A Chemical Analog of Curcumin as an Improved Inhibitor of Amyloid Abeta Oligomerization

Amyloid-like plaques are characteristic lesions defining the neuropathology of Alzheimer's disease (AD). The size and density of these plaques are closely associated with cognitive decline. To combat this disease, the few therapies that are available rely on drugs that increase neurotransmission; however, this approach has had limited success as it has simply slowed an imminent decline and failed to target the root cause of AD. Amyloid-like deposits result from aggregation of the Aβ peptide, and thus, reducing amyloid burden by preventing Aβ aggregation represents an attractive approach to improve the therapeutic arsenal for AD. Recent studies have shown that the natural product curcumin is capable of crossing the blood-brain barrier in the CNS in sufficient quantities so as to reduce amyloid plaque burden. Based upon this bioactivity, we hypothesized that curcumin presents molecular features that make it an excellent lead compound for the development of more effective inhibitors of Aβ aggregation. To explore this hypothesis, we screened a library of curcumin analogs and identified structural features that contribute to the anti-oligomerization activity of curcumin and its analogs. First, at least one enone group in the spacer between aryl rings is necessary for measureable anti-Aβ aggregation activity. Second, an unsaturated carbon spacer between aryl rings is essential for inhibitory activity, as none of the saturated carbon spacers showed any margin of improvement over that of native curcumin. Third, methoxyl and hydroxyl substitutions in the meta- and para-positions on the aryl rings appear necessary for some measure of improved inhibitory activity. The best lead inhibitors have either their meta- and para-substituted methoxyl and hydroxyl groups reversed from that of curcumin or methoxyl or hydroxyl groups placed in both positions. The simple substitution of the para-hydroxy group on curcumin with a methoxy substitution improved inhibitor function by 6-7-fold over that measured for curcumin

BCRP expression does not result in resistance to STX140 in vivo, despite the increased expression of BCRP in A2780 cells in vitro after long-term STX140 exposure

The anti-proliferative and anti-angiogenic properties of the endogenous oestrogen metabolite, 2-methoxyoestradiol (2-MeOE2), are enhanced in a series of sulphamoylated derivatives of 2-MeOE2. To investigate possible mechanisms of resistance to these compounds, a cell line, A2780.140, eightfold less sensitive to the 3,17-O,O-bis-sulphamoylated derivative, STX140, was derived from the A2780 ovarian cancer cell line by dose escalation. Other cell lines tested did not develop STX140 resistance. RT–PCR and immunoblot analysis demonstrated that breast cancer resistance protein (BCRP) expression is dramatically increased in A2780.140 cells. The cells are cross-resistant to the most structurally similar bis-sulphamates, and to BCRP substrates, mitoxantrone and doxorubicin; but they remain sensitive to taxol, an MDR1 substrate, and to all other sulphamates tested. Sensitivity can be restored using a BCRP inhibitor, and this pattern of resistance is also seen in a BCRP-expressing MCF-7-derived cell line, MCF-7.MR. In mice bearing wild-type (wt) and BCRP-expressing tumours on either flank, both STX140 and mitoxantrone inhibited the growth of the MCF-7wt xenografts, but only STX140 inhibited growth of the MCF-7.MR tumours. In conclusion, STX140, a promising orally bioavailable anti-cancer agent in pre-clinical development, is highly efficacious in BCRP-expressing xenografts. This is despite an increase in BCRP expression in A2780 cells in vitro after chronic dosing with STX140

A model for flow in the chalk unsaturated zone incorporating progressive weathering

Groundwater from unconfined chalk aquifers constitutes a major water resource in the UK. The unsaturated zone in such systems plays a crucial role in the hydrological cycle, determining the timing and magnitude of recharge, and the transport and fate of nutrients. However, despite more than three decades of study, our physical understanding of this system is incomplete. In this research, state of the art instrumentation provided high temporal resolution readings of soil moisture status, rainfall and actual evaporation from two sites in the Pang and Lambourn catchments (Berkshire, UK), for a continuous two year period (2004/5). A parsimonious, physically based model for the flow of water through the chalk unsaturated zone, including a novel representation of the soil and weathered chalk layers, was developed. The parameters were identified by inverse modelling using field measurements of water content and matric potential. The model was driven by rainfall and evaporation data, and simulated fluxes throughout the profile (including the discrete matrix and fracture components), down to the water table (but not the water table response). Results showed that the model was able to reproduce closely the observed changes in soil moisture status. Recharge was predominantly through the matrix, and the recharge response was strongly attenuated with depth. However, the activation of fast recharge pathways through fractures in the chalk unsaturated zone was highly sensitive to rainfall intensity. Relatively modest increases in rainfall led to dramatically different recharge patterns, with potentially important implications for groundwater flooding. The development and migration of zero flux planes with time and depth were simulated. The simulations also provided strong evidence that, for water table depths greater than 5 m, recharge fluxes persist throughout the entire year, even during drought conditions, with important implications for the calculation of specific yield from baseflow estimates and the representation of recharge in groundwater models