Biomedical Engineering Reference
In-Depth Information
acid-catalyzed rearrangement, provided intermediates such as
115
. Bromoaryl and
allyl ether functionalities were introduced for further ring construction. [2
+
2] Photo-
cycloaddition reactions between
-unsaturated esters and isolated olefins occurred,
producing complex and condensed polycyclic systems not accessible by other pro-
cedures. The [2
α
,
β
2] intramolecular cycloaddition reaction of the cyclopentene with
the allyl group proceeded easily to give the tetracyclic
116
with a cis-syn-cis struc-
ture. Photocycloaddition with the cyclohexene resulted in the fused-ring product
117
as a single diastereomer, but with poor yield. Surprisingly, only the
S
-allylic ether
underwent the photocycloaddition.
+
3.5 CONCLUSIONS
In recent years, due primarily to the decreasing cost of DNA sequencing [74], there
have been extraordinary advances in genomics that have allowed the identification
and validation of new biological targets underlying human diseases [2]. Unfortu-
nately, many of these new therapeutic targets are considered “undruggable” since
there are no compounds in screening desks able to modulate them [75]. This scenario
demonstrates a clear need for novel molecular scaffolds able to interact specif-
ically with these targets. Chemical libraries with high structural complexity and
skeletal and stereochemical diversity allow for the exploration of larger regions of
chemical space, thereby increasing the chances of success. Certainly, DOS, with
its ability to generate small-molecule libraries with a high degree of structural and
functional diversity, represents one of the best strategies for achieving this goal.
Within DOS, cycloaddition reactions represent a powerful tool to achieve the struc-
tural diversity needed in compound collections. Moreover, the rigidity and restricted
conformation of cyclic and heterocyclic compounds, generated through cycloaddi-
tion reactions, also seem to be responsible for specific and unique interactions with
biological targets, conferring a higher probability of success in screening campaigns.
In addition, as illustrated in this chapter, many DOS compounds address targets that
have traditionally been considered too difficult to hit, thus demonstrating how this
approach might be the best path to follow to take advantage of recent advances
in genomics and to take a step toward meeting society's expectations for scientific
research [76].
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