Synthesis and biological evaluation of new saccharin-based inhibitors of cancer-related carbonic anhydrase IX and XII isoforms & Benzo[b]tiophen-3-ol derivatives as effective inhibitors of hMAOs: design, synthesis and biological activity

Synthesis and biological evaluation of new saccharin-based inhibitors of cancer-related carbonic anhydrase IX and XII isoforms Carbonic anhydrases (CAs, EC 4.2.1.1) are widespread metalloenzymes implicated in many cellular and physiological processes requiring bicarbonate as substrate (e.g. electrolyte secretion, pH homoeostasis, respiration etc.). The fifteen human isoforms of carbonic anhydrase (hCAs) differ in cellular localization (cytosol, mitochondria or cell membrane), sensibility to inhibitors and catalytic activity. hCAs are well established therapeutic targets to treat a wide range of disorders. In particular, hCA IX and XII have been recognized as tumor-related isoforms, participating in the complex machinery which regulate the pH of cells in hypoxic tumors. In our previously reported studies we showed that N-alkylated saccharin derivatives effectively inhibited the two cancer-related isoforms. Here we report the design, synthesis and the inhibitory activity of novel compounds based on saccharin scaffold. We used two different approaches in order to obtain two series of new compounds. In the first approach, we performed a reductive ring opening of N-alkylated saccharin derivatives, obtaining molecules endowed with secondary sulfonamide and primary alcohol. In the second approach, a series of tertiary sulfonamides (saccharin/isoxazole and saccharin/isoxazoline derivatives) were obtained by the insertion of isoxazole or isoxazoline moiety as spacer between the saccharin nitrogen and (un)substituted aryl or heteroaryl rings. All the synthesized compounds were tested to evaluate their inhibitory activity towards the ubiquitous off-target isoforms, hCA I and II, and the cancer-related ones, hCA IX and XII, by a stopped-flow, CO2 hydrase assay. All the compounds were inactive against the two cytosolic off-target hCA I and II (Kis > 10 µM), while showed inhibitory activity in the low nanomolar range against the two cancer-related isoforms hCA IX and XII. Computational approach has been performed in order to better understand the binding mode of these inhibitors. Benzo[b]tiophen-3-ol derivatives as effective inhibitors of hMAOs: design, synthesis and biological activity Monoamine oxidases (MAOs; EC 1.4.3.4) are mitochondrial bound flavoenzymes, which catalyse the oxidative degradation of amines. They have been widely recognised as important pharmacological targets for the treatment of mood disorders (anxiety, depression) and neurodegeneration (Parkinson’s disease, PD) as the result of their effects on monoamine metabolism and level. Furthermore, evidences show the probable implication of these enzymes in some tumors (e.g prostatic cancer) and cardiomyopathies. Based on tissue localization, structural homology, active site differences, substrate/inhibitor selectivity and catalytic efficiency, two isoforms have been characterized (MAO-A and MAO-B). Both of them could be the target of selective inhibitors acting as reversible or irreversible agents. An extensive number of natural and synthetic compounds have shown effective inhibition of human MAOs. Indole analogues, aurones and indanone derivatives are examples of MAO inhibitors. They show a common structural feature that is the chalcone moiety, whose ability to bind hMAO enzymes has been reported by our research group. With the aim to expand our knowledge about hMAO inhibtion, we performed the design, synthesis, characterization and in vitro biological activity evaluation of some novel benzo[b]thiophen-3-ol derivatives. This scaffold retained the above cited chalcone system, differing from the already studied inhibitors in some features like the isosteric replacement of aurones’ oxygen with sulphur one, the presence of 1,3-diketone system giving keto-enol tautomerism and the presence of a carbonyl group instead of methylylidene one, bound at position 2 of the bicyclic system. These compounds have been synthesised through a new simple synthetic approach consisting in a one-step reaction, which led to moderate to high yields. The obtained compounds showed activity in the micromolar/low micromolar range against hMAO-B with the best inhibition profile observed for compounds containing phenyl ring substituted in the meta- position with halogens. These compounds have also been tested with cortex synaptosomes in both basal and LPS-induced inflammatory conditions to evaluate their ability to affect the DOPAC/DA ratio as well as LDH activity. DOPAC/DA ratio is an indirect index of MAO-B activity, and all the tested compounds are effective in reducing this value in cortex synaptosomes challenged with LPS, showing outcomes better than the reference drug deprenyl. Furthermore, all the tested molecules inhibited LDH activity in the concentration range 0.1-1 µM, showing potential activity as neuroprotective agents

Impact of cross-saturation in sensorless control of transverse-laminated synchronous reluctance motors

Synchronous reluctance (SyR) motors are well suited to a zero-speed sensorless control, because of their inherently salient behavior. However, the cross-saturation effect can lead to large errors on the position estimate, which is based on the differential anisotropy. These errors are quantified in the paper, as a function of the working point. The so-calculated errors are then found in good accordance with the purposely obtained experimental measurements. The impact of the amplitude of the carrier voltage is then pointed out, leading to a mixed (carrier injection plus electromotive force estimation) control scheme. Last, a scheme of this type is used, with a commercial transverse-laminated SyR motor. The robustness against cross-saturation is shown, in practice, and the obtained drive performance is pointed out proving to be effective for a general-purpose applicatio

Cross-Saturation Effects in IPM Motors and Related Impact on Sensorless Control

Permanent-magnet-assisted synchronous reluctance motors are well suited to zero-speed sensorless control because of their inherently salient behavior. However, the cross-saturation effect can lead to large errors on the position estimate, which is based on the differential anisotropy. These errors are quantified in this paper as a function of the working point. The errors that are calculated are then found to be in good accordance with the purposely obtained experimental measurement

Impact of the motor magnetic model on direct flux vector control of interior PM motors

The stator-field-oriented, direct-flux vector control has been proven to be effective in terms of linear torque control and model independent performance at limited voltage and current (i.e. in flux weakening) for AC drives of various types. The performance of the direct-flux vector control relies on the accuracy of the flux estimation, as for any field oriented control. The knowledge of the motor magnetic model is critical for flux estimation when the operating at low speed. This paper addresses the effects of a limited knowledge of the motor model on the performance of the control at low speed, for an Interior Permanent Magnet motor drive. Experimental results are give

Unified Direct-Flux Vector Control for AC Motor Drives

The paper introduces a Unified Direct-Flux Vector Control scheme suitable for sinusoidal AC motor drives. The AC drives considered here are Induction Motor, Synchronous Reluctance and synchronous Permanent Magnet motor drives, including Interior and Surface-mounted Permanent Magnet types. The proposed controller operates in stator flux coordinates: the stator flux amplitude is directly controlled by the direct voltage component, while the torque is controlled by regulating the quadrature current component. The unified direct-flux control is particularly convenient when flux-weakening is required, since it easily guarantees maximum torque production under current and voltage limitations. The hardware for control is standard and the control firmware is the same for all the motors under test with the only exception of the magnetic model used for flux estimation at low speed. Experimental results on four different drives are provided, showing the validity of the proposed unified control approac

An Integral Battery Charger with Power Factor Correction for Electric Scooter

This paper presents an integral battery charger for an electric scooter with high voltage batteries and interior-permanent-magnet motor traction drive. The battery charger is derived from the power hardware of the scooter, with the ac motor drive that operates as three-phase boost rectifier with power factor correction capability. The control of the charger is also integrated into the scooter control firmware that is implemented on a fixed-point DSP controller. Current-controlled or voltage-controlled charge modes are actuated according to the requirements of the battery management system, that is embedded into the battery pack. With respect to previous integrated chargers, the ac current is absorbed at unitary power factor with no harmonic distortion. Moreover, no additional filtering is needed since the pulsewidth modulation ripple is minimized by means of phase interleaving. The feasibility of the integral charger with different ac motors (induction motor, surface-mounted phase modulation motor) is also discussed, by means of a general model purposely developed for three-phase ac machines. The effectiveness of the proposed battery charger is experimentally demonstrated on a prototype electric scooter, equipped with two Li-ion battery packs rated 260 V, 20 A

Direct Flux Field Oriented Control of IPM Drives with Variable DC-Link in the Field-Weakening Region

This paper presents the direct flux control of an interior permanent-magnet (IPM) motor drive in the field-weakening region. The output torque is regulated by the coordinated control of the stator flux amplitude and the current component in quadrature with the flux, and it is implemented in the stator flux reference frame. The control system guarantees maximum torque production taking into account voltage and current limits, in particular in case of large dc-link variations. The field-oriented control does not necessarily require an accurate magnetic model of the IPM motor, and it is able to exploit the full inverter voltage at different dc-link levels with no additional voltage control loop. The feasibility of the proposed control method is investigated in discrete-time simulation, then tested on a laboratory rig, and finally implemented on board of an electric scooter prototype. The motor under test is an IPM permanent-magnet-assisted synchronous reluctance machine, with high-saliency and limited permanent-magnet flu