Biomedical Engineering Reference
In-Depth Information
synthesis section below) was abandoned and all subsequent libraries focused
on the Ugi products themselves. This is advantageous from a synthetic stand-
point since these can be prepared in only one step from readily available
starting materials.
In April 2007 Zaharevitz from the National Cancer Institute (NCI) discov-
ered the UsefulChem project through the network of open scientists and
offered free testing of compounds for antitumor activity [37]. The fi rst Ugi
product was submitted shortly thereafter [38], and in May 2007 the compound
was submitted to a tumor inhibition prediction service. Although predicted to
be inactive (as was later confi rmed [39]), it demonstrated for the fi rst time the
“closing of the open-science loop” for drug discovery—where hypothesis for-
mation, docking, synthesis, and assay results were performed openly in real
time [40]. This strategy was extended by prioritizing synthetic targets from a
virtual library of Ugi products based on the predicted ability to inhibit tumor
cell lines. Naphthyl fragments showed up disproportionately in the products
with high predicted activity [41]. Zaharevitz further assisted by inviting one of
us (JCB) to a National Institutes of Health (NIH) workshop on drug develop-
ment in January 2008 [42]. Synthetic focus was directed to Ugi product librar-
ies and Guha initiated a malarial enoyl reductase docking study on a
500,000-compound virtual library based on starting materials that could be
obtained cheaply and quickly [43]. The most highly ranked compounds from
this study were prioritized for synthesis via the Ugi reaction.
Assay results were hosted on CDD and catalyzed the initiation of a new
collaboration with the Rosenthal group at the University of California—San
Francisco (UCSF), which agreed to run malaria assays for UsefulChem com-
pounds at no charge. The Rosenthal group had previously discovered the
malarial enzyme falcipain-2, and it was convenient for them to run an inhibi-
tory assay against that protein, in addition to red blood cell assays to measure
the inhibition of infection by the malarial parasite [44]. The focus of the work
thus shifted from enoyl reductase to falcipain-2. With a crystal structure and
known binding site, docking calculations were performed and two Ugi prod-
ucts in the top 1000 from Guha's docking results were synthesized and shipped
to the Rosenthal lab in December 2007 [45]. Activity at the micromolar range
against both the enzyme and the infection of red blood cells by the parasite
was reported in January 2008 [46]. By August 2008, 4 of the 17 Ugi products
tested showed similar results for inhibition of the enzyme and infection [47],
clearly a very impressive proof of principle.
25.3.3 Chemical Synthesis Strategy: Collaborations Between Synthetic
Chemists, Both Locally and Remotely
A general synthesis was proposed to generate the putative malaria inhibitors
suggested by Find-A-Drug, which were based on a 2,5-diketopiperazine scaf-
fold [48]. Further literature searching revealed some examples of the diketo-
piperazine synthesis on solid support [49, 50]. Finally, in December 2005, a
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