Identification of a series of substituted 2-piperazinyl-5-pyrimidylhydroxamic acids as potent histone deacetylase inhibitors.

Pursuing our efforts in designing 5-pyrimidylhydroxamic acid anti-cancer agents, we have identified a new series of potent histone deacetylase (HDAC) inhibitors. These compounds exhibit enzymatic HDAC inhibiting properties with IC(50) values in the nanomolar range and inhibit tumor cell proliferation at similar levels. Good solubility, moderate bioavailability, and promising in vivo activity in xenograft model made this series of compounds interesting starting points to design new potent HDAC inhibitors.

Can Commercial Digital Cameras Be Used as Multispectral Sensors? A Crop Monitoring Test.

The use of consumer digital cameras or webcams to characterize and monitor different features has become prevalent in various domains, especially in environmental applications. Despite some promising results, such digital camera systems generally suffer from signal aberrations due to the on-board image processing systems and thus offer limited quantitative data acquisition capability. The objective of this study was to test a series of radiometric corrections having the potential to reduce radiometric distortions linked to camera optics and environmental conditions, and to quantify the effects of these corrections on our ability to monitor crop variables. In 2007, we conducted a five-month experiment on sugarcane trial plots using original RGB and modified RGB (Red-Edge and NIR) cameras fitted onto a light aircraft. The camera settings were kept unchanged throughout the acquisition period and the images were recorded in JPEG and RAW formats. These images were corrected to eliminate the vignetting effect, and normalized between acquisition dates. Our results suggest that 1) the use of unprocessed image data did not improve the results of image analyses; 2) vignetting had a significant effect, especially for the modified camera, and 3) normalized vegetation indices calculated with vignetting-corrected images were sufficient to correct for scene illumination conditions. These results are discussed in the light of the experimental protocol and recommendations are made for the use of these versatile systems for quantitative remote sensing of terrestrial surfaces.

Assessment of Unmanned Aerial Vehicles Imagery for Quantitative Monitoring of Wheat Crop in Small Plots.

This paper outlines how light Unmanned Aerial Vehicles (UAV) can be used in remote sensing for precision farming. It focuses on the combination of simple digital photographic cameras with spectral filters, designed to provide multispectral images in the visible and near-infrared domains. In 2005, these instruments were fitted to powered glider and parachute, and flown at six dates staggered over the crop season. We monitored ten varieties of wheat, grown in trial micro-plots in the South-West of France. For each date, we acquired multiple views in four spectral bands corresponding to blue, green, red, and near-infrared. We then performed accurate corrections of image vignetting, geometric distortions, and radiometric bidirectional effects. Afterwards, we derived for each experimental micro-plot several vegetation indexes relevant for vegetation analyses. Finally, we sought relationships between these indexes and field-measured biophysical parameters, both generic and date-specific. Therefore, we established a robust and stable generic relationship between, in one hand, leaf area index and NDVI and, in the other hand, nitrogen uptake and GNDVI. Due to a high amount of noise in the data, it was not possible to obtain a more accurate model for each date independently. A validation protocol showed that we could expect a precision level of 15% in the biophysical parameters estimation while using these relationships.

The unique functioning of a pre-Columbian Amazonian floodplain fishery.

Archaeology provides few examples of large-scale fisheries at the frontier between catching and farming of fish. We analysed the spatial organization of earthen embankments to infer the functioning of a landscape-level pre-Columbian Amazonian fishery that was based on capture of out-migrating fish after reproduction in seasonal floodplains. Long earthen weirs cross floodplains. We showed that weirs bear successive V-shaped features (termed 'Vs' for the sake of brevity) pointing downstream for outflowing water and that ponds are associated with Vs, the V often forming the pond's downstream wall. How Vs channelled fish into ponds cannot be explained simply by hydraulics, because Vs surprisingly lack fishways, where, in other weirs, traps capture fish borne by current flowing through these gaps. We suggest that when water was still high enough to flow over the weir, out-migrating bottom-hugging fish followed current downstream into Vs. Finding deeper, slower-moving water, they remained. Receding water further concentrated fish in ponds. The pond served as the trap, and this function shaped pond design. Weir-fishing and pond-fishing are both practiced in African floodplains today. In combining the two, this pre-Columbian system appears unique in the world.

Impact on farnesyltransferase inhibition of 4-chlorophenyl moiety replacement in the Zarnestra series.

Based on the structure of R115777 (tipifarnib, Zarnestra), a series of farnesyltransferase inhibitors have been synthesized by modification of the 2-quinolinone motif and transposition of the 4-chlorophenyl ring to the imidazole or its replacement by 5-membered rings. This has yielded a novel series of potent farnesyltransferase inhibitors.

Discovery of pyrimidyl-5-hydroxamic acids as new potent histone deacetylase inhibitors.

A series of pyrimidyl-5-hydroxamic acids was prepared for evaluation as inhibitors of histone deacetylase (HDAC). Amino-2-pyrimidinyl can be used as a linker to provide HDAC inhibitors of good enzymatic potency.

JNJ-26481585, a novel "second-generation" oral histone deacetylase inhibitor, shows broad-spectrum preclinical antitumoral activity.

PURPOSE: Histone deacetylase (HDAC) inhibitors have shown promising clinical activity in the treatment of hematologic malignancies, but their activity in solid tumor indications has been limited. Most HDAC inhibitors in clinical development only transiently induce histone acetylation in tumor tissue. Here, we sought to identify a "second-generation" class I HDAC inhibitor with prolonged pharmacodynamic response in vivo, to assess whether this results in superior antitumoral efficacy. EXPERIMENTAL DESIGN: To identify novel HDAC inhibitors with superior pharmacodynamic properties, we developed a preclinical in vivo tumor model, in which tumor cells have been engineered to express fluorescent protein dependent on HDAC1 inhibition, thereby allowing noninvasive real-time evaluation of the tumor response to HDAC inhibitors. RESULTS: In vivo pharmacodynamic analysis of 140 potent pyrimidyl-hydroxamic acid analogues resulted in the identification of JNJ-26481585. Once daily oral administration of JNJ-26481585 induced continuous histone H3 acetylation. The prolonged pharmacodynamic response translated into complete tumor growth inhibition in Ras mutant HCT116 colon carcinoma xenografts, whereas 5-fluorouracil was less active. JNJ-26481585 also fully inhibited the growth of C170HM2 colorectal liver metastases, whereas again 5-fluorouracil/Leucovorin showed modest activity. Further characterization revealed that JNJ-26481585 is a pan-HDAC inhibitor with marked potency toward HDAC1 (IC(50), 0.16 nmol/L). CONCLUSIONS: The potent antitumor activity as a single agent in preclinical models combined with its favorable pharmacodynamic profile makes JNJ-26481585 a promising "second-generation" HDAC inhibitor. The compound is currently in clinical studies, to evaluate its potential applicability in a broad spectrum of both solid and hematologic malignancies.

4-methyl-1,2,4-triazol-3-yl heterocycle as an alternative to the 1-methylimidazol-5-yl moiety in the farnesyltransferase inhibitor ZARNESTRA.

Replacement of the 1-methylimidazol-5-yl moiety in the farnesyltransferase inhibitor ZARNESTRA series by a 4-methyl-1,2,4-triazol-3-yl group gave us compounds with similar structure-activity relationship profiles showing that this triazole is potentially a good surrogate to imidazole for farnesyltransferase inhibition.

Substituted azoloquinolines and -quinazolines as new potent farnesyl protein transferase inhibitors.

A series of (4-chlorophenyl)-alpha-(1-methyl-1H-imidazol-5-yl)azoloquinolines and -quinazolines was prepared. These compounds displayed potent Farnesyl Protein Transferase inhibitory activity and tetrazolo[1,5-a]quinazolines are promising agents for oral in vivo inhibition.