Boronated Polyamines

Polyamines, such as spermidine, spermine, and putrescine, are essential for the growth and proliferation of all the cells (Figure 2.24).52 The presence of quickly dividing cells, such as cancer cells, is closely correlated with an

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Putrescine

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Spermidine

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Spermine

Figure 2.24 Naturally occurring polyamines increase in the cellular polyamines.53 Because of their tumor specificity, the polyamines have been suggested as potential targeting agents for delivering toxic moieties preferentially to cancer cells.54 Other advantages of using the polyamine system are that the transporter is very aggressive, increasing the cellular polyamine concentration to 6mM within a few hours,55 can tolerate structural restrictions,56 and accumulates in close proximity to nuclear and mitochondrial DNA, thereby increasing the potential for lethal damage by BNCT.

Strategies could consist of replacing a carbon sequence, such as the four carbons in putrescine, with a carborane moiety, such as a 1,12-C2B10H10 (p-carboranyl) group. Other approaches would include using carboranes as pendant groups on the polyamine. The polyamines having carborane cages would combine the advantages of tumor specificity and increased boron concentration in tumor cells, which is ideal for BNCT. Representative compounds related to spermine and spermidine are shown in Figure 2.25.

Figure 2.25 Polyamines

DNA-binding studies demonstrated that these structures simulated and competed with the naturally occurring polyamines. At present, the major limitations observed with these boron-containing polyamines is both their cellular and in vivo toxicity. Less toxic analogues have been prepared,57 but it remains to be determined what clinical utility they can offer.

It is known that there are significant differences in the carbohydrate composition of the cell membrane surfaces of malignant cells when compared to normal cells.58 It is possible that boron carbohydrate compounds may achieve elevated concentrations in tumor cells through the action of the glucose transport system.59 The initial boron cage compounds containing a carbohydrate moiety were those that were developed for binding to antibodies.60 The purpose of the carbohydrate functionality was solely to increase the compound's aqueous solubility. Subsequently, carborane-containing analogues of glucose, and gulose have been prepared (Figure 2.26).

More recently, a series of carbohydrates have been synthesized in which the BSH moiety has been attached to the carbohydrate group (Figure 2.27). However, the evaluation of their bio-distribution is limited and much more remains to be accomplished.

The rate of metabolism of low density lipoproteins (LDLs) is higher in tumor cells than in the normal cells.61 This difference is due to the increased need that tumor cells possess for cholesterol in order to facilitate new membrane formation. The overexpression of the LDL receptor on the tumor cell membrane is responsible for its LDL accretion. This observation led Kahl to first propose the use of such receptor mediation as the basis for selectively delivering boron to tumor

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