cis-cyclopropylamines as mechanism-based inhibitors of monoamine oxidases

Cyclopropylamines, inhibitors of monoamine oxidases (MAO) and lysine�specific demethylase (LSD1), provide a useful structural scaffold for the design of mechanism-based inhibitors for treatment of depression and can�cer. For new compounds with the less common cis relationship and with an alkoxy substituent at the 2-position of the cyclopropyl ring, the apparent affinity determined from docking experiments revealed little difference between the enantiomers. Using the racemate, kinetic parameters for the reversible and irreversible inhibition of MAO were determined. No inhibition of LSD1 was observed. For reversible inhibition, most compounds gave high IC50 values with MAO A, but sub-micromolar values with MAO B. After pre-incubation of the cyclopropylamine with the enzyme, the inhibition was irreversible for both MAO A and MAO B, and the activity was not restored by dilution. Spectral changes during inactivation of MAO A included bleaching at 456 nm and an increased absorbance at 400 nm, consistent with flavin modification. These derivatives are MAO B-selective irreversible inhib�itors that do not show inhibition of LSD1. The best inhibitor was cis-N-ben�zyl-2-methoxycyclopropylamine, with an IC50 of 5 nM for MAO B and 170 nM for MAO A after 30 min pre-incubation. This cis-cyclopropylamine is over 20-fold more effective than tranylcypromine, so may be studied as a lead for selective inhibitors of MAO B that do not inhibit LSD1

Discovery of 1-Benzhydryl-Piperazine-Based HDAC Inhibitors with Anti-Breast Cancer Activity: Synthesis, Molecular Modeling, In Vitro and In Vivo Biological Evaluation

Abstract Isoform-selective histone deacetylase (HDAC) inhibition is promoted as a rational strategy to develop safer anti-cancer drugs compared to non-selective HDAC inhibitors. Despite this presumed benefit, considerably more non-selective HDAC inhibitors have undergone clinical trials. In this report, we detail the design and discovery of potent HDAC inhibitors, with 1-benzhydryl piperazine as a surface recognition group, that differ in hydrocarbon linker. In vitro HDAC screening identified two selective HDAC6 inhibitors with nanomolar IC50 values, as well as two non-selective nanomolar HDAC inhibitors. Structure-based molecular modeling was employed to study the influence of linker chemistry of synthesized inhibitors on HDAC6 potency. The breast cancer cell lines (MDA-MB-231 and MCF-7) were used to evaluate compound-mediated in vitro anti-cancer, anti-migratory, and anti-invasive activities. Experiments on the zebrafish MDA-MB-231 xenograft model revealed that a novel non-selective HDAC inhibitor with a seven-carbon-atom linker exhibits potent anti-tumor, anti-metastatic, and anti-angiogenic effects when tested at low micromolar concentrations

QSAR studies on the human sirtuin 2 inhibition by non-covalent 7,5,2-anilinobenzamide derivatives

Sirtuin 2 is a key enzyme in gene expression regulation that is often associated with tumor proliferation control and therefore is a relevant anticancer drug target. Anilinobenzamide derivatives have been discussed as selective sirtuin 2 inhibitors and can be developed further. In the present study, hologram and three-dimensional quantitative structure–activity relationship (HQSAR and 3D-QSAR) analyses were employed for determining structural contributions of a compound series containing human sirtuin-2-selective inhibitors that were then correlated with structural data from the literature. The final QSAR models were robust and predictive according to statistical validation (q2 and r2pred values higher than 0.85 and 0.75, respectively) and could be employed further to generate fragment contribution and contour maps. 3D-QSAR models together with information about the chemical properties of sirtuin 2 inhibitors can be useful for designing novel bioactive ligands

SNEE: a query processor for wireless sensor networks

A wireless sensor network (WSN) can be construed as an intelligent, large-scale device for observing and measuring properties of the physical world. In recent years, the database research community has championed the view that if we construe a WSN as a database (i.e., if a significant aspect of its intelligent behavior is that it can execute declaratively-expressed queries), then one can achieve a significant reduction in the cost of engineering the software that implements a data collection program for the WSN while still achieving, through query optimization, very favorable cost:benefit ratios. This paper describes a query processing framework for WSNs that meets many desiderata associated with the view of WSN as databases. The framework is presented in the form of compiler/optimizer, called SNEE, for a continuous declarative query language over sensed data streams, called SNEEql. SNEEql can be shown to meet the expressiveness requirements of a large class of applications. SNEE can be shown to generate effective and efficient query evaluation plans. More specifically, the paper describes the following contributions: (1) a user-level syntax and physical algebra for SNEEql, an expressive continuous query language over WSNs; (2) example concrete algorithms for physical algebraic operators defined in such a way that the task of deriving memory, time and energy analytical cost-estimation models (CEMs) for them becomes straightforward by reduction to a structural traversal of the pseudocode; (3) CEMs for the concrete algorithms alluded to; (4) an architecture for the optimization of SNEEql queries, called SNEE, building on well-established distributed query processing components where possible, but making enhancements or refinements where necessary to accommodate the WSN context; (5) algorithms that instantiate the components in the SNEE architecture, thereby supporting integrated query planning that includes routing, placement and timing; and (6) an empirical performance evaluation of the resulting framework

Spiruchostatin A Inhibits Proliferation and Differentiation of Fibroblasts from Patients with Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a progressive scarring disorder characterized by the proliferation of interstitial fibroblasts and the deposition of extracellular matrix causing impaired gas exchange. Spiruchostatin A (SpA) is a histone deacetylase inhibitor (HDI) with selectivity toward Class I enzymes, which distinguishes it from other nonspecific HDIs that are reported to inhibit (myo)fibroblast proliferation and differentiation. Because the selectivity of HDIs may be important clinically, we postulated that SpA inhibits the proliferation and differentiation of IPF fibroblasts. Primary fibroblasts were grown from lung biopsy explants obtained from patients with IPF or from normal control subjects, using two-dimensional or three-dimensional culture models. The effect of SpA on fibroproliferation in serum-containing medium ± transforming growth factor (TGF)–?1 was quantified by methylene blue binding. The acetylation of histone H3, the expression of the cell-cycle inhibitor p21waf1, and the myofibroblast markers ?–smooth muscle actin (?-SMA) and collagens I and III were determined by Western blotting, quantitative RT-PCR, immunofluorescent staining, or colorimetry. SpA inhibited the proliferation of IPF or normal fibroblasts in a time-dependent and concentration-dependent manner (concentration required to achieve 50% inhibition = 3.8 ± 0.4 nM versus 7.8 ± 0.2 nM, respectively; P < 0.05), with little cytotoxicity. Western blot analyses revealed that SpA caused a concentration-dependent increase in histone H3 acetylation, paralleling its antiproliferative effect. SpA also increased p21waf1 expression, suggesting that direct cell-cycle regulation was the mechanism of inhibiting proliferation. Although treatment with TGF-?1 induced myofibroblast differentiation associated with increased expression of ?-SMA, collagen I and collagen III and soluble collagen release, these responses were potently inhibited by SpA. These data support the concept that bicyclic tetrapeptide HDIs merit further investigation as potential treatments for IPF