4 research outputs found
Synthesis and Discovery of <i>N</i>-Carbonylpyrrolidine- or <i>N</i>-Sulfonylpyrrolidine-Containing Uracil Derivatives as Potent Human Deoxyuridine Triphosphatase Inhibitors
Recently, deoxyuridine triphosphatase (dUTPase) has emerged
as a potential target for drug development as part of a new strategy
of 5-fluorouracil-based combination chemotherapy. We have initiated
a program to develop potent drug-like dUTPase inhibitors based on
structure–activity relationship (SAR) studies of uracil derivatives. <i>N</i>-Carbonylpyrrolidine- and <i>N</i>-sulfonylpyrrolidine-containing
uracils were found to be promising scaffolds that led us to human
dUTPase inhibitors (<b>12k</b>) having excellent potencies (IC<sub>50</sub> = 0.15 μM). The X-ray structure of a complex of <b>16a</b> and human dUTPase revealed a unique binding mode wherein
its uracil ring and phenyl ring occupy a uracil recognition region
and a hydrophobic region, respectively, and are stacked on each other.
Compounds <b>12a</b> and <b>16a</b> markedly enhanced
the growth inhibition activity of 5-fluoro-2′-deoxyuridine
against HeLa S3 cells in vitro (EC<sub>50</sub> = 0.27–0.30
μM), suggesting that our novel dUTPase inhibitors could contribute
to the development of chemotherapeutic strategies when used in combination
with TS inhibitors
1,2,3-Triazole-Containing Uracil Derivatives with Excellent Pharmacokinetics as a Novel Class of Potent Human Deoxyuridine Triphosphatase Inhibitors
Deoxyuridine triphosphatase (dUTPase) has emerged as
a potential
target for drug development as a 5-fluorouracil-based combination
chemotherapy. We describe the design and synthesis of a novel class
of human dUTPase inhibitors, 1,2,3-triazole-containing uracil derivatives.
Compound <b>45a</b>, which possesses 1,5-disubstituted 1,2,3-triazole
moiety that mimics the amide bond of <i>tert</i>-amide-containing
inhibitor <b>6b</b> locked in a cis conformation showed potent
inhibitory activity, and its structure–activity relationship
studies led us to the discovery of highly potent inhibitors <b>48c</b> and <b>50c</b> (IC<sub>50</sub> = ∼0.029
μM). These derivatives dramatically enhanced the growth inhibition
activity of 5-fluoro-2′-deoxyuridine against HeLa S3 cells
in vitro (EC<sub>50</sub> = ∼0.05 μM). In addition, compound <b>50c</b> exhibited a markedly improved pharmacokinetic profile
as a result of the introduction of a benzylic hydroxy group and significantly
enhanced the antitumor activity of 5-fluorouracil against human breast
cancer MX-1 xenograft model in mice. These data indicate that <b>50c</b> is a promising candidate for combination cancer chemotherapies
with TS inhibitors
Discovery of Highly Potent Human Deoxyuridine Triphosphatase Inhibitors Based on the Conformation Restriction Strategy
Human deoxyuridine triphosphatase (dUTPase) inhibition
is a promising
approach to enhance the efficacy of thymidylate synthase (TS) inhibitor
based chemotherapy. In this study, we describe the discovery of a
novel class of human dUTPase inhibitors based on the conformation
restriction strategy. On the basis of the X-ray cocrystal structure
of dUTPase and its inhibitor compound <b>7</b>, we designed
and synthesized two conformation restricted analogues, i.e., compounds <b>8</b> and <b>9</b>. These compounds exhibited increased
in vitro potency compared with the parent compound <b>7</b>.
Further structure–activity relationship (SAR) studies identified
a compound <b>43</b> with the highest in vitro potency (IC<sub>50</sub> = 39 nM, EC<sub>50</sub> = 66 nM). Furthermore, compound <b>43</b> had a favorable oral PK profile and exhibited potent antitumor
activity in combination with 5-fluorouracil (5-FU) in the MX-1 breast
cancer xenograft model. These results suggested that a dUTPase inhibitor
may have potential for clinical usage
Discovery of a Novel Class of Potent Human Deoxyuridine Triphosphatase Inhibitors Remarkably Enhancing the Antitumor Activity of Thymidylate Synthase Inhibitors
Inhibition of human deoxyuridine triphosphatase (dUTPase)
has been
identified as a promising approach to enhance the efficacy of 5-fluorouracil
(5-FU)-based chemotherapy. This study describes the development of
a novel class of dUTPase inhibitors based on the structure–activity
relationship (SAR) studies of uracil derivatives. Starting from the
weak inhibitor <b>7</b> (IC<sub>50</sub> = 100 μM), we
developed compound <b>26</b>, which is the most potent human
dUTPase inhibitor (IC<sub>50</sub> = 0.021 μM) reported to date.
Not only does compound <b>26</b> significantly enhance the growth
inhibition activity of 5-fluoro-2′-deoxyuridine (FdUrd) against
HeLa S3 cells in vitro (EC<sub>50</sub> = 0.075 μM) but also
shows robust antitumor activity against MX-1 breast cancer xenograft
model in mice when administered orally with a continuous infusion
of 5-FU. This is the first in vivo evidence that human dUTPase inhibitors
enhance the antitumor activity of TS inhibitors. On the basis of these
findings, it was concluded that compound <b>26</b> is a promising
candidate for clinical development