Edge effects on tree architecture exacerbate biomass loss of fragmented Amazonian forests.

Habitat fragmentation could potentially affect tree architecture and allometry. Here, we use ground surveys of terrestrial LiDAR in Central Amazonia to explore the influence of forest edge effects on tree architecture and allometry, as well as forest biomass, 40 years after fragmentation. We find that young trees colonising the forest fragments have thicker branches and architectural traits that optimise for light capture, which result in 50% more woody volume than their counterparts of similar stem size and height in the forest interior. However, we observe a disproportionately lower height in some large trees, leading to a 30% decline in their woody volume. Despite the substantial wood production of colonising trees, the lower height of some large trees has resulted in a net loss of 6.0 Mg ha-1 of aboveground biomass - representing 2.3% of the aboveground biomass of edge forests. Our findings indicate a strong influence of edge effects on tree architecture and allometry, and uncover an overlooked factor that likely exacerbates carbon losses in fragmented forests.

Highly potent first examples of dual aromatase-steroid sulfatase inhibitors based on a biphenyl template.

Single agents against multiple drug targets are of increasing interest. Hormone-dependent breast cancer (HDBC) may be more effectively treated by dual inhibition of aromatase and steroid sulfatase (STS). The aromatase inhibitory pharmacophore was thus introduced into a known biphenyl STS inhibitor to give a series of novel dual aromatase-sulfatase inhibitors (DASIs). Several compounds are good aromatase or STS inhibitors and DASI 20 (IC(50): aromatase, 2.0 nM; STS, 35 nM) and its chlorinated congener 23 (IC(50): aromatase, 0.5 nM; STS, 5.5 nM) are examples that show exceptional dual potency in JEG-3 cells. Both biphenyls share a para-sulfamate-containing ring B and a ring A, which contains a triazol-1-ylmethyl meta to the biphenyl bridge and para to a nitrile. At 1 mg/kg po, 20 and 23 reduced plasma estradiol levels strongly and inhibited liver STS activity potently in vivo. 23 is nonestrogenic and potently inhibits carbonic anhydrase II (IC(50) 86 nM). A complex was crystallized and its structure was solved by X-ray crystallography. This class of DASI should encourage further development toward multitargeted therapeutic intervention in HDBC.

Non-steroidal aromatase inhibitors based on a biphenyl scaffold: synthesis, in vitro SAR, and molecular modelling.

The synthesis and in vitro biological evaluation (JEG-3 cells) of a series of novel and potent aromatase inhibitors, prepared by microwave-enhanced Suzuki cross-coupling methodology, are reported. These compounds possess a biphenyl template incorporated with the haem-ligating triazolylmethyl moiety, either on its own or in combination with other substituent(s) at various positions on the phenyl rings. The most potent aromatase inhibitor reported herein has an IC(50) value of 0.12 nM, although seven of its congeners are also highly potent (IC(50)

Dual aromatase-sulfatase inhibitors based on the anastrozole template: synthesis, in vitro SAR, molecular modelling and in vivo activity.

The synthesis and biological evaluation of a series of novel Dual Aromatase-Sulfatase Inhibitors (DASIs) are described. It is postulated that dual inhibition of the aromatase and steroid sulfatase enzymes, both responsible for the biosynthesis of oestrogens, will be beneficial in the treatment of hormone-dependent breast cancer. The compounds are based upon the Anastrozole aromatase inhibitor template which, while maintaining the haem ligating triazole moiety crucial for enzyme inhibition, was modified to include a phenol sulfamate ester motif, the pharmacophore for potent irreversible steroid sulfatase inhibition. Adaption of a synthetic route to Anastrozole was accomplished via selective radical bromination and substitution reactions to furnish a series of inhibitory aromatase pharmacophores. Linking these fragments to the phenol sulfamate ester moiety employed S(N)2, Heck and Mitsunobu reactions with phenolic precursors, from where the completed DASIs were achieved via sulfamoylation. In vitro, the lead compound, 11, had a high degree of potency against aromatase (IC(50) 3.5 nM), comparable with that of Anastrozole (IC(50) 1.5 nM) whereas, only moderate activity against steroid sulfatase was found. However, in vivo, 11 surprisingly exhibited potent dual inhibition. Compound 11 was modelled into the active site of a homology model of human aromatase and the X-ray crystal structure of steroid sulfatase.

Dual aromatase-sulfatase inhibitors based on the anastrozole template: synthesis, in vitro SAR, molecular modelling and in vivo activity.

The synthesis and biological evaluation of a series of novel Dual Aromatase-Sulfatase Inhibitors (DASIs) are described. It is postulated that dual inhibition of the aromatase and steroid sulfatase enzymes, both responsible for the biosynthesis of oestrogens, will be beneficial in the treatment of hormone-dependent breast cancer. The compounds are based upon the Anastrozole aromatase inhibitor template which, while maintaining the haem ligating triazole moiety crucial for enzyme inhibition, was modified to include a phenol sulfamate ester motif, the pharmacophore for potent irreversible steroid sulfatase inhibition. Adaption of a synthetic route to Anastrozole was accomplished via selective radical bromination and substitution reactions to furnish a series of aromatase inhibitory pharmacophores. Linking these fragments to the phenol sulfamate ester moiety employed SN2, Heck and Mitsunobu reactions with phenolic precursors, from where the completed DASIs were achieved via sulfamoylation. In vitro, the lead compound, 11, had a high degree of potency against aromatase (IC50 3.5 nM), comparable with that of Anastrozole (IC50 1.5 nM) whereas, only moderate activity against steroid sulfatase was found. However, in vivo, 11 surprisingly exhibited potent dual inhibition. Compound 11 was modelled into the active site of a homology model of human aromatase and the X-ray crystal structure of steroid sulfatase.