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Pure and Applied Chemistry

The Scientific Journal of IUPAC

Ed. by Burrows, Hugh / Stohner, Jürgen


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Volume 84, Issue 11

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Imitation and modification of bioactive lead structures via integration of boron clusters

Sven Stadlbauer
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  • Institute of Inorganic Chemistry, Universität Leipzig, Johannisallee 29, D-04103 Leipzig, Germany
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/ René Frank
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  • Institute of Inorganic Chemistry, Universität Leipzig, Johannisallee 29, D-04103 Leipzig, Germany
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/ Matthias Scholz
  • Corresponding author
  • Institute of Inorganic Chemistry, Universität Leipzig, Johannisallee 29, D-04103 Leipzig, Germany
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/ Solveig Boehnke
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  • Institute of Inorganic Chemistry, Universität Leipzig, Johannisallee 29, D-04103 Leipzig, Germany
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/ Verena M. Ahrens
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  • Institute of Biochemistry, Universität Leipzig, Brüderstraße 34, D-04103 Leipzig, Germany
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/ Annette G. Beck-Sickinger
  • Corresponding author
  • Institute of Biochemistry, Universität Leipzig, Brüderstraße 34, D-04103 Leipzig, Germany
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/ Evamarie Hey-Hawkins
  • Corresponding author
  • Institute of Inorganic Chemistry, Universität Leipzig, Johannisallee 29, D-04103 Leipzig, Germany
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Published Online: 2012-05-22 | DOI: https://doi.org/10.1351/PAC-CON-11-11-02

In medicinal chemistry, carbaboranes can be employed either as boron carriers for boron neutron capture therapy (BNCT) or as scaffolds for radiodiagnostic or therapeutic agents. We have developed a suitable synthesis employing the phosphoramidite method to connect meta-carbaboranyl bis-phosphonites with the 6'-OH group of isopropylidene-protected galactose, followed by oxidation or sulfurization to give the corresponding bis-phosphonates. Deprotection yielded water-soluble compounds. The corresponding disodium salts exhibit especially low cytotoxicity. Preliminary results on the in vivo toxicity and biodistribution of two compounds in mice indicated a lack of selectivity for the cotton rat lung (CRL) tumor chosen for the experiment. For the incorporation of carbaboranes into breast tumor-selective modified neuropeptide Y, [F7, P34]-NPY, a synthesis of a carbaborane-modified lysine derivative was developed. Linkage of the lysine to the boron cluster was achieved by using a propionic acid spacer. Incorporation of the amino acid derivatives into NPY and [F7, P34]-NPY by solid-phase peptide synthesis was successful. Preliminary studies showed that the receptor binding affinity and signal transduction of the boron-modified peptides were very well retained. Asborin, the carbaborane analogue of aspirin, is a rather weak inhibitor of cyclooxygenase-1 (COX-1) and COX-2, but a highly potent aldo/keto reductase 1A1 (AKR1A1) inhibitor. Modification either at the carboxyl group or at the chlorophenyl ring in indomethacin with ortho- and meta-carbaboranyl derivatives gave active derivatives only for the ortho-carbaborane directly attached to the carboxyl group, while the corresponding adamantyl and meta-carbaboranyl derivatives were inactive.

Keywords: asborin; boron neutron capture therapy (BNCT); carbaboranes; carboranes; cyclooxygenase (COX) inhibitors; indomethacin derivatives; neuropeptide Y (NPY)-carbaborane conjugates; nonsteroidal anti-inflammatory drugs (NSAIDs); pharmacophores; phosphonates; tumor selectivity

Conference

International Meeting on Boron Chemistry (IMEBORON-XIV), International Symposium on Boron Chemistry, IMEB, Boron Chemistry, 14th, Niagara Falls, Canada, 2011-09-11–2011-09-15

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About the article

Published Online: 2012-05-22

Published in Print: 2012-05-22


Citation Information: Pure and Applied Chemistry, Volume 84, Issue 11, Pages 2289–2298, ISSN (Online) 1365-3075, ISSN (Print) 0033-4545, DOI: https://doi.org/10.1351/PAC-CON-11-11-02.

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