Vascular endothelial growth factor receptor-2 (VEGFR-2) plays a crucial role in cancer angiogenesis. In this study, a series of novel furo[2,3-d]pyrimidine and thieno[2,3-d]pyrimidine based-derivatives were designed and synthesized as VEGFR-2 inhibitors, in accordance to the structure activity relationship (SAR) studies of known type II VEGFR-2 inhibitors. The synthesized compounds were evaluated for their ability to in vitro inhibit VEGFR-2 kinase enzyme. Seven compounds (15b, 16c, 16e, 21a, 21b, 21c and 21e) demonstrated highly potent dose-related VEGFR-2 inhibition with IC50 values in nanomolar range, of which the thieno[2,3-d]pyrimidine based-derivatives (21b, 21c and 21e) exhibited IC50 values of 33.4, 47.0 and 21 nM respectively. Moreover, furo[2,3-d]pyrimidine-based derivative (15b) showed the strongest inhibition of human umbilical vein endothelial cells (HUVEC) proliferation with 99.5% inhibition at 10 μM concentration. Consistent with our in vitro findings, compounds (21b and 21e) orally administered at 5 and 10 mg/kg/day for 8 consecutive days demonstrated potent anticancer activity in Erhlich ascites carcinoma (EAC) solid tumor murine model. Such compounds blunted angiogenesis in EAC as evidenced by reduced percent microvessel via decreasing VEGFR-2 phosphorylation with subsequent induction of apoptotic machinery. Furthermore, Miles vascular permeability assay confirmed their antiangiogenic effects in vivo. Intriguingly, such compounds showed no obvious toxicity.

Deregulation and changes in energy metabolism are emergent and important biomarkers of cancer cells. The uptake of hexoses in cancer cells is mediated by a family of facilitative hexose membrane-transporter proteins known as Glucose Transporters (GLUTs). In the clinic, numerous breast cancers do not show elevated glucose metabolism (which is mediated mainly through the GLUT1 transporter) and may use fructose as an alternative energy source. The principal fructose transporter in most cancer cells is GLUT5, and its mRNA was shown to be elevated in human breast cancer. This offers an alternative strategy for early detection using fructose analogs. In order to selectively scout GLUT5 binding-pocket requirements, we designed, synthesized and screened a new class of fructose mimics based upon the 2,5-anhydromannitol scaffold. Several of these compounds display low millimolar IC50 values against the known high-affinity 18F-labeled fructose-based probe 6-deoxy-6-fluoro-D-fructose (6-FDF) in murine EMT6 breast cancer cells. In addition, this work used molecular docking and molecular dynamics simulations (MD) with previously reported GLUT5 structures to gain better insight into hexose–GLUT interactions with selected ligands governing their preference for GLUT5 compared to other GLUTs. The improved inhibition of these compounds, and the refined model for their binding, set the stage for the development of high-affinity molecular imaging probes targeting cancers that express the GLUT5 biomarker.

Abstract-WindSat, the first polarimetric radiometer on orbit, launched in January 2003, provides the promise of passive ocean wind vector retrievals on a continuous basis, simultaneous with the retrieval of many other geophysical variables such as sea surface temperature, atmospheric water vapor, cloud liquid water, and sea ice extent and concentration. WindSat also serves as risk reduction for the upcoming National Polar-orbiting Operational Environmental Satellite System (NPOESS) Conical Scanning Microwave Imager/Sounder (CMIS). Since the dependence of microwave brightness temperatures on wind direction is small relative to that of other parameters such as wind speed, wind direction retrieval relies on increasingly accurate knowledge of the ocean surface microwave emission, which depends upon surface properties such as roughness and foam due to wave breaking. Coordinated near-surface measurements of ocean surface microwave emission and air-sea interaction parameters are needed to quantify the effects of the processes mentioned above in surface emission models to improve the accuracy of wind vector retrievals. Such coordinated observations were performed during the Fluxes, Air-Sea Interaction, and Remote Sensing (FAIRS) experiment conducted on the R/P Floating Instrument Platform (FLIP) in the northeastern Pacific Ocean during the Fall of 2000. X-and Ka-band partially polarimetric radiometers were mounted at the end of the port boom of R/P FLIP to measure ocean surface emission at incidence angles of 45 , 53 , and 65 . A bore-sighted video camera recorded the fractional area of foam in the field of view of the radiometers. Air-sea interaction parameters that were measured concurrently include wind speed, friction velocity, heat fluxes, and significant wave height. The measured dependence of ocean surface emissivity on wind speed and friction velocity is in good agreement with, and extends, earlier observations and empirical models based on satellite data. Concurrent radiometric measurements and fractional Manuscript received March 31, 2004; revised March 7, 2005. This was supported in part by the Department of the Navy, Office of Naval Research under Awards N0014-00-1-0280 and N00014-03-1-0044 to the University of Massachusetts, Award N0014-00-1-0152 to the University of Washington, and Award N0014-00-WX2-1032 to the Naval Research Laboratory, and in part by the National Polar-orbiting Operational Environmental Satellite System (NPOESS) area foam coverage data strengthen the possibility of retrieval of sea surface foam coverage using airborne or spaceborne radiometry. The dependence of emissivity on atmospheric stability is shown to be much smaller than the dependence of emissivity on wind speed. Analysis of emissivity dependence on atmospheric stability alone was inconclusive, due to the variation in atmospheric stability with wind speed. The effect of long-wave incidence angle modulation on sea surface emissivity for near-surface measurements was found to be negligible when emissivity measurements were averag...

A. Shouman (2020) Design, synthesis and biological evaluation of a new thieno[2,3-d]pyrimidine-based urea derivative with potential antitumor activity against tamoxifen sensitive and resistant breast cancer cell lines,