Деградација протеина индукована PROTAC молекулима као нова стратегија у развоју лекова

The traditional concept of drug discovery is based on the occupancydriven pharmacology model. It implies the development of inhibitors occupying binding sites that directly affect protein functions. Therefore, proteins that do not have such binding sites are generally considered as pharmacologically intractable. Furthermore, drugs that act in this way must be administered in dosage regimens that often result in high systemic drug exposures in order to maintain sufficient protein inhibition. Thus, there is a risk of the onset of off-target binding and side effects. The landscape of drug discovery has been markedly changed since proteolysis targeting chimera (PROTAC) molecules emerged twenty years ago as a part of the event-driven pharmacology model. These are bifunctional molecules that harness the ubiquitin-proteasome system, and are composed of a ligand that binds the protein of interest (POI), a ligand that recruits E3 ubiquitin ligase (E3UL) and a linker that connects these two parts. Pharmacologically, PROTACs bring POI and E3UL into close proximity, which triggers the formation of a functional ternary complex POI-PROTAC-E3UL. This event drives polyubiquitination and subsequent POI degradation by the 26S proteasome. The development and exceptional properties of PROTAC molecules that brought them to clinical studies will be discussed in this paper. © 2022 Serbian Chemical Society. All rights reserved.Традиционални концепт открића лекова базиран је на фармаколошком моделу заснованом на окупираности циљних протеина. То подразумева развој инхибитора који окупирају везујућа места директно повезана са функцијама протеина. Стога, протеини који немају таква везујућа места се генерално сматрају фармаколошки недодирљивим. Осим тога, лекови који делују на овакав начин морају се примењивати у режимима дозирања који често доводе до претеране системске изложености леку ради одржања довољне инхибиције протеина. Дакле, постоји ризик од појаве везивања лека ван свог примарног места дејства и нежељених ефеката. Окосница развоја лекова је значајно измењена откако су се појавили PROTAC (енг. proteolysis targeting chimera) молекули пре двадесет година као део фармаколошког модела заснованог на покретању догађаја који доводе до разградње циљних протеина. Ово су бифункционални молекули који користе убиквитин-протеазом систем, а састоје се од лиганда који се везује за протеин од инте- реса (POI), лиганда који регрутује Е3 убиквитин лигазу (E3UL) и линкера који повезује ова два дела. Фармаколошки, PROTAC молекули доводе POI и Е3UL у близину, што води формирању функционалног тернарног комплекса POI–PROTAC–Е3UL. Овај догађај води полиубиквитинацији и следственој деградацији POI 26S протеазомом. Развој и изу- зетна својства PROTAC молекула која су их довела до клиничких студија дискутовани су овом раду

Remaining life assessment of a high pressure turbine casing in creep and low cycle service regime

Thick walled components such as high pressure (HP) steam turbine casings operating under high parameter conditions are subjected to a complex stress state. As a result of that stress state, some parts of HP turbine casing undergo to the creep fatigue caused by the combination of thermal fatigue resulted from repeated start/stop operation and the creep which occurs during long-term operation at high temperature and high-pressure. It is well known that domestic thermal power plants have been in use over 100000 h which means that significant cost is required not only for maintenance, but often for renewal of equipment. Based on comprehensive investigation, the results of residual life assessment of one high pressure steam turbine casing, which belongs to the older turbine generation, taking into account simultaneous action of thermal fatigue and creep, are presented in this paper. Also, the critical flaw crack size of HP turbine casing is determined because this parameter has a strong influence on casing integrity and residual life. The results of residual life assessment provide not only a basis for further maintenance, but also estimated time for reparation or renewal

Stereoselektivne sinteze α-hidroksi-β-aminokiselina iz prirodnih hiralnih prekursora

A method for the stereoselective homologation of -amino acids into syn-α-hydroxy-β-amino acids is described, based on the conversion of stereoisomeric cyanohydrins into trans-oxazolines. The synthetic potential of the method is illustrated in the enantioselective formal synthesis of Bestatin.Opisana je metoda za stereoselektivnu sintezu α-hidroksi-β-aminokiselina syn-konfiguracije, polazeći od α-aminokiselina, kao prirodnih hiralnih prekursora. Enantioselektivnost procesa zavisi od strukture polazne aminokiseline, kao i reakcionih uslova. Primena ove metode ilustrovana je u sintezi (2S,3R)-3-amino-2-hidroksi-4-fenilbutanske kiseline, konstituenta nekoliko važnih biološki aktivnih jedinjenja

Supplementary data for article: Tasić, G.; Randjelovic, J.; Vusurovic, N.; Maslak, V.; Husinec, S.; Savić, V. A Highly Regioselective, Protecting Group Controlled, Synthesis of Bicyclic Compounds via Pd-Catalysed Intramolecular Cyclisations. Tetrahedron Letters 2013, 54 (18), 2243–2246. https://doi.org/10.1016/j.tetlet.2013.02.068

Supplementary material for: [https://doi.org/10.1016/j.tetlet.2013.02.068]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/1586

Remaining life assessment of a high pressure turbine casing in creep and low cycle service regime

Thick walled components such as high pressure (HP) steam turbine casings operating under high parameter conditions are subjected to a complex stress state. As a result of that stress state, some parts of HP turbine casing undergo to the creep fatigue caused by the combination of thermal fatigue resulted from repeated start/stop operation and the creep which occurs during long-term operation at high temperature and high-pressure. It is well known that domestic thermal power plants have been in use over 100000 h which means that significant cost is required not only for maintenance, but often for renewal of equipment. Based on comprehensive investigation, the results of residual life assessment of one high pressure steam turbine casing, which belongs to the older turbine generation, taking into account simultaneous action of thermal fatigue and creep, are presented in this paper. Also, the critical flaw crack size of HP turbine casing is determined because this parameter has a strong influence on casing integrity and residual life. The results of residual life assessment provide not only a basis for further maintenance, but also estimated time for reparation or renewal

Public health significance of pronunciation of voices in pre-school children

A survey conducted in the pre-school "Čika Jova Zmaj" in Belgrade between February and April 2016 in the pre-school age population showed significant representation of articulation disorders. In relation to the total number of children surveyed (427), the correct pronunciation was registered in 259 children (60.65%), while the dyslalia was registered with 168 children (39.34%). The reality that about 40% of preschool children today have a distortion of excuses, imposes the need to correct these disorders and highlights their public health significance from the perspective of potential problems in social integration and psychosocial development of these children. The results of our research on articulation disorders in pre-school children, depending on gender, were: in the pre-school age, 53% of speech disorders were recorded. Voice disorders of fricative, africat and lateral were present in over 80%, with prevalence from the group frikative. They dominated the distortion of the pronunciation of the following voices: L, Č, Š, Ž, S and Z, with the presence of distortion in over onethird of boys. In the population of pre-school age, speech disorders are represented by 46%. The voice disorders of fricative and africat are dominant. Distortion of pronunciation of voices CH, Š, S, C, Z and L, with prevalence of distortion, is singled out. The reality that articulation disorders are the most common speech disorders, imposes the need for systematic monitoring of articulation development at the earliest age. The first step towards the prevention of speech disorders is team work carried out in the framework of primary health care

In vitro студија редокс особина азолил-лактона у хуманом серуму

Disruption of the redox balance in the body causes oxidative stress that can initiate many diseases. While antioxidants reduce the level of oxidiz- ing compounds in the medium, prooxidants promote the opposite process and have been used in therapies in particular those of cancer diseases. In this study, a series of azolyl lactones, were tested in human serum as a biological matrix and the obtained values of their oxy scores (OS) were compared. The antioxid- ative properties of these compounds were also tested under conditions of ind- uced oxidative stress using an external prooxidant, t-butylhydroperoxide. The results showed that the sulphur analogue 4-azolyl coumarin 5 has the best anti- oxidant properties (OS –2.2), while the halogenated derivatives of pyrazolyl- coumarin 7 and 8 act as prooxidants, but successfully resist oxidative stress (OS 2.7 and 2.0, respectively). Related phthalides and isocoumarins showed prooxidative properties, but azolyl isocoumarins 10 and 11 show the strongest resistance to oxidative stress, reflected in their negative oxy score value (OS –2.1 and –1.1, respectively). The results demonstrated that combining two pharmacophores with known redox properties can produce potent compounds in both directions, with the antioxidative and the prooxidative characteristics.Поремећај редокс баланса у организму може узроковати оксидативни стрес, који је окидач за настанак многих болести. Антиоксиданси снижавају ниво оксидујућих једи- њења у медијуму у коме се налазе, док прооксиданси делују супротно и као такви могу наћи примену у терапији канцера. У овом истраживању, испитиване су антиоксидативне и прооксидативне особине серије азолил-лактона у хуманом серуму као биолошком матриксу. Антиоксидативне особине су представљене помоћу окси скорова (ОS), а испи- тивано је и понашање ових једињења у условима индукованог оксидативног стреса нас- талог додатком терц-бутил-хидропероксида као спољног прооксиданса. Резултати су показали да сумпорни дериват, 4-бензимидазолил кумарин 5 има најизраженије анти- оксидативне особине (ОS –2,2), док халогеновани деривати пиразолил-кумарина 7 и 8 реагују као прооксиданси (ОS 2,7 и 2,0). Утицају додатог прооксиданса се најбоље опиру једињења 7 и 8. Испитивани деривати изокумарина и фталида такође показују проокси- дативне особине, док се оксидативном стресу најбоље опиру азолил-изокумарини (ОS < 0)

Imidazolone derivatives synthesis promoted by 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)

Imidazoloni 2 pokazuju različita zanimljiva svojstva u biologiji, farmakologiji i fotohemiji.1,2 Razvijena je blaga i efikasna intramolekulska ciklizacija diamidnih jedinjenja 1, dobijenih Ugijevom reakcijom, koja dovodi do nastanka derivata imidazolona. Ovom transformacijom se dobijaju proizvodi u dobrim prinosima u kratkom reakcionom vremenuImidazolones 2 exhibit a variety of interesting properties in biology, pharmacology and photochemistry.1,2 Mild and efficient intramolecular cyclization of diamide compounds, obtained by the Ugi reaction, leading to imidazolone derivatives has been developed. The transformation affords the products in good yields in a short reaction time.Fifth Conference of Young Chemists of Serbia. September 29-30. 2017. Belgrade, Serbi

Synthesis of substituted allyl acetates from heterocyclic dienes by a Pd-promoted arylation-acetoxylation cascade

Pd-catalysed arylation-acetoxylation cascade, a previously reported methodology, was applied in the functionalisation of unsymmetrical dienes. Both explored classes of compounds, isoquinoline and ss-carboline-derived dienes, afforded single regioisomers. Although further improvements of the process are necessary, primarily due to lower yields, the described functionalisation of the studied compounds might be useful in the synthesis of emetine and related naturally occurring compounds

Sequential reaction of organometallics in synthesis of fused pyrrole derivatives

Kondenzovani piroli ulaze u sastav mnogih prirodnih proizvoda i biološki aktivnih jedinjenja.1,2 U ovoj studiji prikazana je reakciona sekvenca koja omogućuje dobijanje različitih pirolizinona, kondenzovanih derivata pirola i ciklopentanona, primenom hemije organometala. Adicijom vinilmagnezijum bromida na N-alilovane imide, zatvaranjem prstena olefinskom metatezom koje je praćeno dehidratacijom i aromatizacijom moguće je dobiti različite pirolizinone u dobrom prinosuPyrrole based fused heterocyclic compounds are widespread in various natural products and bioactive compounds. In this report we describe the reaction sequence for synthesis of various pyrrolizinone derivatives, utilising the chemistry of organometallic compounds. Addition of vinylmagnesium bromide to N-allyl imides, followed by RCM reaction, dehydration and aromatisation, pyrrolizinones were obtained in good yields