A series of unconjugated ferrocenyl phenols: prospects as anticancer agents

We recently reported that a ferrocenyl diphenol butene derivative showed a very strong cytotoxic effect on both hormone-dependent and -independent breast cancer cell lines. In order to obtain more information about the structure-activity relationship in the cytotoxicity of small ferrocene compounds, we have prepared a series of simple unconjugated ferrocenyl diphenol complexes (ortho,para; meta,para; para,para). These compounds retain a reasonable to good affinity for both estrogen receptor types, with higher values for the beta form, and superior binding for the para,para diphenol complex (RBA=28%). In vitro these complexes exhibit significant cytotoxic effects on hormone-independent prostate (PC3) and breast cancer cell lines (MDA-MB231), with IC50 values between 2.5 and 4.1 microM. This effect is more marked with PC3, the ortho,para diphenol complex proving the most effective. On the hormone-dependent MCF7 breast cancer cell line, the observed effect seems to be the result of two components, one cytotoxic (antiproliferative), the other estrogenic (proliferative). Electrochemical studies show that the cytotoxic effect of the complexes correlates with the ease of oxidation of the ferrocene group. All these complexes are much less cytotoxic than the ferrocenyl diphenol butene derivative.     

Simultaneous determination of psychoactive drugs and their metabolites in aqueous matrices by liquid chromatography mass Spectrometry

A multi-residue method was developed that allows for the simultaneous determination of psychoactive compounds such as opioids, tranquilizers, antiepileptics (primidone, carbamazepine plus two metabolites),the cocaine metabolite benzoylecgonine, the antidepressant doxepin, as well as the calcium channel blocker verapamil in raw and treated wastewater, surface water, groundwater, and drinking water. After solid-phase extraction with Oasis HLB at neutral pH, the analytes were detected by LC electrospray tandem MS in the positive ion mode. With a few exceptions relative recoveries of the analytes exceeded 70%. The limits of quantification were in the low ng/L range. Matrix effects were compensated by using appropriate deuterated or 13C-15N-labeled surrogate standards. For raw and treated wastewater, concentration factors were lowered to reduce matrix effects. Most analytes (15 of 20) were found in raw and treated wastewater as well as in surface water, and hence, are presumably ubiquitously present in the environment. Antiepileptics, the opium alkaloids morphine and codeine, dihydrocodeine, the two tranquilizers oxazepam and temazepam, the opioid tramadol, doxepin, and verapamil were detected in STP discharges and German rivers at concentrations up to the microg/L range. In drinking water, only carbamazepine, its metabolite 10,11-dihydroxy-10,11-dihydrocarbamazepine, and primidone were present at concentrations up to 0.020 microg/L.     

Robust estimates in generalized partially linear single-index models

A natural generalization of the well known generalized linear models is to allow only for some of the predictors to be modeled linearly while others are modeled nonparametrically. However, this model can face the so called ??curse of dimensionality?? problem that can be solved by imposing a nonparametric dependence on some unknown projection of the carriers. More precisely, we assume that the observations (y _i ,x _i ,t _i ), 1??i??n, are such that t _i ??? ^q , x _i ??? ^p and y _i |(x _i ,t _i )??F(?,?? _i ) with $\mu_{i}=H (\eta(\boldsymbol{\alpha}^{\mathrm{T}}\mathbf{t}_{i})+\mathbf {x}_{i}^{\mathrm{T}}\boldsymbol{\beta} )$ , for some known distribution function F and link function?H. The function ??:???? and the parameters ?? and ?? are unknown and to be estimated. This model is known as the generalized partly linear single-index model. In this paper, we introduce a family of robust estimates for the parametric and nonparametric components under a generalized partially linear single-index model. It is shown that the estimates of ?? and ?? are root-n consistent and asymptotically normally distributed. Through a Monte Carlo study, we compare the performance of the proposed estimators with that of the classical ones.     

Compatibility of different polymers for cord blood-derived hematopoietic progenitor cells

The low yield of hematopoietic progenitor cells (HPC) present in cord blood grafts limits their application in clinics. A reliable strategy for ex vivo expansion of functional HPC is a present goal in regenerative medicine. Here we evaluate the capacity of several two-dimensional polymers to support HPC proliferation. Basic compatibility was tested by measuring cell viability, cytotoxicity and apoptosis of CD34⁺ progenitors that were short and long-term exposed to sixteen bio and synthetic polymers. Resomer^? RG503, PCL and Fibrin might be good alternatives to tissue culture plastic for culture of CB-derived CD34⁺ progenitors. Further, these polymers will be produced in three-dimensional structures and tested for their cytocompatibility.     

Fully digital strategy for fast calibration and test of ΣΔ ADC's

This work describes a novel test strategy that uses digital stimuli for cheap, fast, though accurate, testing of high resolution ΣΔ ADC's. Simulation results showed a detection sensitivity on specifications parameters of up to −100 dB. The proposed method can also help to reduce the cost of ADC production test, to extend test coverage and to enable built-in self-test and test-based self-calibration.     

An Endoperoxide‐Based Hybrid Approach to Deliver Falcipain Inhibitors Inside Malaria Parasites

The emergence of artemisinin‐resistant Plasmodium falciparum malaria in Southeast Asia has reinforced the urgent need to discover novel chemotherapeutic strategies to treat and control malaria. To address this problem, we prepared a set of dual‐acting tetraoxane‐based hybrid molecules designed to deliver a falcipain‐2 (FP‐2) inhibitor upon activation by iron(II) in the parasite digestive vacuole. These hybrids are active in the low nanomolar range against chloroquine‐sensitive and chloroquine‐resistant P. falciparum strains. We also demonstrate that in the presence of FeBr₂ or within infected red blood cells, these molecules fragment to release falcipain inhibitors with nanomolar protease inhibitory activity. Molecular docking studies were performed to better understand the molecular interactions established between the tetraoxane‐based hybrids and the cysteine protease binding pocket residues. Our results further indicate that the intrinsic activity of the tetraoxane partner compound can be masked, suggesting that a tetraoxane‐based delivery system offers the potential to attenuate the off‐target effects of known drugs.     

Molecular Diversity Sculpted by Fungal PKS–NRPS Hybrids

Fungal polyketide synthase–nonribosomal peptide synthetase (PKS–NRPS) hybrids manufacture a wide range of structurally diverse secondary metabolites that play an eminent role in the environment, as molecular tools and leads for therapeutic development. To date, a dozen PKS–NRPS megasynthetases can be linked to the corresponding secondary metabolites, which stand out because of their structural complexity. The diversity of their structures, biological activities, and biosynthetic routes are particularly intriguing considering the iterative use of the catalytic domains of the biosynthetic enzymes—implying an enigmatic biosynthetic code. This review provides an overview of the characterized fungal PKS–NRPS hybrids, their manifold functionalities, and the diversity of the resulting secondary metabolites, as well as molecular engineering attempts that highly improved the understanding of their cryptic programming.