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1.
《Bioorganic & medicinal chemistry》2020,28(11):115492
Effective chemotherapy for solid cancers is challenging due to a limitation in permeation that prevents anticancer drugs from reaching the center of the tumor, therefore unable to limit cancer cell growth. To circumvent this issue, we planned to apply the drugs directly at the center by first collapsing the outer structure. For this, we focused on cell–cell communication (CCC) between N-glycans and proteins at the tumor cell surface. Mature N-glycans establish CCC; however, CCC is hindered when numerous immature N-glycans are present at the cell surface. Inhibition of Golgi mannosidases (GMs) results in the transport of immature N-glycans to the cell surface. This can be employed to disrupt CCC. Here, we describe the molecular design and synthesis of an improved GM inhibitor with a non-sugar mimic scaffold that was screened from a compound library. The synthesized compounds were tested for enzyme inhibition ability and inhibition of spheroid formation using cell-based methods. Most of the compounds designed and synthesized exhibited GM inhibition at the cellular level. Of those, AR524 had higher inhibitory activity than a known GM inhibitor, kifunensine. Moreover, AR524 inhibited spheroid formation of human malignant cells at low concentration (10 µM), based on the disruption of CCC by GM inhibition. 相似文献
2.
《Bioorganic & medicinal chemistry》2020,28(24):115819
The exploitation of GLU988 and LYS903 residues in PARP1 as targets to design isoquinolinone (I & II) and naphthyridinone (III) analogues is described. Compounds of structure I have good biochemical and cellular potency but suffered from inferior PK. Constraining the linear propylene linker of structure I into a cyclopentene ring (II) offered improved PK parameters, while maintaining potency for PARP1. Finally, to avoid potential issues that may arise from the presence of an anilinic moiety, the nitrogen substituent on the isoquinolinone ring was incorporated as part of the bicyclic ring. This afforded a naphthyridinone scaffold, as shown in structure III. Further optimization of naphthyridinone series led to identification of a novel and highly potent PARP1 inhibitor 34, which was further characterized as preclinical candidate molecule. Compound 34 is orally bioavailable and displayed favorable pharmacokinetic (PK) properties. Compound 34 demonstrated remarkable antitumor efficacy both as a single-agent as well as in combination with chemotherapeutic agents in the BRCA1 mutant MDA-MB-436 breast cancer xenograft model. Additionally, compound 34 also potentiated the effect of agents such as temozolomide in breast cancer, pancreatic cancer and Ewing’s sarcoma models. 相似文献
3.
Three series of bitobic arylpiperazine-phenyl-hexahydropyrazinoquino- lines analogues were designed, synthesizedand evaluated as a novel class of selective ligands for the dopamine D3 receptor. Compounds 15a (Ki of 11.7 ± 1.8 and 373 nM at D3 and D2, respectively), 15c (Ki of 5.49 and 264 nM at D3 and D2, respectively), 15e (Ki of 14.9 and 325 nM at D3 and D2, respectively), 15i (Ki of 13.8 and 401 nM at D3 and D2, respectively) and 15l (Ki of 13.6 and 870 nM at D3 and D2, respectively) were found to demonstrate good binding affinity and selectivity, and especially compound 15c showeda similar binding affinity and selectivity compared with the contrast drug BP897. 相似文献
4.
We determined the relationship between plant height and whole-plant relative growth rate (g g-1 day-1) for ten genotypes of Sporobolus kentrophyllus collected from an intensively grazed site on the Serengeti Plains, Tanzania. Plants were grown for 7 weeks in a greenhouse in Syracuse, N.Y., and harvested weekly. Plants that received simulated bovine urine showed a negative relationship between plant height and growth rate, suggesting a genetic tradeoff between competitive ability if ungrazed (height) and ability to recover from grazing (growth rate). There was no height-growth rate relationship under nitrogen addition rates similar to field mineralization rates. In addition, faster-growing, shorter plants tended to have relatively higher above-ground growth rates than slower-growing, taller plants. These results suggest that natural selection has maintained a gradient of morphologies within this species ranging from short, rapidly growing genotypes adapted to intense grazing conditions to tall, slow-growing, grazer-susceptible genotypes that are superior light competitors in absence of herbivory. 相似文献
5.
Andrew B. Stein Todd K. Fuller Laurie L. Marker 《Biodiversity and Conservation》2008,17(14):3579-3587
In northcentral Namibia, Waterberg Plateau Park (WPP) is a protected area that acts as a refuge for rare and endangered species,
while the farmlands surrounding the Park are managed for livestock production, but support populations of wildlife for game
farming, trophy hunting, and conservation. During June–October 2006, camera-traps were set within and surrounding WPP to assess
leopard (Panthera pardus) density (n = 19 camera stations and 946 camera-trap-nights). Fortuitously, photographic results (2,265 photos of identifiable mammal
(n = 37) and bird (n = 25) species) allowed us to assess aspects of species diversity and differences among the Park, the farmland areas along
the Waterberg Plateau escarpment, and the flatlands surrounding the escarpment. Species composition among the three areas
was markedly different, and made sense with respect to differences in habitat and management features. Camera-trapping efforts,
although intended for a narrow purpose, may also provide a rather robust record of differences in mammal and bird diversity
in adjacent habitats and can be incorporated into long-term monitoring programs. 相似文献
6.
7.
David C. Nickle Gerald H. Learn Matthew W. Rain James I. Mullins John E. Mittler 《Journal of molecular evolution》2002,54(1):134-137
Studies of ancient DNA have attracted considerable attention in scientific journals and the popular press. Several of the
more extreme claims for ancient DNA have been questioned on biochemical grounds (i.e., DNA surviving longer than expected)
and evolutionary grounds (i.e., nucleotide substitution patterns not matching theoretical expectations for ancient DNA). A
recent letter to Nature from Vreeland et al. (2000), however, tops all others with respect to age and condition of the specimen. These researchers
extracted and cultured a bacterium from an inclusion body from what they claim is a 250 million-year (Myr)-old salt crystal.
If substantiated, this observation could fundamentally alter views about bacterial physiology, ecology and evolution. Here
we report on molecular evolutionary analyses of the 16S rDNA from this specimen. We find that 2-9-3 differs from a modern
halophile, Salibacillus marismortui, by just 3 unambiguous bp in 16S rDNA, versus the ∼59 bp that would be expected if these bacteria evolved at the same rate
as other bacteria. We show, using a Poisson distribution, that unless it can be shown that S. marismortui evolves 5 to 10 times more slowly than other bacteria for which 16S rDNA substitution rates have been established, Vreeland
et al.'s claim would be rejected at the 0.05 level. Also, a molecular clock test and a relative rates test fail to substantiate
Vreeland et al.'s claim that strain 2-9-3 is a 250-Myr-old bacterium. The report of Vreeland et al. thus falls into a long
series of suspect ancient DNA studies.
Received: 12 April 2001 / Accepted: 9 June 2001 相似文献
8.
9.
F. -W. Bentrup 《European biophysics journal : EBJ》1980,6(3):175-189
This review treats some examples of electrogenic transport across the outer plasmamembrane (plasmalemma) of plant cells. The selection includes primary active uniport by membrane ATPases (e.g., the proton pump), secondary active transport of hexoses by proton-dependent cotransport, and passive uniport of amines. Primacy is given to the presentation of electrophysiological data and to the discussion of voltage-dependence of the transport mechanisms.Lecture from the Annual Meeting of the Deutsche Gesellschaft für Biophysik at Konstanz 相似文献
10.
Stanislav Lhota Veronika Roubov Vendula Gregorov Martina Kone
n 《American journal of primatology》2019,81(9)
Grooming in primates is often considered a “currency” that can be exchanged for other “services” or “commodities” such as reciprocal grooming, coalitionary support, infant handling, tolerance around food sources, active food sharing, or mating opportunities. Previous studies on primate grooming‐for‐sex exchange viewed the males as the demanding class, with the females as suppliers of mating opportunities. In this study, we examine the broader context of grooming‐for‐mating exchange in Barbary macaques in Gibraltar. Our data show that Barbary macaque males groom females with whom they are mating more frequently and for longer periods than other females, and the relationship between grooming and mating remains significant in both sexual and nonsexual contexts. In addition, females groomed males with whom they were mating more frequently and for longer periods than other males. In both sexes, grooming was observed to be far more frequent and to occur for longer durations in sexual compared to nonsexual contexts. We did not find any difference in grooming behavior between presexual and postsexual contexts. Our data suggest that there is no simple model to describe Barbary macaque grooming patterns in sexual contexts. Although our results are partly consistent with male use of grooming as payment for mating, broadly assessed grooming‐mating patterns cannot be solely explained by a male‐driven grooming‐for‐mating exchange. 相似文献