Synthesis, characterization and biological evaluation of In(III) complexes anchored by DOTA-like chelators bearing a quinazoline moiety.
Identifieur interne : 001702 ( Main/Exploration ); précédent : 001701; suivant : 001703Synthesis, characterization and biological evaluation of In(III) complexes anchored by DOTA-like chelators bearing a quinazoline moiety.
Auteurs : RBID : pubmed:21072342English descriptors
- KwdEn :
- Animals, Cell Line, Chelating Agents (chemistry), Chromatography, High Pressure Liquid, Crystallography, X-Ray, Drug Evaluation, Preclinical, Female, Heterocyclic Compounds, 1-Ring (chemistry), Humans, Indium (chemistry), Indium (pharmacokinetics), Indium (pharmacology), Magnetic Resonance Spectroscopy, Mice, Potentiometry, Quinazolines (chemistry), Spectrophotometry, Infrared, Spectrophotometry, Ultraviolet, Tissue Distribution.
- MESH :
- chemical , chemistry : Chelating Agents, Heterocyclic Compounds, 1-Ring, Indium, Quinazolines.
- chemical , pharmacokinetics : Indium.
- chemical , pharmacology : Indium.
- Animals, Cell Line, Chromatography, High Pressure Liquid, Crystallography, X-Ray, Drug Evaluation, Preclinical, Female, Humans, Magnetic Resonance Spectroscopy, Mice, Potentiometry, Spectrophotometry, Infrared, Spectrophotometry, Ultraviolet, Tissue Distribution.
Abstract
Following previous studies with a DOTA-like bifunctional chelator (H(3)L1) containing an ethylenic linker between the macrocycle backbone and a quinazoline pharmacophore, we synthesized and fully characterized a congener macrocyclic ligand (H(3)L2) having a longer, five-carbon spacer for the linkage of the quinazoline moiety. Both H(3)L1 and H(3)L2 were used to prepare indium(III) complexes aiming at their evaluation as radioactive probes for in vivo targeting of EGFR-TK. The protonation constants (log K(Hi)) of H(3)L2 were determined by potentiometry and UV-Vis spectrophotometry and the values found are 12.18, 9.74, 4.99, 3.91 and 2.53. The stability and protonation constants of InL (L = L1, L2) were also obtained from a combined potentiometry and UV-VIS spectrophotometry study. The reaction of InCl(3) with H(3)L1 and H(3)L2 led to the formation of the well-defined complexes InL1 and InL2, containing In(iii) ions coordinated by a seven (N(4),O(3)) donor atom set. These new complexes were fully characterized by spectroscopic methods (IR, NMR, ESI-MS), HPLC and by X-ray diffraction analysis in the case of InL1. The radioactive congener (111)InL2 was prepared from the reaction of (111)In-chloride with H(3)L2, in high yield and high radiochemical purity. (111)InL2 is a neutral complex that presents a hydrophilic character and exhibits a high in vitro and in vivo stability. H(3)L2 and InL2 do not inhibit the cell growth of A431 cervical carcinoma cells. In this EGFR-expressing cell line, (111)InL2 has shown very low cell internalization. These findings indicate that these DOTA-like chelators are not the best suited bifunctional ligands to obtain In(iii) complexes with adequate biological properties for targeting the EGFR-TK.
DOI: 10.1039/c004797j
PubMed: 21072342
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Synthesis, characterization and biological evaluation of In(III) complexes anchored by DOTA-like chelators bearing a quinazoline moiety.</title><author><name sortKey="Garcia, Raquel" uniqKey="Garcia R">Raquel Garcia</name><affiliation wicri:level="1"><nlm:affiliation>Unidade de Ciências Químicas e Radiofarmacêuticas, Instituto Tecnológico e Nuclear, Estrada Nacional 10, Sacavém, Portugal.</nlm:affiliation><country xml:lang="fr">Portugal</country><wicri:regionArea>Unidade de Ciências Químicas e Radiofarmacêuticas, Instituto Tecnológico e Nuclear, Estrada Nacional 10, Sacavém</wicri:regionArea></affiliation></author><author><name sortKey="Kub Ek, Vojt Ch" uniqKey="Kub Ek V">Vojtěch Kubíček</name></author><author><name sortKey="Draho, Bohuslav" uniqKey="Draho B">Bohuslav Drahoš</name></author><author><name sortKey="Gano, Lurdes" uniqKey="Gano L">Lurdes Gano</name></author><author><name sortKey="Santos, Isabel C" uniqKey="Santos I">Isabel C Santos</name></author><author><name sortKey="Campello, Paula" uniqKey="Campello P">Paula Campello</name></author><author><name sortKey="Paulo, Ant Nio" uniqKey="Paulo A">António Paulo</name></author><author><name sortKey="T Th, Eva" uniqKey="T Th E">Eva Tóth</name></author><author><name sortKey="Santos, Isabel" uniqKey="Santos I">Isabel Santos</name></author></titleStmt><publicationStmt><date when="2010">2010</date><idno type="doi">10.1039/c004797j</idno><idno type="RBID">pubmed:21072342</idno><idno type="pmid">21072342</idno><idno type="wicri:Area/Main/Corpus">001706</idno><idno type="wicri:Area/Main/Curation">001706</idno><idno type="wicri:Area/Main/Exploration">001702</idno></publicationStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term><term>Cell Line</term><term>Chelating Agents (chemistry)</term><term>Chromatography, High Pressure Liquid</term><term>Crystallography, X-Ray</term><term>Drug Evaluation, Preclinical</term><term>Female</term><term>Heterocyclic Compounds, 1-Ring (chemistry)</term><term>Humans</term><term>Indium (chemistry)</term><term>Indium (pharmacokinetics)</term><term>Indium (pharmacology)</term><term>Magnetic Resonance Spectroscopy</term><term>Mice</term><term>Potentiometry</term><term>Quinazolines (chemistry)</term><term>Spectrophotometry, Infrared</term><term>Spectrophotometry, Ultraviolet</term><term>Tissue Distribution</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Chelating Agents</term><term>Heterocyclic Compounds, 1-Ring</term><term>Indium</term><term>Quinazolines</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacokinetics" xml:lang="en"><term>Indium</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Indium</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Cell Line</term><term>Chromatography, High Pressure Liquid</term><term>Crystallography, X-Ray</term><term>Drug Evaluation, Preclinical</term><term>Female</term><term>Humans</term><term>Magnetic Resonance Spectroscopy</term><term>Mice</term><term>Potentiometry</term><term>Spectrophotometry, Infrared</term><term>Spectrophotometry, Ultraviolet</term><term>Tissue Distribution</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Following previous studies with a DOTA-like bifunctional chelator (H(3)L1) containing an ethylenic linker between the macrocycle backbone and a quinazoline pharmacophore, we synthesized and fully characterized a congener macrocyclic ligand (H(3)L2) having a longer, five-carbon spacer for the linkage of the quinazoline moiety. Both H(3)L1 and H(3)L2 were used to prepare indium(III) complexes aiming at their evaluation as radioactive probes for in vivo targeting of EGFR-TK. The protonation constants (log K(Hi)) of H(3)L2 were determined by potentiometry and UV-Vis spectrophotometry and the values found are 12.18, 9.74, 4.99, 3.91 and 2.53. The stability and protonation constants of InL (L = L1, L2) were also obtained from a combined potentiometry and UV-VIS spectrophotometry study. The reaction of InCl(3) with H(3)L1 and H(3)L2 led to the formation of the well-defined complexes InL1 and InL2, containing In(iii) ions coordinated by a seven (N(4),O(3)) donor atom set. These new complexes were fully characterized by spectroscopic methods (IR, NMR, ESI-MS), HPLC and by X-ray diffraction analysis in the case of InL1. The radioactive congener (111)InL2 was prepared from the reaction of (111)In-chloride with H(3)L2, in high yield and high radiochemical purity. (111)InL2 is a neutral complex that presents a hydrophilic character and exhibits a high in vitro and in vivo stability. H(3)L2 and InL2 do not inhibit the cell growth of A431 cervical carcinoma cells. In this EGFR-expressing cell line, (111)InL2 has shown very low cell internalization. These findings indicate that these DOTA-like chelators are not the best suited bifunctional ligands to obtain In(iii) complexes with adequate biological properties for targeting the EGFR-TK.</div></front></TEI><pubmed><MedlineCitation Owner="NLM" Status="MEDLINE"><PMID Version="1">21072342</PMID><DateCreated><Year>2010</Year><Month>11</Month><Day>12</Day></DateCreated><DateCompleted><Year>2011</Year><Month>03</Month><Day>01</Day></DateCompleted><DateRevised><Year>2013</Year><Month>11</Month><Day>21</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1756-591X</ISSN><JournalIssue CitedMedium="Internet"><Volume>2</Volume><Issue>8</Issue><PubDate><Year>2010</Year><Month>Aug</Month></PubDate></JournalIssue><Title>Metallomics : integrated biometal science</Title><ISOAbbreviation>Metallomics</ISOAbbreviation></Journal><ArticleTitle>Synthesis, characterization and biological evaluation of In(III) complexes anchored by DOTA-like chelators bearing a quinazoline moiety.</ArticleTitle><Pagination><MedlinePgn>571-80</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1039/c004797j</ELocationID><Abstract><AbstractText>Following previous studies with a DOTA-like bifunctional chelator (H(3)L1) containing an ethylenic linker between the macrocycle backbone and a quinazoline pharmacophore, we synthesized and fully characterized a congener macrocyclic ligand (H(3)L2) having a longer, five-carbon spacer for the linkage of the quinazoline moiety. Both H(3)L1 and H(3)L2 were used to prepare indium(III) complexes aiming at their evaluation as radioactive probes for in vivo targeting of EGFR-TK. The protonation constants (log K(Hi)) of H(3)L2 were determined by potentiometry and UV-Vis spectrophotometry and the values found are 12.18, 9.74, 4.99, 3.91 and 2.53. The stability and protonation constants of InL (L = L1, L2) were also obtained from a combined potentiometry and UV-VIS spectrophotometry study. The reaction of InCl(3) with H(3)L1 and H(3)L2 led to the formation of the well-defined complexes InL1 and InL2, containing In(iii) ions coordinated by a seven (N(4),O(3)) donor atom set. These new complexes were fully characterized by spectroscopic methods (IR, NMR, ESI-MS), HPLC and by X-ray diffraction analysis in the case of InL1. The radioactive congener (111)InL2 was prepared from the reaction of (111)In-chloride with H(3)L2, in high yield and high radiochemical purity. (111)InL2 is a neutral complex that presents a hydrophilic character and exhibits a high in vitro and in vivo stability. H(3)L2 and InL2 do not inhibit the cell growth of A431 cervical carcinoma cells. In this EGFR-expressing cell line, (111)InL2 has shown very low cell internalization. These findings indicate that these DOTA-like chelators are not the best suited bifunctional ligands to obtain In(iii) complexes with adequate biological properties for targeting the EGFR-TK.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Garcia</LastName><ForeName>Raquel</ForeName><Initials>R</Initials><Affiliation>Unidade de Ciências Químicas e Radiofarmacêuticas, Instituto Tecnológico e Nuclear, Estrada Nacional 10, Sacavém, Portugal.</Affiliation></Author><Author ValidYN="Y"><LastName>Kubíček</LastName><ForeName>Vojtěch</ForeName><Initials>V</Initials></Author><Author ValidYN="Y"><LastName>Drahoš</LastName><ForeName>Bohuslav</ForeName><Initials>B</Initials></Author><Author ValidYN="Y"><LastName>Gano</LastName><ForeName>Lurdes</ForeName><Initials>L</Initials></Author><Author ValidYN="Y"><LastName>Santos</LastName><ForeName>Isabel C</ForeName><Initials>IC</Initials></Author><Author ValidYN="Y"><LastName>Campello</LastName><ForeName>Paula</ForeName><Initials>P</Initials></Author><Author ValidYN="Y"><LastName>Paulo</LastName><ForeName>António</ForeName><Initials>A</Initials></Author><Author ValidYN="Y"><LastName>Tóth</LastName><ForeName>Eva</ForeName><Initials>E</Initials></Author><Author ValidYN="Y"><LastName>Santos</LastName><ForeName>Isabel</ForeName><Initials>I</Initials></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType>Journal Article</PublicationType><PublicationType>Research Support, Non-U.S. Gov't</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2010</Year><Month>07</Month><Day>01</Day></ArticleDate></Article><MedlineJournalInfo><Country>England</Country><MedlineTA>Metallomics</MedlineTA><NlmUniqueID>101478346</NlmUniqueID><ISSNLinking>1756-5901</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance>Chelating Agents</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance>Heterocyclic Compounds, 1-Ring</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance>Quinazolines</NameOfSubstance></Chemical><Chemical><RegistryNumber>045A6V3VFX</RegistryNumber><NameOfSubstance>Indium</NameOfSubstance></Chemical><Chemical><RegistryNumber>60239-18-1</RegistryNumber><NameOfSubstance>1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName MajorTopicYN="N">Animals</DescriptorName></MeshHeading><MeshHeading><DescriptorName MajorTopicYN="N">Cell Line</DescriptorName></MeshHeading><MeshHeading><DescriptorName MajorTopicYN="N">Chelating Agents</DescriptorName><QualifierName MajorTopicYN="Y">chemistry</QualifierName></MeshHeading><MeshHeading><DescriptorName MajorTopicYN="N">Chromatography, High Pressure Liquid</DescriptorName></MeshHeading><MeshHeading><DescriptorName MajorTopicYN="N">Crystallography, X-Ray</DescriptorName></MeshHeading><MeshHeading><DescriptorName MajorTopicYN="N">Drug Evaluation, Preclinical</DescriptorName></MeshHeading><MeshHeading><DescriptorName MajorTopicYN="N">Female</DescriptorName></MeshHeading><MeshHeading><DescriptorName MajorTopicYN="N">Heterocyclic Compounds, 1-Ring</DescriptorName><QualifierName MajorTopicYN="Y">chemistry</QualifierName></MeshHeading><MeshHeading><DescriptorName MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName MajorTopicYN="N">Indium</DescriptorName><QualifierName MajorTopicYN="Y">chemistry</QualifierName><QualifierName MajorTopicYN="N">pharmacokinetics</QualifierName><QualifierName MajorTopicYN="Y">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName MajorTopicYN="N">Magnetic Resonance Spectroscopy</DescriptorName></MeshHeading><MeshHeading><DescriptorName 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