DNA AS A TOOL FOR MOLECULAR DISCOVERY - Modern Tools for the Synthesis of Complex Bioactive Molecules - page 535

synthetic organic chemistry. This emerging field is now growing exponentially and is
starting to offer tremendous opportunities for a wide range of synthetic applications.
16.1. DEOXYRIBOZYMES
The identification in 1994 of the first artificial catalytic DNA (also called deoxy-
ribozyme, DNAzyme, or DNA enzyme) [7] has paved the way for both fundamental
studies and synthetic applications. Initially focused on deoxyribozymes that cleave
RNA, the investigation of the catalytic abilities of DNAwas an opportunity to develop a
newway of doing chemistry. Although catalytic RNA enzymes are naturally occurring
in many organisms, their DNA counterparts are developed through in vitro selection/
evolution starting from random sequence libraries as illustrated in Figure 16.1 [8-10].
Hence, the process begins with the synthesis of a pool of random oligonucleotides
containing a DNA sequence (in black) and a short stretch of ribonucleotides (in grey)
required for PCR amplification. The latter is linked to a biotin tag (black pentagon)
necessary for the in vitro selection. This population is eventually loaded onto a
streptavidin-coated matrix and the selection step is then initiated by incubating the
DNA pool under carefully devised conditions. The rare DNAs that can cleave the RNA
region detach themselves from the matrix and can be eluted. The catalytically active
DNAs are thus separated from the inactive ones, amplified by PCR, and submitted to a
new round of selection. The full process is repeated under increased selection pressure
until a high catalytic activity is finally obtained.
Since the first report pertaining to catalytic DNA, numerous studies have been
devoted to the identification of deoxyribozymes with various catalytic activities.
Some representative examples are provided in Table 16.1.
The exciting results obtained on nucleic acids prompted many researchers to
develop deoxyribozymes for other types of substrates, thus demonstrating the
astonishing catalytic power of DNA. Indeed, deoxyribozymes have been identified
for the formation of nucleopeptide linkages [27], the metalation of porphyrin
substrates [28], or for carbon-carbon bond formation [29]. In the latter case,
Silverman et al. reported the first Diels-Alder reaction between suitably functiona-
lized anthracene and maleimide substrates catalyzed by a deoxyribozyme
(Figure 16.2). Interestingly, the catalytic activity of the deoxyribozymes was found
to be as powerful as the previously reported ribozymes [30], suggesting that DNA and
RNA were equally efficient catalysts for C-C bond formation.
One can anticipate that this is just the beginning as the thorough investigation of
the structures and mechanisms of the deoxyribozymes will most certainly lead to the
discovery of new DNA-catalyzed reactions with practical applications in organic
synthesis.
16.2. DNA-TEMPLATED SYNTHESIS
DNA-templated synthesis (DTS) relies on a proximity-based translation of a DNA
sequence into a corresponding synthetic small molecule. Until recently, however,