DNA binders

There has been a special interest in the development of boron compounds that could be concentrated at or near the cell's DNA and a number of boron-containing DNA intercalators have been evaluated as BNCT agents. The development of boron-containing pyrimidines, purines, nucleosides and nucleotides is predicated on the basis that the effectiveness of a boron species incorporated into the tumor's DNA would enhance the effectiveness of the capture reaction by a factor of 2-5 over what would be if the boron compounds were evenly distributed in the cytoplasm.31 Neidle and coworkers32 have recently shown that substituted fluor-enones and anthraquinones act as telomerase inhibitors. Since the telomerase enzyme is a reverse transcriptase which elongates the 3' ends of the telomerase DNA,33a a number of carborane-substituted fluorenone, anthracene-9,10-dione, and sulfone compounds have been synthesized (Figure 2.2).33b In fact, the use of large-cage polyhedral boranes, such as B10H102~ and B12H122~, and carboranes, such as the o-carborane, as efficient boron transfer agents in BNCT has been the subject of a number of studies.34,35 In Figure 2.2, and subsequent figures, the boranes are normally depicted as idealized polyhedra with B—H units understood to be at the unlabeled vertices. Only when a non-boron atom replaces a boron vertex, its symbol is shown. Thus the carborane cages shown in Figure 2.2 represent the C2B9H9 cage. They have taken advantage of the DNA affinity of the fluorenones and anthraquinones and the high boron content of the polyhedral boron cages in the synthesis of a series of structurally related anthracene-9,10-diones, fluorenones, phenylsulfones, along with the corresponding open cage nido derivatives as possible precursors to BNCT agents that could bind to DNA.

It should be noted that in the carborane cage all the atoms are boron except the two carbons drawn. Chemotherapeutic alkylating agents are electrophiles that can be covalently incorporated into tumor DNA and, as a result, interfere with tumor replication. Therefore, a number of boron analogues have been synthesized; some examples are shown in Figure 2.3.36

Anthraquinones

Anthraquinones

Fluorenones

Fluorenones

-CMt

Figure 2.2 Boronated anthraquinones and fluorenones

Figure 2.2 Boronated anthraquinones and fluorenones

1-(carboranyl)-3-(2-methylaziridino)-2-propanol OO

1,2-bis(methanesulfonoxymethyl)carborane

_yCl

4-[bis(2-chloroethyl)amino]phenylcarborane Figure 2.3 Alkylating agents

Figure 2.4 Boron containing the phenanthradinium moiety

More recent work has focused on the development of boron-containing phenanthridinium analogues.37 The basic ring structure in these tricyclic planar compounds intercalates readily into the DNA molecule; this has been the basis for the synthesis of the boronated analogues - a representative structure is given in Figure 2.4.

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