Inhibitors of lipogenic enzymes as a potential therapy against cancer

Cancer cells rely on several metabolic pathways such as lipid metabolism to meet the increase in energy demand, cell division, and growth and successfully adapt to challenging environments. Fatty acid synthesis is therefore commonly enhanced in many cancer cell lines. Thus, relevant efforts are being made by the scientific community to inhibit the enzymes involved in lipid metabolism to disrupt cancer cell proliferation. We review the rapidly expanding body of inhibitors that target lipid metabolism, their side effects, and current status in clinical trials as potential therapeutic approaches against cancer. We focus on their molecular, biochemical and structural properties, selectivity and effectiveness and discuss their potential role as antitumor drugs. Keywords: cancer drugs; lipid metabolism; lipogenic enzyme inhibitors

Convenient synthesis of C75, an inhibitor of FAS and CPT1

C75 is a synthetic racemic α-methylene-γ-butyrolactone exhibiting anti-tumoral properties in vitro and in vivo as well as inducing hypophagia and weight loss in rodents. These interesting properties are thought to be a consequence of the inhibition of the key enzymes FAS and CPT1 involved in lipid metabolism. The need for larger amounts of this compound for biological evaluation prompted us to develop a convenient and reliable route to multigram quantities of C75 from easily available ethyl penta-3,4-dienoate 6. A recently described protocol for the addition of 6 to a mixture of dicyclohexylborane and nonanal followed by acidic treatment of the crude afforded lactone 8, as a mixture of cis and trans isomers, in good yield. The DBU-catalyzed isomerization of the methyl esters 9 arising from 8 gave a 10:1 trans/cis mixture from which the trans isomer was isolated and easily transformed into C75. The temporary transformation of C75 into a phenylseleno ether derivative makes its purification, manipulation and storage easier

Inhibition of fatty acid synthesis induces differentiation and reduces tumor burden in childhood neuroblastoma

Many metabolic pathways, including lipid metabolism, are rewired in tumors tosupport energy and biomass production and to allow adaptation to stressful en-vironments. Neuroblastoma is the second deadliest solid tumor in children. Ge-netic aberrations, as the amplification of theMYCN-oncogene, correlate stronglywith disease progression. Yet, there are only a few molecular targets successfullyexploited in the clinic. Here we show that inhibition of fatty acid synthesis led toincreased neural differentiation and reduced tumor burden in neuroblastomaxenograft experiments independently ofMYCN-status. This was accompaniedby reduced levels of the MYCN or c-MYC oncoproteins and activation of ERKsignaling. Importantly, the expression levels of genes involved inde novofattyacid synthesis showed prognostic value for neuroblastoma patients. Our findingsdemonstrate that inhibition ofde novofatty acid synthesis is a promising pharma-cological intervention strategy for the treatment of neuroblastoma indepen-dently ofMYCN-status

(−)-UB006: A new fatty acid synthase inhibitor and cytotoxic agent without anorexic side effects

C75 is a synthetic anticancer drug that inhibits fatty acid synthase (FAS) and shows a potent anorexigenic side effect. In order to find new cytotoxic compounds that do not impact food intake, we synthesized a new family of C75 derivatives. The most promising anticancer compound among them was UB006 ((4SR,5SR)-4-(hydroxymethyl)-3-methylene-5-octyldihydrofuran-2(3H)-one). The effects of this compound on cytotoxicity, food intake and body weight were studied in UB006 racemic mixture and in both its enantiomers separately. The results showed that both enantiomers inhibit FAS activity and have potent cytotoxic effects in several tumour cell lines, such as the ovarian cell cancer line OVCAR-3. The (−)-UB006 enantiomer's cytotoxic effect on OVCAR-3 was 40-fold higher than that of racemic C75, and 2- and 38-fold higher than that of the racemic mixture and its opposite enantiomer, respectively. This cytotoxic effect on the OVCAR-3 cell line involves mechanisms that reduce mitochondrial respiratory capacity and ATP production, DDIT4/REDD1 upregulation, mTOR activity inhibition, and caspase-3 activation, resulting in apoptosis. In addition, central and peripheral administration of (+)-UB006 or (−)-UB006 into rats and mice did not affect food intake or body weight. Altogether, our data support the discovery of a new potential anticancer compound (−)-UB006 that has no anorexigenic side effects

RECENT RESEARCH IN VLSI, MEMS AND POWER DEVICES WITH PRACTICAL APPLICATION TO THE ITER AND DREAM PROJECTS

Several MEMS (Micro Electro-Mechanical Systems) devices have been analysed and simulated. The new proposed model of SiC MPS (Merged PIN-Schottky) diodes is in full agreement with the real MPS devices. The real size DLL (Dynamic Lattice Liquid) simulator as well as the research on modelling and simulation of modern VLSI devices with practical applications have been presented. In the basis of experience in the field of ATCA (Advanced Telecommunications Computing Architecture) based systems a proof-of-concept DAQ (data acquisition) system for ITER (International Thermonuclear Experimental Reactor) have been proposed

Grupy interesu w polskim systemie politycznym

Grupy interesu są nieodłącznie związane z instytucją państwa. Ich powstanie można wiązać z wyodrębnieniem się interesów społecznych. W miarę rozwoju organizacji państwowej grupy interesu przybierały bardziej zorganizowana formę i odgrywały coraz znaczniejszą rolę ustrojową. W początkowym etapie swojej działalności grupy interesu działały podobnie jak partie polityczne. Po czasie jednak dostrzeżono różnicę i grupy interesu zaczęły być rozumiane jako zorganizowane grupy ludzkie dążące do osiągnięcia własnego interesu. Wprowadzono w tej sytuacji podział na partie polityczne realizujące sprawy publiczne oraz grupy interesu realizujące partykularne interesy. Znaczenie grup interesu w państwie demokratycznym jest ogromne, a ich wpływ na proces stanowienia prawa sprzyja poprawie jego jakości. Grupy interesu dostarczają deputowanym informacji oraz niezbędnych, dla poznania konkretnego problemu społecznego, analiz i statystyk. Działalność grup interesu nie pozostaje jednak wolna od wad. Największym zagrożeniem w ich działalności jest możliwość korumpowania osób publicznych, będących jed- nocześnie osobami decyzyjnymi w organach państwowych. Korupcja stanowi ogromne zagrożenie dla ustroju demokratycznego i powoduje, że grupy nacisku pełnią szkodliwą funkcję w porządku prawnym państwa. To warunkuje ich negatywny odbiór społeczny.There is an inextricable link between interest groups and the Polish state. Their origins can be traced back to the emergence of collective interests. As the state developed, interest groups advanced their organizational forms and secured more prominent influence on public policy. In the beginnings, interest groups played similar role as political parties. Eventually, their activities diverged and differences became apparent. The term „interest group” began to reflect an organized group of people pursuing particular interests of their members. That allowed to draw a demarcation line between political party and interest group based on the type of affairs they are engaging in, i.e. public versus particular, respectively. The importance of interest groups in democracy cannot be underestimated. It is argued that their participation in policy making improves the quality of law, as they are able to supply legislators with relevant data and analyses concerning particular social issues. However, in some instances, activities of interest groups are far from desirable in a democratic society. The most obvious threat stems from ability to corrupt government representatives vested with powers in policy making. Moreover, this particular characteristic is responsible for a negative image of different interest groups in society

ACE2-derived peptides with enhanced efficacy for inhibition of SARS-COV-2 infection

The coronavirus disease (COVID-19) originated the current world-wide pandemic situation. This disease is caused by the severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) and the structural and biochemical basis of the infection mechanism has been widely investigated showing that the receptor binding domain (RBD) of the virus surface spike protein interacts with the peptidase domain (PD) of angiotensin-converting enzyme 2 (ACE2). [1-3] Crystallographic studies of the RBD of SARS-CoV-2 with the full-length human ACE2 receptor exposed the amino acid residues that play a key role at the contact interface of the two proteins. [3,4] Most of the interactions between RBD and ACE2 receptor reside on the helix 1 of ACE2. It has been reported that the ¿-helix secondary structure is essential to obtain antiviral activity against the SARS-CoV-2 pseudovirus. [5] Several strategies have been published to increase the helicity content of the helix 1 peptide of ACE2. Curreli et al. designed four stapled peptides [5] while Karoyan et al. substituted the non-essential positions of the native helix 1 of ACE2 by amino acid residues such as Ala and/or Leu that display a higher helical folding propensity. [1] Both strategies showed an increase in the helical content and a potent SARS-CoV-2 inhibitory activity. Here, we report the development of a long-range macrocycle ACE2 derived peptides with the aim to stabilise the helical structure of the peptides and consequently, increase the potential ability to block SARS-CoV-2 attachment to the host cell. Chemical modifications of the peptides that show greater affinity against RBD will be conducted to obtain irreversible versions of the peptides. These modified peptides should be chemically stable and maintain the binding properties. Nonetheless, crosslinking between both components is expected due to the chemical reaction of the modified peptide with amino acid residues of the RBD that have a nucleophilic character. Finally, multivalent platforms will be synthesized following methodologies well established in our laboratory with the peptide candidates that show better results. References [1] P. Karoyan, V. Vieillard, E. Odile, et al. Eur. bioRxiv. 2020, 1-17. [2] J. Shang, G. Ye, K. Shi, et al. Nature. 2020, 581, 221-224. [3] R. Yan, Y. Zhang, Y. Li, et al. Science. 2020, 367, 1444-1448. [4] D. Wrapp, N. Wang, K. Corbett, et al. Science. 2020, 367, 1260-1263. [5] F. Curreli, S. Victor, X. Tong, et al. MBio. 2020, 11, 1-13

Targeting Energy Expenditure—Drugs for Obesity Treatment

Obesity and overweight are associated with lethal diseases. In this context, obese and overweight individuals infected by COVID-19 are at greater risk of dying. Obesity is treated by three main pharmaceutical approaches, namely suppressing appetite, reducing energy intake by impairing absorption, and increasing energy expenditure. Most compounds used for the latter were first envisaged for other medical uses. However, several candidates are now being developed explicitly for targeting obesity by increasing energy expenditure. This review analyzes the compounds that show anti-obesity activity exerted through the energy expenditure pathway. They are classified on the basis of their development status: FDA-approved, Withdrawn, Clinical Trials, and Under Development. The chemical nature, target, mechanisms of action, and description of the current stage of development are described for each one.Related work in the author’s laboratories was funded in part by the National Research Foundation (NRF) (Blue Sky’s Research Programme # 120386), CIBER-BBN, and Yachay Tech University.Peer reviewe

Myocardial infarction of interior wall: a case study

Cardiovascular diseases are the primary death factors of people in the world. Myocardial infarctions and strokes are the most predominant among them. Securing a patient with myocardial infarction requires a rapid pre-hospital procedure and a fast cardiac intervention at an invasive cardiology centre. The paper describes a case of a 55-year-old man diagnosed with acute coronary syndrome with ST-segment elevation myocardial infarction (STEMI), i.e. myocardial infarction of the bottom wall. The operative procedure requires following the MONA algorithm (M – morphine, O – oxygen, N – nitroglycerin, A – aspirin). The process of data tele-transmission is an important element of the pre-hospital proceedings at the level of Medical Emergency Team. It makes it possible to send quickly the ECG record from the ambulance or patient’s home to a cardiology centre

Sudemycin K: a synthetic antitumor splicing inhibitor variant with improved activity and versatile chemistry

Important links exist between the process of pre-mRNA splicing and cancer, as illustrated by the frequent mutation of splicing factors in tumors and the emergence of various families of antitumor drugs that target components of the splicing machinery, notably SF3B1, a protein subunit of spliceosomal U2 small nuclear ribonucleoprotein particle (snRNP). Sudemycins are synthetic compounds that harbor a pharmacophore common to various classes of splicing inhibitors. Here, we describe the synthesis and functional characterization of novel sudemycin analogues that functionally probe key chemical groups within this pharmacophore. Our results confirm the importance of a conjugated diene group and in addition reveal significant spatial flexibility in this region of the molecule. Sudemycin K, a derivative that replaces the pharmacophore's oxycarbonyl by an amide group, displays improved potency as an inhibitor of cancer cell proliferation, as a regulator of alternative splicing in cultured cells and as an inhibitor of in vitro spliceosome assembly. Sudemycin K displays higher stability, likely related to the replacement of the oxycarbonyl group, which can be a substrate of esterases, by an amide group. The activity and special reactivity of sudemycin K can pave the way to the synthesis and evaluation of a variety of novel sudemycin derivatives.This study was supported by Fundación Botín, Banco de Santander through its Santander Universities Global Division, Consolider RNAREG, AGAUR, MINECO and the European Research Council. We acknowledge support of the Spanish Ministry of Economy and Competitiveness, ‘Centro de Excelencia Severo Ochoa 2013-2017.’ This work was partially funded by the CICYT (CTQ2015-67870P) and Generalitat de Catalunya (2014 SGR 137