Plinabulin,a potent microtubule-targeting agent,is derived from marine natural diketopiperazine ‘phenylahistin'.To develop novel plinabulin analogue that could display better pharmacokinetic properties and less s...Plinabulin,a potent microtubule-targeting agent,is derived from marine natural diketopiperazine ‘phenylahistin'.To develop novel plinabulin analogue that could display better pharmacokinetic properties and less side effects,deuterated plinabulin 9 was synthesized and evaluated in vitro and in vivo.In comparison with plinabulin,in vivo pharmacokinetic studies indicated that the deuterated derivative 9 could alter blood circulation behavior obviously,which was proved by increased area under the plasma concentration-time curve(AUC_(0–∞)),reduced clearance(CL),and prolonged total body mean residence time(MRT).The derivative 9 also has higher inhibition rates against Bx PC-3,Jurkat and A-431 tumor cell lines as compared with its prototype plinabulin.Therefore,the deuterated compound 9 might be developed as a potential agent for different cancer treatments.展开更多
Cytarabine(1-β-D-arabinofuranosylcytosine, Ara-C), isolated from a Caribbean sponge species Tethyacrypta, is the first antitumor drug from a marine resource. In 1980, the US Food and Drug Administration approved this...Cytarabine(1-β-D-arabinofuranosylcytosine, Ara-C), isolated from a Caribbean sponge species Tethyacrypta, is the first antitumor drug from a marine resource. In 1980, the US Food and Drug Administration approved this drug for the treatment of different types of leukemia. This drug has a short plasma half-life, low stability, limited bioavailability, and severe side effects. To improve stability and bioavailability, we synthesized nine novel derivatives by blocking the cytarabine metabolic sites and improving lipophilicity. The c Log P values of the newly synthesized compounds were calculated. All the synthesized compounds were more lipophilic than cytarabine, resulting in membrane permeability and bioavailability improvement. The antitumor activities against leukemia cell line HL-60 were evaluated by using the MTT assay. The bioassay results revealed that the IC_(50) values of compounds 5, 8 and 9 were 0.080, 0.090 and 0.057 μmol L^(-1), respectively, which was similar with that of cytarabine(0.056 μmol L^(-1),). In comparison, compound 4 with a phosphate group at O5' was inactive. Because phosphoester bonds are easily hydrolyzed by alkaline phosphatase and are commonly used in producing prodrug strategies, compound 4 might also be metabolized in vivo and generate compound 3 or even cytarabine through a multi-step reaction. Thus, compound 4 might be a promising compound to be developed as a prodrug.展开更多
The late Quaternary ice rafted detritus (IRD) events in the Chukchi Basin, western Arctic Ocean are indications of the provenance of the coarser detritus and ice export events, and also document the evolutionary histo...The late Quaternary ice rafted detritus (IRD) events in the Chukchi Basin, western Arctic Ocean are indications of the provenance of the coarser detritus and ice export events, and also document the evolutionary histories of Beaufort Gyre and the North American Ice Sheet (NAIS). The sediment of core M03 from the Chukchi Basin was selected to study the regional response to the ice export events and the NAIS variability. The stratigraphic framework of M03 was established by a combination of lithological features and downcore color change cycles, AMS14C dating with foraminifera abundance and IRD events. The core was also compared with the adjacent core NWR 5 from the Northwind Ridge area. The core extends back to Marine Isotope Stage (MIS) 7. A sedimentary hiatus of 10―20 ka might occur between 16 to 20 cm core depth. Seven IRD events are distinguished from the studied core and are presented during the early MIS 1, MIS 3, MIS 5 and late MIS 7. These IRD are transported by sea ice and icebergs, which were exported to the Beaufort Sea from the M'Clure Strait Ice Stream, Canadian Arctic Archipelago, and brought to the Chukchi Basin by the Beaufort Gyre.展开更多
Southern Hemisphere mid-latitude westerlies contribute to the ventilation of the deep Southern Ocean(SO),and drive changes in atmospheric carbon dioxide(CO2) and the global climate.As the westerlies control directly o...Southern Hemisphere mid-latitude westerlies contribute to the ventilation of the deep Southern Ocean(SO),and drive changes in atmospheric carbon dioxide(CO2) and the global climate.As the westerlies control directly oceanic fronts,the movement of the subtropical front(STF) reflects the westerlies migration.Thus it is important to understand the relationships between STF movement and the weaterlies,ventilation of the deep SO,ice volume and atmospheric CO2.To this end,we use two new high-resolution records from early Marine Isotope Stage(MIS) 20(～800 ka) of sea surface temperature(SST) based on U k' 37 paleo-thermometer and benthic oxygen isotope(δ 18OB) at Ocean Drilling Program(ODP) Site 1170B in the southern Tasman Sea(STS),to construct linkages between the marine records and atmospheric proxies from Antarctic ice-cores.During the last 800 ka,the average SST(10.2℃) at Site 1170B is 1.8℃ lower than today(annual average 12℃).The highest average SST of 11.6℃ occurred during MIS 1,and the lowest average SST of 7.8℃ occurred during MIS 2.The warmest and coldest records of 14.7℃ and 6.2℃ occurred in the MIS 5 and MIS 2,respectively.In the glacial-interglacial cycles of the last 800 ka,variability of reconstructed SST shows that the STF moved northward or southward more than 3° of latitude compared with its present location.In the warmest stage MIS 5,the STF shifted to its southernmost location of ～49°S.In contrast,in the coldest stage MIS 2,the STF moved to its northernmost location of ～43°S.In response to orbital cycles,the westerlies movement led ice volume and atmospheric CO2 changes,but it was in phase with change in Antarctic atmospheric temperature.Ice volume only preceded atmospheric CO2 only a little at the 23-ka precession band,lagged the atmospheric CO2 at the 100-ka eccentricity band,and was in phase with atmospheric CO2 at the 40-ka obliquity band.展开更多
基金supported by‘Zhufeng Scholar Program’of Ocean University of China(No.841412016)‘Major Projects of Independent Innovation’of Qingdao(15-4-13-zdzx-hy)‘Outstanding Talents Plan’of Qingdao(15-10-3-15-(34)-zch)to Dr.Wenbao Li
文摘Plinabulin,a potent microtubule-targeting agent,is derived from marine natural diketopiperazine ‘phenylahistin'.To develop novel plinabulin analogue that could display better pharmacokinetic properties and less side effects,deuterated plinabulin 9 was synthesized and evaluated in vitro and in vivo.In comparison with plinabulin,in vivo pharmacokinetic studies indicated that the deuterated derivative 9 could alter blood circulation behavior obviously,which was proved by increased area under the plasma concentration-time curve(AUC_(0–∞)),reduced clearance(CL),and prolonged total body mean residence time(MRT).The derivative 9 also has higher inhibition rates against Bx PC-3,Jurkat and A-431 tumor cell lines as compared with its prototype plinabulin.Therefore,the deuterated compound 9 might be developed as a potential agent for different cancer treatments.
基金supported by the‘Zhufeng Scholar Program’of Ocean University of China(No.841412016)the‘Outstanding Talents Plan’of Qingdao(No.15-10-3-15-(34)-zch)to Dr.Wenbao Liyouth special fund for PhD of Qingdao(No.16-5-1-61-jch)
文摘Cytarabine(1-β-D-arabinofuranosylcytosine, Ara-C), isolated from a Caribbean sponge species Tethyacrypta, is the first antitumor drug from a marine resource. In 1980, the US Food and Drug Administration approved this drug for the treatment of different types of leukemia. This drug has a short plasma half-life, low stability, limited bioavailability, and severe side effects. To improve stability and bioavailability, we synthesized nine novel derivatives by blocking the cytarabine metabolic sites and improving lipophilicity. The c Log P values of the newly synthesized compounds were calculated. All the synthesized compounds were more lipophilic than cytarabine, resulting in membrane permeability and bioavailability improvement. The antitumor activities against leukemia cell line HL-60 were evaluated by using the MTT assay. The bioassay results revealed that the IC_(50) values of compounds 5, 8 and 9 were 0.080, 0.090 and 0.057 μmol L^(-1), respectively, which was similar with that of cytarabine(0.056 μmol L^(-1),). In comparison, compound 4 with a phosphate group at O5' was inactive. Because phosphoester bonds are easily hydrolyzed by alkaline phosphatase and are commonly used in producing prodrug strategies, compound 4 might also be metabolized in vivo and generate compound 3 or even cytarabine through a multi-step reaction. Thus, compound 4 might be a promising compound to be developed as a prodrug.
基金part of the project "Second Chinese National Arctic Research Expedition" (or CHINARE-2003) supported by the Ministry of Finance of China and organized by the Chinese Arctic and supported by the National Basic Research Program of China (Grant No. G2007CB815903)National Natural Science Foundation of China (Grant Nos. 40321603 and 40676030)Chinese IPY Program (Grant No. 2007―2009)
文摘The late Quaternary ice rafted detritus (IRD) events in the Chukchi Basin, western Arctic Ocean are indications of the provenance of the coarser detritus and ice export events, and also document the evolutionary histories of Beaufort Gyre and the North American Ice Sheet (NAIS). The sediment of core M03 from the Chukchi Basin was selected to study the regional response to the ice export events and the NAIS variability. The stratigraphic framework of M03 was established by a combination of lithological features and downcore color change cycles, AMS14C dating with foraminifera abundance and IRD events. The core was also compared with the adjacent core NWR 5 from the Northwind Ridge area. The core extends back to Marine Isotope Stage (MIS) 7. A sedimentary hiatus of 10―20 ka might occur between 16 to 20 cm core depth. Seven IRD events are distinguished from the studied core and are presented during the early MIS 1, MIS 3, MIS 5 and late MIS 7. These IRD are transported by sea ice and icebergs, which were exported to the Beaufort Sea from the M'Clure Strait Ice Stream, Canadian Arctic Archipelago, and brought to the Chukchi Basin by the Beaufort Gyre.
基金supported by the National Natural Science Foundation of China (40321603 and 40676030)the National Basic Research Program of China (2007CB815903)the Chinese IPY Program (2007–2009)
文摘Southern Hemisphere mid-latitude westerlies contribute to the ventilation of the deep Southern Ocean(SO),and drive changes in atmospheric carbon dioxide(CO2) and the global climate.As the westerlies control directly oceanic fronts,the movement of the subtropical front(STF) reflects the westerlies migration.Thus it is important to understand the relationships between STF movement and the weaterlies,ventilation of the deep SO,ice volume and atmospheric CO2.To this end,we use two new high-resolution records from early Marine Isotope Stage(MIS) 20(～800 ka) of sea surface temperature(SST) based on U k' 37 paleo-thermometer and benthic oxygen isotope(δ 18OB) at Ocean Drilling Program(ODP) Site 1170B in the southern Tasman Sea(STS),to construct linkages between the marine records and atmospheric proxies from Antarctic ice-cores.During the last 800 ka,the average SST(10.2℃) at Site 1170B is 1.8℃ lower than today(annual average 12℃).The highest average SST of 11.6℃ occurred during MIS 1,and the lowest average SST of 7.8℃ occurred during MIS 2.The warmest and coldest records of 14.7℃ and 6.2℃ occurred in the MIS 5 and MIS 2,respectively.In the glacial-interglacial cycles of the last 800 ka,variability of reconstructed SST shows that the STF moved northward or southward more than 3° of latitude compared with its present location.In the warmest stage MIS 5,the STF shifted to its southernmost location of ～49°S.In contrast,in the coldest stage MIS 2,the STF moved to its northernmost location of ～43°S.In response to orbital cycles,the westerlies movement led ice volume and atmospheric CO2 changes,but it was in phase with change in Antarctic atmospheric temperature.Ice volume only preceded atmospheric CO2 only a little at the 23-ka precession band,lagged the atmospheric CO2 at the 100-ka eccentricity band,and was in phase with atmospheric CO2 at the 40-ka obliquity band.
