Boroncontaining nucleic acid precursors

Since the presumed target of the high LET radiation generated by a boron capture reaction is the cell nucleus,43b a great deal of effort has been devoted to the design and synthesis of potential precursors of the nucleic acids that could be incorporated into cellular DNA.

Initial studies in this effort were focused on the nucleic acid bases, the purines and the pyrimidines. Some structures of these boronated compounds are given in Figure 2.11.

Many of these compounds are of low hydrolytic stability. When stability was enhanced by introducing aromatic group on the borons, the compounds ceased to emulate biochemical processes. However, it was found that when the hydro-xyboryl group was bonded directly to a nitrogen atom, as shown in Figure 2.12, an increased hydrolytic stability was achieved. However, it remains to be seen how such compounds will behave under physiological conditions.

Figure 2.11 Boron-containing nucleic acid bases

Figure 2.11 Boron-containing nucleic acid bases

r NH

Figure 2.12 Hydroxoboryl isoesters of benzopyrimidines

Another approach is to attach the boron moiety directly on a pyrimidine nucleus, giving boron-containing nucleosides; the first such compound that was synthesized is shown in Figure 2.13.23a Other boronated nucleosides, such as those shown in Figure 2.14, have been synthesized starting with the respective 5-halogenated nucleoside derivatives.40,19c

A series of single-boron-atom nucleosides, such as those shown in Figure 2.15, have been reported by Spielvogel and coworkers.4 One of the limitations of these


Figure 2.13 Structure of 5-(dihydroxylboryl)-2'-deoxyuridme

Figure 2.15 Single-boron-atom nucleosides

compounds is that they have a low percentage of boron. Therefore, work has been directed toward incorporating stable boron clusters into nucleosides.45 Examples are shown in Figures 2.14 and 2.16. Because of their chemical inertness, derivatives of c/oso-C2B10H12 clusters are most often incorporated (see Figures 2.16 and 2.17) into nucleosides. These carboranyl nucleosides suffer from their significant lipo-philicities that compromise any assessment of their enzymatic reactivity or in vitro cellular evaluation.

Polyhydroxyl groups have been introduced in order to achieve suitable hydrophilic/lipophilic balance (Figure 2.18).

In addition to nucleosides, several boronated nucleotides have been prepared and evaluated (Figure 2.19).10,46 Although such ionic structures at present lack an ability to cross the cell membrane, their penetrability will be based ultimately upon the overall lipophilic/hydrophilic balance, which could be adjusted by chemical manipulation. Moreover, the enzymatic cleavage of such phosphates under in vivo conditions may make these compounds a basis for prototype drugs.

Figure 2.16 Carborane-containing nucleoside derivatives


Figure 2.17 Tethered carborane nucleoside pyrimidines


Figure 2.17 Tethered carborane nucleoside pyrimidines

Hr fll^C OH


Figure 2.18 Hydrophilically enhanced carboranyl pyrimidine nucleosides

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