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Synthesis and radioiodination of some daunorubicin and doxorubicin derivatives
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry.
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry.
2005 (English)In: Carbohydrate Research, ISSN 0008-6215, E-ISSN 1873-426X, Vol. 340, no 1, 15-24 p.Article in journal (Refereed) Published
Abstract [en]

Daunorubicin and doxorubicin are efficient agents for cancer treatment. Their clinical efficacy is, however, hampered by their indiscriminant toxicity. This problem may be circumvented by encapsulating the drugs in liposomes and selectively targeting the tumor cells using tumor targeting agents. Furthermore, the antitumor effect could be enhanced by attaching the Auger electron emitter, 125I, to daunorubicin an ddoxorubicin derivatives. In this context a number of ester, amide, and amine derivatives of daunorubicin an ddoxorubicin were synthesized. Benzoic acid ester derivatives of daunorubicin were synthesized by nucleophilic esterification of the 14-bromodaunorubicin with the potassium salt of the corresponding benzoic acid, resulting in good yields. Nicotinic acids and benzoic acids, activated with a succinimidyl group, were coupled to the amino group of daunorubicien to give the corresponding amide derivatives. Amine derivatives were obtained by the reductive amination of aromatic aldehydes with daunorubicin hydrochloride. The stannylated ester and amide derivatives were uses as precursors for radioiodination. Radiolabeling with 125I was performed using chloroamine-T as an oxidant. The optimized labeling resulted in high radiolabeling yields (85-95%) of the radioiodinated daunorubicin and doxorubicin derivatives. Radioiodination of the amines was conducted at the ortho position of the activated phenyl rings providing moderate radiochemical yields (55-75%).

Place, publisher, year, edition, pages
2005. Vol. 340, no 1, 15-24 p.
Keyword [en]
Daunorubicin, Doxorubicin, Radioiodination, 125I, Chloramine-T
National Category
Organic Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-70001DOI: doi:10.1016/j.carres.2004.10.014PubMedID: 15620662OAI: oai:DiVA.org:uu-70001DiVA: diva2:97912
Available from: 2006-06-29 Created: 2006-06-29 Last updated: 2017-11-21Bibliographically approved
In thesis
1. Synthesis of Organic Compounds for Nuclide Therapy: Derivatives of Carboranes, 9-Aminoacridine and Anthracyclines
Open this publication in new window or tab >>Synthesis of Organic Compounds for Nuclide Therapy: Derivatives of Carboranes, 9-Aminoacridine and Anthracyclines
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
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.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2004. 56 p.
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1104-232X ; 978
Keyword
Organic chemistry, 9-Aminoacridin, Carborane, Daunorubicin, Doxorubicin, BNCT, Iodine-125, Organisk kemi
National Category
Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-4264 (URN)91-554-5969-2 (ISBN)
Public defence
2004-05-14, Room B41, BMC, Husargatan 3, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2004-04-22 Created: 2004-04-22 Last updated: 2011-04-14Bibliographically approved
2. Radiohalogenated Compounds for Tumor Targeting: Synthesis and Radiolabeling
Open this publication in new window or tab >>Radiohalogenated Compounds for Tumor Targeting: Synthesis and Radiolabeling
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
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.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2005. 51 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 22
Keyword
Inorganic chemistry, 9-Aminoacridine, Daunorubicin, Doxorubicin, Carborane, Radiobromination, Radioiodination, Affibody, Monoclonal antibody, Oorganisk kemi
National Category
Inorganic Chemistry
Identifiers
urn:nbn:se:uu:diva-4817 (URN)91-554-6165-4 (ISBN)
Public defence
2005-04-25, Room B42, BMC, Husargatan 3, Uppsala, 10:15 (English)
Opponent
Supervisors
Available from: 2005-03-04 Created: 2005-03-04 Last updated: 2009-11-23Bibliographically approved

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Mume, EskenderTolmachev, VladimirSjöberg, Stefan

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