Biological Evaluation of Dodecaborate-Containing L-Amino Acids for Boron Neutron Capture Therapy

Research Center of Boron Neutron Capture Therapy, Research Organization for the 21st Century, Osaka Prefecture University, 1-1 Gakuen-cho, Nakaku 599-8531, Sakai, Japan.
Journal of Medicinal Chemistry (Impact Factor: 5.45). 07/2012; 55(15):6980-4. DOI: 10.1021/jm300749q
Source: PubMed


To develop a boron carrier for practical purposes, new boron-containing amino acids with an undecahydro-closo-dodecaboranylthio ([(10)B(12)H(11)S](2-)-) unit in the side chain of the α-amino acid have already been designed and synthesized. In the present paper, cytotoxicity, the incorporation amounts into tumor cells, and the tumor cell killing effects of these compounds were elucidated to evaluate their usefulness as boron carriers. Furthermore, the microdistribution of the amino acids in tumor cells was established.

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    • "Boron neutron capture therapy (BNCT) is based on the nuclear capture and fission reactions of the 10B nucleus with low energy thermal/epithermal neutrons to yield high linear energy transfer α particles and recoiling 7Li nuclei. Since the path lengths of the particles are approximately 9 to 10 µm, equal to the dimensions of a single cell, 10B-containing cells are selectively destroyed by BNCT [1]. "
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    ABSTRACT: Boron neutron capture therapy (BNCT) is a binary treatment involving selective accumulation of boron carriers in a tumor followed by irradiation with a thermal or epithermal neutron beam. The neutron capture reaction with a boron-10 nucleus yields high linear energy transfer (LET) particles, alpha and (7)Li, with a range of 5 to 9 µm. These particles can only travel very short distances and release their damaging energy directly into the cells containing the boron compound. We aimed to evaluate proliferation, apoptosis and extracellular matrix (ECM) modifications of B16F10 melanoma and normal human melanocytes after BNCT. The amounts of soluble collagen and Hsp47, indicating collagen synthesis in the ECM, as well as the cellular markers of apoptosis, were investigated. BNCT decreased proliferation, altered the ECM by decreasing collagen synthesis and induced apoptosis by regulating Bcl-2/Bax in melanoma. Additionally, BNCT also increased the levels of TNF receptor and the cleaved caspases 3, 7, 8 and 9 in melanoma. These results suggest that multiple pathways related to cell death and cell cycle arrest are involved in the treatment of melanoma by BNCT.
    PLoS ONE 03/2013; 8(3):e59639. DOI:10.1371/journal.pone.0059639 · 3.23 Impact Factor
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    ABSTRACT: A series of new boron-containing amino acids 1-HOOCCH(NH2)(CH2)(n)S-1,2-C2B10H11 (n = 4-6) was prepared by alkylation of 1-mercapto-ortho-carborane with omega-bromoalkylacetamido diethylmalonates followed by acid hydrolysis and decarboxylation. Mild deboronation of the c/oso-carborane cage with CsF gives cesium salts of the corresponding nido-carborane based amino acids Cs[7-HOOccH(NH2)(CH2)(n) S-7,8-C(2)B9H(l1)] d (n = 4-6). The compounds synthesized can be used in radionuclide diagnostics and boron neutron capture therapy of cancer
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    ABSTRACT: A series of C-hydroxy carborane derivatives of (S)-2-(3-((S)-5-amino-1-carboxypentyl)ureido)-pentanedioic acid were prepared as a new class of boron rich inhibitors of prostate specific membrane antigen (PSMA), which is overexpressed on prostate cancer tumours and metastases. Closo-, nido- and iodo-carborane conjugates were prepared and screened in vitro where the water soluble iodinated cluster had the highest affinity with an IC50 value (73.2 nM) that was comparable to a known PSMA inhibitor 2-(phosphonomethyl)-pentanedioic acid (PMPA, 63.9 nM). The radiolabeled analogue was prepared using (123)I and the biodistribution determined in a prostate cancer model derived from a PSMA positive cell line (LNCaP) at 1, 2, 4, 6 and 24 h post injection (n = 4 per time point). The results showed good initial tumour uptake of 4.17% at 1 h, which remained at that level only decreasing somewhat at 6 h (3.59%). At the latter time point tumour-to-blood and tumour-to-muscle ratios peaked at 3.47 at 25.52 respectively. There was significant off-target binding particularly in the liver and gall bladder and a surprising amount of deiodination in vivo. Notwithstanding, this work demonstrates that carboranes can be used to prepare potent ligands for PSMA creating the opportunity to develop a new class of BNCT agents for prostate cancer.
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