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Synthesis and Radioiodination of Some 9-Aminoacridine Derivatives
Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Kemiska institutionen.
Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Kemiska institutionen.
Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Kemiska institutionen.
Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Kemiska institutionen.
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2004 (Engelska)Ingår i: European Journal of Organic Chemistry, ISSN 1434-193X, E-ISSN 1099-0690, Vol. 17, s. 3719-3725Artikel i tidskrift (Refereegranskat) Published
Ort, förlag, år, upplaga, sidor
2004. Vol. 17, s. 3719-3725
Nationell ämneskategori
Organisk kemi
Identifikatorer
URN: urn:nbn:se:uu:diva-69939DOI: 10.1002/ejoc.200400296OAI: oai:DiVA.org:uu-69939DiVA, id: diva2:97850
Tillgänglig från: 2006-05-17 Skapad: 2006-05-17 Senast uppdaterad: 2017-11-21Bibliografiskt granskad
Ingår i avhandling
1. Synthesis of Organic Compounds for Nuclide Therapy: Derivatives of Carboranes, 9-Aminoacridine and Anthracyclines
Öppna denna publikation i ny flik eller fönster >>Synthesis of Organic Compounds for Nuclide Therapy: Derivatives of Carboranes, 9-Aminoacridine and Anthracyclines
2004 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

This thesis addresses the synthesis of organic compounds, some of them are derivatives of compounds with DNA binding properties, for potential use in targeted nuclide therapy. The compounds synthesized therefore also need to contain potent nuclides. Here the nuclides considered are the radionuclide 125I, and the stable isotope 10B, which becomes radioactive upon neutron activation. 125I is an Auger-electron emitter, which emits particles that can travel only about 1-2 µm through human tissue and hence has to be delivered to the cancer cell nucleus to cause DNA damage. Neutron activated 10B emits highly cell killing α-particles and 7Li3+ ions, the application of which in Boron Nuclide Capture Therapy (BNCT) has proven very promising.

The thesis can be divided into three parts:

i) A nido-carborate, 7-(3´-ammoniopropyl)-7,8-dicarba-nido-undecaborate(-1), has been synthesized and radioiodinated for use as a pendant group for attachment of 125I to tumor-seeking macromolecules. Radiolabeling was achieved in greater than 95% yield.

ii) Both enantiomers of m-carboranylalanine, a carborane analogue of phenylalanine, have been prepared in high enantiomeric excess, and are of potential interest in BNCT. The synthesis involved amination of the N-acyl derivative formed from [3-(1,7-dicarba-closo-dodecarborane(12)-1-yl)-2-propanoic acid and Oppolzer’s camphor sultam.

iii) Derivatives of the DNA intercalating compounds 9-aminoacridine, daunorubicin and doxorubicin have been synthesized and labeled with 125I. The 9-aminoacridines were synthesised with a variety of functional groups such as carboxyl, amino and hydroxyl. The anthracylines daunorubicin and doxorubicin are efficient chemotherapeutic agents; the synthesis routes of ester, amide and amine derivatives of these compounds are presented.

The Chloramine T method was used for the radioiodinations, and the radioiodination precursors of both the acridine and the anthracycline derivatives, were made to contain either a trimethylstannyl group or a phenolic substituent. In the former case the trimethylstannyl group was replaced by 125I, and in the latter case, the compounds were radiolabeled directly at the o- position to the phenolic hydroxyl group. Both methods gave high radiolabeling yields.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2004. s. 56
Serie
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1104-232X ; 978
Nyckelord
Organic chemistry, 9-Aminoacridin, Carborane, Daunorubicin, Doxorubicin, BNCT, Iodine-125, Organisk kemi
Nationell ämneskategori
Organisk kemi
Identifikatorer
urn:nbn:se:uu:diva-4264 (URN)91-554-5969-2 (ISBN)
Disputation
2004-05-14, Room B41, BMC, Husargatan 3, Uppsala, 13:15 (Engelska)
Opponent
Handledare
Tillgänglig från: 2004-04-22 Skapad: 2004-04-22 Senast uppdaterad: 2011-04-14Bibliografiskt granskad
2. Radiohalogenated Compounds for Tumor Targeting: Synthesis and Radiolabeling
Öppna denna publikation i ny flik eller fönster >>Radiohalogenated Compounds for Tumor Targeting: Synthesis and Radiolabeling
2005 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

This thesis describes the synthesis and radiohalogenation of compounds of potential use for tumor targeting.

The first section describes the synthesis and radioiodination of DNA intercalating compounds. The compounds are derivatives of 9-aminoacridine, and the anthracyclins daunorubicin and doxorubicin. The precursor compounds were labeled with 125I (T1/2 = 60 days), which is an Auger emitting nuclide. 125I decaying in the close vicinity of DNA is known to have a much higher cell killing effect than 125I decaying in the cytoplasm and some of the labeled compounds prepared in this thesis are currently being tested for use in targeted radionuclide therapy for cancer.

The second section describes the radiobromination of closo-carboranes by subjecting the corresponding iodinated compounds to palladium-catalyzed halogen exchange using [76Br]bromide. The 76Br isotope (T1/2 = 16.2 h) is a positron emitting nuclide that is suitable for PET studies. Via the halogen exchange reaction good to excellent radiochemical yields of radiobrominated closo-carboranes were obtained. The results of the present study may prove to be applicable to pharmacokinetic studies of carboranes and their derivatives.

The third and final section describes the indirect radiobromination of the trastuzumab anti-HER2 monoclonal antibody and of the anti-HER2 Affibody by means of an “one-pot” procedure using N-succinimidyl-5-(tributylstannyl)-3-pyridinecarboxylate (SPC) and ((4-hydroxyphenyl)ethyl))maleimide (HPEM), respectively. It was found that SPC and HPEM can be efficiently radiobrominated and thereafter coupled to the antibody and Affibody, respectively. The labeled proteins retained their capacity to bind specifically to HER2 expressing SKOV-3 cells in vitro. Application of this method to 76Br might enable the use of PET in the detection of HER2 expression in breast, ovarian, and urinary bladder carcinomas.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2005. s. 51
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 22
Nyckelord
Inorganic chemistry, 9-Aminoacridine, Daunorubicin, Doxorubicin, Carborane, Radiobromination, Radioiodination, Affibody, Monoclonal antibody, Oorganisk kemi
Nationell ämneskategori
Oorganisk kemi
Identifikatorer
urn:nbn:se:uu:diva-4817 (URN)91-554-6165-4 (ISBN)
Disputation
2005-04-25, Room B42, BMC, Husargatan 3, Uppsala, 10:15 (Engelska)
Opponent
Handledare
Tillgänglig från: 2005-03-04 Skapad: 2005-03-04 Senast uppdaterad: 2009-11-23Bibliografiskt granskad

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