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
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
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 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