Boroncontaining amino acids and related peptides

Interest in the boronated amino acids and peptides stems from the fact that p-BPA is one of only two clinically used BNCT agents. The strategy for concentrating the boronated compounds in tumor cells is that the cellular building blocks are required in greater number in rapidly dividing cells than in their normal counterparts; this may lead to a greater concentration of boron-containing peptides and proteins in the tumor cell. In addition to the para-isomer of BPA, the ortho- and meta-isomers have also been evaluated (Figure 2.5).38 However, only the para-isomer has undergone extensive biological testing. Since BPA has limited water solubility, advantage has been taken of the ability of its boronic acid group to complex with carbohydrates as a means of increasing water solubility.39 There have been other attempts to increase water solubility by incorporating hydrophilic groups into BPA.40 Some structures are given in Figure 2.6.

Not all of the syntheses of boron-containing amino acids have focused on those of the boronic acid moiety. Others have incorporated the borane zwitterionic groups. The first such amino acid analogue was boroglycine, H3NBH2COOH, which was prepared from trimethylamine carboxyborane (Me3NBH2COOH) by amine exchange.41 The replacement of carbon by a boron atom showed a profound effect on the pKas of both the carboxyl and amine protons. For example, boroglycine has a carboxyl pKa of 8.3 as compared to 2.4 for glycine. Similarly, the pKa of the ammonia nitrogen deproto-nation in H3NBH2COOH is >11.42 The synthesis of boron analogues of other common amino acids such as alanine, leucine, etc. have also been reported.41

B HO

O OH

para-BPA meta-BPA ortho-BPA

Figure 2.5 Structure of BPA isomers

Figure 2.6 Derivatives of BPA

Several of these borane-containing amino acids are shown in Figure 2.7. There has also been interest in making analogues that contain clusters of boron atoms, with special interest centered on the carboranes. Figure 2.8 shows the isomers of o-carboranylalanine.43,19c

Such analogues are biologically active and demonstrate the advantages of incorporating functionalities that will balance the carboranyl's lipophilic character. A number of different carborane-containing amino acids have been synthesized and evaluated,44 some of which are shown in Figure 2.9.

^NHEt

Figure 2.7 Boranoamino acid derivatives

COOH

(R)-o-carboranylalanine

COOH

(R)-o-carboranylalanine

COOH

(S)-o-carboranylalanine

COOH

(S)-o-carboranylalanine

Figure 2.8 Structures of carboranylalanine

COOH

COOH

COOH

nh2 oh

COOH

Figure 2.9 Carborane-containing amino acids

H2 H

H2 H

BN H2 H

BN H2 H

O-CH

Figure 2.10 Some boron-containing peptides

The synthesis of these boranoamino acids leads to the development of boron-containing peptides. Since tumor cells require increased amounts of proteins, small peptides that may cross cell membranes can be utilized by tumor cells. Examples of these different types of peptides are shown in Figure 2.10.

Soloway suggested that boronated amino acids could also produce a possible twofold attack on tumors, they could serve as anti-metabolites and inhibit tumor growth as well as being selectively incorporated into the proteins of the neoplasm.21 The preparation and evaluation of small boron-containing peptides are only in their early stages of development.

Was this article helpful?

0 0
The Ketosis Plan Diet

The Ketosis Plan Diet

Top Low Carb Internet Guru Speaks Out. An Open Letter To Anyone Who Wants To Lose Up To 20 Pounds In 30 Days The 'Low Carb' Way. 30-Day Low Carb Diet 'Ketosis Plan' has already helped scores of people lose their excess pounds and inches faster and easier than they ever thought possible. Why not find out what 30-Day Low Carb Diet 'Ketosis Plan' can do for you by trying it out for yourself.

Get My Free Ebook


Post a comment