual topoisomerase I/II inhibitors

Dual topoisomerase I/II inhibitors

Role of the Linker Domain and the 203–214 N-Terminal Residues in the Human Topoisomerase I DNA Complex Dynamics

Structure and Hydration of the DNA-Human Topoisomerase I Covalent Complex

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