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Structure-Activity Relationship Study of 16 a-Thiocamptothecins: an Integrated In Vitro and In Silico Approach

The instability of the hydroxylactone E ring represents a critical drawback of camptothecins, because the lactone ring is recognized to be essential for stabilization of topoisomerase I‐mediated DNA cleavage. In an attempt to investigate the effect of the thiopyridone pharmacophofore on the molecula...

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Published in:ChemMedChem 2010-12, Vol.5 (12), p.2006-2015
Main Authors: Samorì, Cristian, Beretta, Giovanni L., Varchi, Greta, Guerrini, Andrea, Di%emsp14, Micco, Simone, Basili, Serena, Bifulco, Giuseppe, Riccio, Raffaele, Moro, Stefano, Bombardelli, Ezio, Zunino, Franco, Fontana, Gabriele
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cited_by cdi_FETCH-LOGICAL-c2279-d11bb12688126f7f388e24f12fee7771627dce91ade533565826c199e4e340143
cites cdi_FETCH-LOGICAL-c2279-d11bb12688126f7f388e24f12fee7771627dce91ade533565826c199e4e340143
container_end_page 2015
container_issue 12
container_start_page 2006
container_title ChemMedChem
container_volume 5
creator Samorì, Cristian
Beretta, Giovanni L.
Varchi, Greta
Guerrini, Andrea
Di%emsp14
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Basili, Serena
Bifulco, Giuseppe
Riccio, Raffaele
Moro, Stefano
Bombardelli, Ezio
Zunino, Franco
Fontana, Gabriele
description The instability of the hydroxylactone E ring represents a critical drawback of camptothecins, because the lactone ring is recognized to be essential for stabilization of topoisomerase I‐mediated DNA cleavage. In an attempt to investigate the effect of the thiopyridone pharmacophofore on the molecular and pharmacological features of the drug, we prepared a series of novel 16 a‐thiocamptothecin analogues. Due to the sulfur atom, a destabilization of the hydrogen bond between the hydroxy group in position 17 of the opened E ring and the carbonyl of the pyridone moiety is predicted, thus shifting the equilibrium toward the closed lactone form and increasing the lipophilic properties of the compounds. This feature was associated with superior antiproliferative potency, with reduced interaction with the human serum albumin and with substantial increase of the persistence of the topoisomerase I–DNA cleavable complex. These effects were prominent for thio‐SN38, the most active compound of the series. The favorable interactions at the molecular and cellular level of the reported thiocamptothecins confer promising features, and these compounds warrant preclinical development. Camping it up! 16 a‐thiocamptotecins analogues show superior antiproliferative potency, with reduced interaction with human serum albumin and a substantial increase in the persistence of the topoisomerase I–DNA cleavable complex. The favorable interactions at a molecular and cellular level of the reported thiocamptothecins confer promising features, and these compounds warrant preclinical development.
doi_str_mv 10.1002/cmdc.201000369
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In an attempt to investigate the effect of the thiopyridone pharmacophofore on the molecular and pharmacological features of the drug, we prepared a series of novel 16 a‐thiocamptothecin analogues. Due to the sulfur atom, a destabilization of the hydrogen bond between the hydroxy group in position 17 of the opened E ring and the carbonyl of the pyridone moiety is predicted, thus shifting the equilibrium toward the closed lactone form and increasing the lipophilic properties of the compounds. This feature was associated with superior antiproliferative potency, with reduced interaction with the human serum albumin and with substantial increase of the persistence of the topoisomerase I–DNA cleavable complex. These effects were prominent for thio‐SN38, the most active compound of the series. The favorable interactions at the molecular and cellular level of the reported thiocamptothecins confer promising features, and these compounds warrant preclinical development. Camping it up! 16 a‐thiocamptotecins analogues show superior antiproliferative potency, with reduced interaction with human serum albumin and a substantial increase in the persistence of the topoisomerase I–DNA cleavable complex. The favorable interactions at a molecular and cellular level of the reported thiocamptothecins confer promising features, and these compounds warrant preclinical development.</description><identifier>ISSN: 1860-7179</identifier><identifier>EISSN: 1860-7187</identifier><identifier>DOI: 10.1002/cmdc.201000369</identifier><identifier>PMID: 21069656</identifier><language>eng</language><publisher>Weinheim: WILEY-VCH Verlag</publisher><subject>antitumor agents ; Binding Sites ; Camptothecin - analogs &amp; derivatives ; Camptothecin - chemical synthesis ; Camptothecin - toxicity ; camptothecins ; cancer ; Cell Line, Tumor ; Computer Simulation ; DNA - metabolism ; DNA Cleavage ; DNA Topoisomerases, Type I - chemistry ; DNA Topoisomerases, Type I - metabolism ; Humans ; Lactones - chemistry ; Structure-Activity Relationship ; structure-activity relationships ; Thermodynamics ; Topoisomerase I Inhibitors - chemical synthesis ; Topoisomerase I Inhibitors - chemistry ; Topoisomerase I Inhibitors - toxicity ; topoisomerase I</subject><ispartof>ChemMedChem, 2010-12, Vol.5 (12), p.2006-2015</ispartof><rights>Copyright © 2010 WILEY‐VCH Verlag GmbH &amp; Co. 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In an attempt to investigate the effect of the thiopyridone pharmacophofore on the molecular and pharmacological features of the drug, we prepared a series of novel 16 a‐thiocamptothecin analogues. Due to the sulfur atom, a destabilization of the hydrogen bond between the hydroxy group in position 17 of the opened E ring and the carbonyl of the pyridone moiety is predicted, thus shifting the equilibrium toward the closed lactone form and increasing the lipophilic properties of the compounds. This feature was associated with superior antiproliferative potency, with reduced interaction with the human serum albumin and with substantial increase of the persistence of the topoisomerase I–DNA cleavable complex. These effects were prominent for thio‐SN38, the most active compound of the series. The favorable interactions at the molecular and cellular level of the reported thiocamptothecins confer promising features, and these compounds warrant preclinical development. Camping it up! 16 a‐thiocamptotecins analogues show superior antiproliferative potency, with reduced interaction with human serum albumin and a substantial increase in the persistence of the topoisomerase I–DNA cleavable complex. The favorable interactions at a molecular and cellular level of the reported thiocamptothecins confer promising features, and these compounds warrant preclinical development.</abstract><cop>Weinheim</cop><pub>WILEY-VCH Verlag</pub><pmid>21069656</pmid><doi>10.1002/cmdc.201000369</doi><tpages>10</tpages></addata></record>
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subjects antitumor agents
Binding Sites
Camptothecin - analogs & derivatives
Camptothecin - chemical synthesis
Camptothecin - toxicity
camptothecins
cancer
Cell Line, Tumor
Computer Simulation
DNA - metabolism
DNA Cleavage
DNA Topoisomerases, Type I - chemistry
DNA Topoisomerases, Type I - metabolism
Humans
Lactones - chemistry
Structure-Activity Relationship
structure-activity relationships
Thermodynamics
Topoisomerase I Inhibitors - chemical synthesis
Topoisomerase I Inhibitors - chemistry
Topoisomerase I Inhibitors - toxicity
topoisomerase I
title Structure-Activity Relationship Study of 16 a-Thiocamptothecins: an Integrated In Vitro and In Silico Approach
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