Pressure effects upon asymmetric photosensitization have been investigated for the first time in the
enantiodifferentiating Z
−
E photoisomerization of cyclooctene (1), sensitized by chiral aromatic esters (2−7).
The product's enantiomeric excess (ee) and E/Z ratio were critical functions of the applied pressure, exhibiting
an unprecedented switching of the product chirality. Depending upon the chiral sensitizer employed, the
differential activation volume (ΔΔV
⧧) varies widely from −3.7 to +5.6 cm3 mol-1, which is unexpectedly
large for an enantiodifferentiation in the excited state. However, the ΔΔV
⧧ values obtained do not correlate
with the differential activation enthalpy (ΔΔH
⧧) or entropy (ΔΔS
⧧) obtained from temperature-dependence
studies, indicating that pressure and temperature function as independent perturbants for the photoenantiodifferentiation process. Further investigations on the pressure dependence of ee at low temperatures enable us
to construct the first three-dimensional diagram that correlates the product's ee with pressure and temperature
changes. The combined effects of temperature and pressure provide us with a versatile tool for the
multidimensional control of asymmetric photochemical reactions, in which we can switch and/or enhance the
product chirality at more readily accessible temperatures and pressures, without using antipodal sensitizers.
TAS-114 has shown both a favorable safety and pharmacokinetic profile after single and repeated doses. TAS-114 was considered to possess a moderate DPD inhibitory effect. These findings will facilitate clinical studies of the combination chemotherapies in cancer patients and may reduce the safety risk in the frail cancer patients.
5-Fluorouracil (5-FU) is an antimetabolite and exerts antitumor activity via intracellularly and physiologically complicated metabolic pathways. In this study, we designed a novel small molecule inhibitor, TAS-114, which targets the intercellular metabolism of 5-FU to enhance antitumor activity and modulates catabolic pathway to improve the systemic availability of 5-FU. TAS-114 strongly and competitively inhibited deoxyuridine 5'-triphosphate nucleotidohydrolase (dUTPase), a gatekeeper protein preventing aberrant base incorporation into DNA, and enhanced the cytotoxicity of fluoropyrimidines in cancer cells; however, it had little intrinsic activity. In addition, TAS-114 had moderate and reversible inhibitory activity on dihydropyrimidine dehydrogenase (DPD), a catabolizing enzyme of 5-FU. Thus, TAS-114 increased the bioavailability of 5-FU when coadministered with capecitabine in mice, and it significantly improved the therapeutic efficacy of capecitabine by reducing the required dose of the prodrug by dual enzyme inhibition. Enhancement of antitumor efficacy caused by the addition of TAS-114 was retained in the presence of a potent DPD inhibitor containing oral fluoropyrimidine (S-1), indicating that dUTPase inhibition plays a major role in enhancing the antitumor efficacy of fluoropyrimidine-based therapy. In conclusion, TAS-114, a dual dUTPase/DPD inhibitor, demonstrated the potential to improve the therapeutic efficacy of fluoropyrimidine. Dual inhibition of dUTPase and DPD is a novel strategy for the advancement of oral fluoropyrimidine-based chemotherapy for cancer treatment. .
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