Biomedical Engineering Reference
In-Depth Information
gradually been gaining importance in HTS and, as a consequence, is influenced by
DOS strategies. The ZINC database is a freely available collection of over 1 million
commercially available small molecules that can be applied to docking experiments
[15]. A more focused use of MCRs is found in the ANCHOR database [16], which was
created by Alexander D omling, who received doctoral training from Ugi. ANCHOR is
a database that is populated with MCR products that are “enumerated,” or synthesized
in silico
from commercially available components. The majority of the compounds
have never been synthesized but all can, in theory, be prepared in a one-step synthesis
from one of 22 different MCRs (Figure 2.2). Although the collection can probably
be used in many different docking experiments, it is constructed to use key peptide
side chains (e.g., the phenyl, indole, or isopropyl groups of Phe, Trp, or Ile/Val,
respectively) in protein-protein reactions as “anchors” or fixed appendages that are
used to identify small molecules that mimic one side of a protein-protein interface.
The software ranks MCR products in the database based on their ability to properly
position the anchored appendage. Users can then synthesize individual compounds
or small collections of small molecules using one or more MCRs for evaluation in
their assay of choice. Although similar functionality is possible with any chemical
reaction, MCRs provide ANCHOR with the unique opportunity to populate the
database with an enormous quantity of compounds that are, conceivably, extremely
easy to synthesize.
2.2.2 Expanding Accessible Diversity: New MCRs
One of the most versatile compounds seen in a wide array of MCRs is the isonitrile,
with two of the best-known MCRs, the Passerini and Ugi, featuring these components
[17]. The unique ability of isocyanides to serve as C-nucleophiles toward imines and
aldehydes, resulting in nitrilium ion electrophiles, enables the Ugi 4CR and Passerini
3CR, respectively. This topic has been reviewed extensively, and a great number of
recently disclosed MCRs incorporate this unique reactivity to access a diverse array
of heterocyclic structures [18]. Recent examples have expanded the core diversity
available from MCRs and pushed the limits of complexity that are attainable in a single
transformation. The work of Santra and Andreana in the area of novel isocyanide-
based MCRs is noteworthy, due to their lab's ability to access diverse scaffolds from
the same components. This is achieved through the use of bifunctional components
that participate in a Michael-type cyclization step directly following a Ugi reaction
[19]. The Ugi cascades are also unique due to the use of microwave irradiation, the
absence of any additives, and the use of water as the solvent (Scheme 2.1). More
recently, Santra and Andreana have expanded this work to the preparation of natural
product-like [20] fused azaspiro-tricycles by a Ugi/Michael/aza-Michael (UMAM)
cascade reaction [21]. This particular cascade process generates a quaternary center,
four stereogenic centers, and six contiguous bonds, and provides moderate to high
yields, excellent regioselectivities, and significant diastereoselectivity (Scheme 2.2).
In addition to the isocyanide-based MCRs of Andreana's lab, several others
have been reported in recent years. In one such example, functionalized spiroben-
zofuranones were prepared from 3-cyanochromones, acetylenecarboxylates, and
