Design, synthesis, cytotoxic activity and molecular docking studies of new 20(S)-sulfonylamidine camptothecin derivatives

20(S)-Sulfonylamidine CPT-derivatives were prepared and tested for cytotoxicity.Several analogs showed superior cytotoxic activity compared to irinotecan.Key structural features related to cytotoxicity were identified by SAR analysis.Compounds 9 and 15c interacted with Topo I-DNA by a different binding mode from CPT.These compounds are new generation CPT-derived antitumor agents.In an ongoing investigation of 20-sulfonylamidine derivatives (9, YQL-9a) of camptothecin (1) as potential anticancer agents directly and selectively inhibiting topoisomerase (Topo) I, the sulfonylamidine pharmacophore was held constant, and a camptothecin derivatives with various substitution patterns were synthesized. The new compounds were evaluated for antiproliferative activity against three human tumor cell lines, A-549, KB, and multidrug resistant (MDR) KB subline (KBvin). Several analogs showed comparable or superior antiproliferative activity compared to the clinically prescribed 1 and irinotecan (3). Significantly, the 20-sulfonylamidine derivatives exhibited comparable cytotoxicity against KBvin, while 1 and 3 were less active against this cell line. Among them, compound 15c displayed much better cytotoxic activity than the controls 1, 3, and 9. Novel key structural features related to the antiproliferative activities were identified by structure–activity relationship (SAR) analysis. In a molecular docking model, compounds 9 and 15c interacted with Topo I-DNA through a different binding mode from 1 and 3. The sulfonylamidine side chains of 9 and 15c could likely form direct hydrogen bonds with Topo I, while hydrophobic interaction with Topo I and π–π stacking with double strand DNA were also confirmed as binding driving forces. The results from docking models were consistent with the SAR conclusions. The introduction of bulky substituents at the 20-position contributed to the altered binding mode of the compound by allowing them to form new interactions with Topo I residues. The information obtained in this study will be helpful for the design of new derivatives of 1 with most promising anticancer activity.CPT (green), 9 (magenta), and 15c (blue) in the binding site of DNA-Topo-I

Evolution of the Reactor Antineutrino Flux and Spectrum at Daya Bay

The Daya Bay experiment has observed correlations between reactor core fuel evolution and changes in the reactor antineutrino flux and energy spectrum. Four antineutrino detectors in two experimental halls were used to identify 2.2 million inverse beta decays (IBDs) over 1230 days spanning multiple fuel cycles for each of six 2.9 GW$_{\textrm{th}}$ reactor cores at the Daya Bay and Ling Ao nuclear power plants. Using detector data spanning effective $^{239}$Pu fission fractions, $F_{239}$, from 0.25 to 0.35, Daya Bay measures an average IBD yield, $\bar{\sigma}_f$, of $(5.90 \pm 0.13) \times 10^{-43}$ cm$^2$/fission and a fuel-dependent variation in the IBD yield, $d\sigma_f/dF_{239}$, of $(-1.86 \pm 0.18) \times 10^{-43}$ cm$^2$/fission. This observation rejects the hypothesis of a constant antineutrino flux as a function of the $^{239}$Pu fission fraction at 10 standard deviations. The variation in IBD yield was found to be energy-dependent, rejecting the hypothesis of a constant antineutrino energy spectrum at 5.1 standard deviations. While measurements of the evolution in the IBD spectrum show general agreement with predictions from recent reactor models, the measured evolution in total IBD yield disagrees with recent predictions at 3.1$\sigma$. This discrepancy indicates that an overall deficit in measured flux with respect to predictions does not result from equal fractional deficits from the primary fission isotopes $^{235}$U, $^{239}$Pu, $^{238}$U, and $^{241}$Pu. Based on measured IBD yield variations, yields of $(6.17 \pm 0.17)$ and $(4.27 \pm 0.26) \times 10^{-43}$ cm$^2$/fission have been determined for the two dominant fission parent isotopes $^{235}$U and $^{239}$Pu. A 7.8% discrepancy between the observed and predicted $^{235}$U yield suggests that this isotope may be the primary contributor to the reactor antineutrino anomaly.Comment: 7 pages, 5 figure

Improved Measurement of the Reactor Antineutrino Flux and Spectrum at Daya Bay

A new measurement of the reactor antineutrino flux and energy spectrum by the Daya Bay reactor neutrino experiment is reported. The antineutrinos were generated by six 2.9~GW$_{\mathrm{th}}$ nuclear reactors and detected by eight antineutrino detectors deployed in two near (560~m and 600~m flux-weighted baselines) and one far (1640~m flux-weighted baseline) underground experimental halls. With 621 days of data, more than 1.2 million inverse beta decay (IBD) candidates were detected. The IBD yield in the eight detectors was measured, and the ratio of measured to predicted flux was found to be $0.946\pm0.020$ ($0.992\pm0.021$) for the Huber+Mueller (ILL+Vogel) model. A 2.9~$\sigma$ deviation was found in the measured IBD positron energy spectrum compared to the predictions. In particular, an excess of events in the region of 4-6~MeV was found in the measured spectrum, with a local significance of 4.4~$\sigma$. A reactor antineutrino spectrum weighted by the IBD cross section is extracted for model-independent predictions.Comment: version published in Chinese Physics

New measurement of θ13\theta_{13} via neutron capture on hydrogen at Daya Bay

This article reports an improved independent measurement of neutrino mixing angle $\theta_{13}$ at the Daya Bay Reactor Neutrino Experiment. Electron antineutrinos were identified by inverse $\beta$-decays with the emitted neutron captured by hydrogen, yielding a data-set with principally distinct uncertainties from that with neutrons captured by gadolinium. With the final two of eight antineutrino detectors installed, this study used 621 days of data including the previously reported 217-day data set with six detectors. The dominant statistical uncertainty was reduced by 49%. Intensive studies of the cosmogenic muon-induced $^9$Li and fast neutron backgrounds and the neutron-capture energy selection efficiency, resulted in a reduction of the systematic uncertainty by 26%. The deficit in the detected number of antineutrinos at the far detectors relative to the expected number based on the near detectors yielded $\sin^22\theta_{13} = 0.071 \pm 0.011$ in the three-neutrino-oscillation framework. The combination of this result with the gadolinium-capture result is also reported.Comment: 26 pages, 23 figure