Boronic therapeutics

Since the time of the aforementioned reviews, more recent advances in the chemistry of boron therapeutics have been covered by others (2009MI1275). Advances in the chemistry of azaborines have been reviewed recently (2012AG(I)6074), as have those in the medicinal chemistry of boronic acid derivatives, 1,2-azaborines, and icosahedral boranes (carboranes) (2013AJC1118). Advances in the chemistry of tetrahedraUy coordinated B-heterocycles have been reviewed (2000CCR85), and advances in luminescent dyes containing tetrahedral boron centers... 

Like PAMAM dendrimers, polylysine dendrimers are largely characterised by amide bonds. They attracted interest as potential therapeutic agents for use in boron neutron capture therapy and in magnetic resonance imaging (MRI) (see Chapter 8), since dendritic polylysines apparently have a lower toxicity than their linear counterparts. The polylysine shown in Fig. 4.10 with a total of 80 terminal boron atoms in the carborane units and a dansyl group was designed specifically for boron neutron capture therapy [20]. 

The dual-mechanism of cytotoxic activity of amine-boranes, possessing significant antineoplastic activity and useful also in boron neutron capture therapy (BNCT), initiated the search during recent years for therapeutic compounds of this class which accumulate preferentially in the tumor tissue194,195. The title compound 192, one of the... 

Although diesters of folates were sketchily described much earlier [291], the idea of using lipid soluble diesters of MTX as therapeutic agents, first proposed in 1962 [292], was not elaborated systematically until the early 1970 s [293-298]. Direct esterification of MTX as well as DCM with a variety of primary and secondary aliphatic alcohols was shown to proceed in good yield with dry HCl [296] or boron trifluoride [293] as the catalyst, giving products (VIII.l 13)-(VIII.131), the lipophilicity of which could be shown to vary with the length of the alkyl group. 

Barth, R. E., A. H. Soloway, J. H. Goodman, R. A. Gahbauer, N. Gupta, T. E. Blue, W. Yang, and W. Tjarks. 1999. Boron neutron capture therapy of brain tumors An emerging therapeutic modality. Neurosurgery 44 433 51. 

The boron is injected into the patient usually as a carborane (e.g. the ring-compound C2H12B10) which is furnished with two mercapto-groups to give affinity for protein. Although there is 19% of B in natural boric acid (the rest is mainly B), the therapeutic material is further enriched. One hour after the injection, a neutron beam from a thermonuclear reactor is lined up with an appropriately localized hole made in the patient s skull. The pioneer clinical work was done in Tokyo (Hatanaka and Sano, 1973 cf Wong, Tolpin and Lipscomb, 1974). 

Besides their fundamental interest, proteasomes are relevant therapeutic targets. The peptide boronic acid, bortezomib (Velcade, Figure 12.2) is the first proteasome inhibitor to have reached the clinic and is used to treat late-stage multiple myeloma [4]. Originally developed as a p5-specific inhibitor, it was later on found to target also pi, pSi, and pii and, moreover, it became clear that exclusive inhibition of p5 is not sufficiently effective for tumor eradication. 

Boron chemicals in diagnosis and therapeutics 13FMC653. Chromenes Potential new chemotherapeutic agents for cancer 13FMC 1647. 

Large concentrations of boron are, in fact, necessary for the therapeutic technique for cancer known as boron neutron capture therapy (BNCT). This unique technique has the promise of destroying tumorous tissue with minimum damage to surrounding tissue that is normal. The basis of BNCT is that the B isotope of boron will absorb slow-moving neutrons and give off o -particles in the nuclear reaction. 

Boranophosphate linkages have been of interest because they mimic natural DNA, and may have potential in diagnostic and therapeutic applications (boron neutron capture therapy). Boranophosphate-modified siRNA has been shown to possess potent gene-silencing properties compared to the unmodified siRNA. Two novel methods have been reported for the synthesis of boranophosphate oligonucleotides, one using phosphoramidite chemistry, the other boranophosphotriester chemistry. Dinucleoside boranophosphates and a-borano nucleoside triphosphates have also been described. " ... 

Nitric oxide (NO) displays potent activities in the cardiovascular system as well as in the central and peripheral nervous systems. NO and its co-product L-citruUine are produced by the oxidation of L-arginine (28) by nitric oxide synthase (NOS) (Scheme 13.4). Selective modulation of NO biosynthesis offers the opportunity for therapeutic intervention of neurodegenerative diseases, among others. Based on the mechanism proposed for NO biosynthesis, two boronic acid analogues (29 and 30, Figure 13.7) of... 

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