Towards new boron carriers for boron neutron capture therapy: metallacarboranes and their nucleoside conjugates Zbigniew J. Les ´nikowski, a, * Edyta Paradowska, a Agnieszka B. Olejniczak, a Mirosława Studzin ´ ska, a Petra Seekamp, b Uw Schu ¨ ßler, b Detlef Gabel, b Raymond F. Schinazi c,d and Jaromir Ples ˇek e a Center of Medical Biology, Laboratory of Molecular Virology and Biological Chemistry, Polish Academy of Sciences, 106 Lodowa Street, Lodz 93-232, Poland b Department of Chemistry, University of Bremen, D-28334 Bremen, Germany c Veterans Affairs Medical Center, Decatur, GA 30033, USA d Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA e Institute of Inorganic Chemistry, Academy of Sciences of the Czech Republic, 250-68 Rez ˇ, Czech Republic Received 23 June 2004; accepted 15 April 2005 Available online 5 May 2005 Abstract—Thymidine conjugates containing metallacarborane, {8-[5-(N 3 -thymidine)-3-oxa-pentoxy]-3-cobalt bis(1,2-dicarbol- lide)} À (5) and {8-[5-(O 4 -thymidine)-3-oxa-pentoxy]-3-cobalt bis(1,2-dicarbollide)} À (6) ions and several simple [3-cobalt bis(1,2- dicarbollide)] À ion (1) derivatives have been studied as potential boron carriers for BNCT. Compound 6 and some nonnucleoside derivatives of 1 were not toxic above 100 lM. The partition coefficient for both metallacarborane bearing thymidine conjugates 5 and 6 was more than 500 times higher than that of unmodified nucleoside. The cellular uptake studies showed accumulation of com- pounds 6 in V79 Chinese hamster cells but not of compound 5. The low toxicity of conjugate type of 6 together with its high par- tition coefficient suggest that judicially designed derivatives of metallacarboranes can be considered as potential boron carriers for BNCT. Ó 2005 Elsevier Ltd. All rights reserved. 1. Introduction Boron neutron capture therapy (BNCT) is a binary sys- tem for treatment of cancers, based on absorption of low-energy neutrons by nonradioactive boron-10 ( 10 B) atoms delivered to neoplastic cells in the form of a boron carrying drug. 1–3 The two independent, separately non- lethal constituents of this binary modality are radiosen- sitiser (boron carrier) containing 10 B and nonionising neutron radiation. Capture of neutron by 10 B, a stable isotope, results in the formation of excited boron-11 ( 11 B). 11 B is unstable and instantly fissions yielding high linear energy transfer (LET) lithium-7 ( 7 Li) and ener- getic a-particles ( 4 He). The kinetic energy of 7 Li and a-particles is about 2.8 million electron volts (eV) of energy (100 million times more than was put in). This, together with high linear energy transfer (LET) makes these particles highly lethal to the cells. It is assumed, that preferential neutron capture of 10 B-containing, tumor selective boron carrier in tumor tissue as com- pared to healthy cells, due to higher accumulation of the carrier in the tumor, will cause preferential killing of cancer cells and induce therapeutic effect (Fig. 1). For BNCT to be successful, 10 9 10 B atoms must be local- ised on or preferably within neoplastic cells (20–40 lg of B in one gram of tumor), and a sufficient number of ther- mal neutrons must be delivered to sustain a lethal 10 B (n, alpha) lithium-7 reaction. Therefore, the development of highly boron loaded, tumor-selective drugs play an important role if BNCT is to evolve into clinically ac- cepted treatment for cancer. A number of potential boron carriers such as boron-containing porphyrins, amino acids, carbohydrates, nucleic acid bases, nucleosides, polyamines, DNA groove binders, low-density lipopro- teins, biopolymers such as peptides, oligophosphates and oligonucleotides have been synthesised and tested. 4–6 The persistent interest in the design and synthesis of 0968-0896/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmc.2005.04.042 Keywords: BNCT; Boron carriers; Metallacarboranes; Nucleoside conjugates. * Corresponding author. Tel.: +48 42 677 12 49; fax: +48 42 677 12 30; e-mail: zlesnik@cbm.pan.pl Bioorganic & Medicinal Chemistry 13 (2005) 4168–4175