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Predškolska ustanova je prva vaspitno-obrazovna institucija u celovitom sistemu vaspitanja i obrazovanja deteta. U najranijoj fazi svoga razvoja, dete dobija različite vidove podrške upravo u vrtiću, odnosno u vaspitnoj grupi kojom koordinira vaspitač. Međutim, predškolska ustanova treba da pruži mogućnost za razvojne kompetencije, kako dece tipičnog razvoja, tako i dece kojima je neophodna dodatna pomoć i podrška u razvoju. Dodatni vidovi podrške deci sa smetnjama u razvoju iziskuju određene uslove za rad, zatim pripremu i planiranje, kao i kompetentnost vaspitača. Boljem razumevanju problematike i stručnom radu vaspitača doprinose, pre svega njegovi pozitivni stavovi prema inkluzivnom radu, motivacija za rad, osobine njegove ličnosti, kao i njegova potreba za permanentnim razvojem i usavršavanjem različitih vidova kompetentnosti, socijalno-emocionalne, kognitivne i dr. Ispravna procena i psihološko-pedagoški takt vaspitača da kreira socijalno-emocionalnu atmosferu u grupi u kojoj će doživljaj zadovljstva boravkom u njoj,jednako biti prisutan kod sve dece, imperativ su u inkluzivnom radu vaspitača u okviru predškolske ustanove., Kindergarten institution is the first educational institution within the entire system of a child’s education. During the earliest stage of development, a child is provided with various aspects of support in kindergarten, or, more exactly, in the group coordinated by the kindergarten teacher. However, a kindergarten institution is there to offer the possibility of developmental competence to both the children of typical development, and those in need of additional help and support in their development. Additional ways of supporting children with developmental disorders require specific working conditions, preparation and planning, and the teacher’s competence likewise. Factors that contribute to a kindergarten teacher’s better understanding and professionalism in work, are positive attitude towards inclusion work, motivation for work, personality characteristics, and the need for permanent development and professional improvement in various aspects of competence, social-emotional, cognitive, etc.Properly assessing and being tactful in psychological and pedagogical approach in order to create such social and emotional atmosphere in the group that all the children will be equally pleased to be part of the group, is an imperative in kindergarten teacher’s inclusion work within a kindergarten institution.

Predškolska ustanova je prva vaspitno-obrazovna institucija u celovitom sistemu vaspitanja i obrazovanja deteta. U najranijoj fazi svoga razvoja, dete dobija različite vidove podrške upravo u vrtiću, odnosno u vaspitnoj grupi kojom koordinira vaspitač. Međutim, predškolska ustanova treba da pruži mogućnost za razvojne kompetencije, kako dece tipičnog razvoja, tako i dece kojima je neophodna dodatna pomoć i podrška u razvoju. Dodatni vidovi podrške deci sa smetnjama u razvoju iziskuju određene uslove za rad, zatim pripremu i planiranje, kao i kompetentnost vaspitača. Boljem razumevanju problematike i stručnom radu vaspitača doprinose, pre svega njegovi pozitivni stavovi prema inkluzivnom radu, motivacija za rad, osobine njegove ličnosti, kao i njegova potreba za permanentnim razvojem i usavršavanjem različitih vidova kompetentnosti, socijalno-emocionalne, kognitivne i dr. Ispravna procena i psihološko-pedagoški takt vaspitača da kreira socijalno-emocionalnu atmosferu u grupi u kojoj će doživljaj zadovljstva boravkom u njoj,jednako biti prisutan kod sve dece, imperativ su u inkluzivnom radu vaspitača u okviru predškolske ustanove., Kindergarten institution is the first educational institution within the entire system of a child’s education. During the earliest stage of development, a child is provided with various aspects of support in kindergarten, or, more exactly, in the group coordinated by the kindergarten teacher. However, a kindergarten institution is there to offer the possibility of developmental competence to both the children of typical development, and those in need of additional help and support in their development. Additional ways of supporting children with developmental disorders require specific working conditions, preparation and planning, and the teacher’s competence likewise. Factors that contribute to a kindergarten teacher’s better understanding and professionalism in work, are positive attitude towards inclusion work, motivation for work, personality characteristics, and the need for permanent development and professional improvement in various aspects of competence, social-emotional, cognitive, etc.Properly assessing and being tactful in psychological and pedagogical approach in order to create such social and emotional atmosphere in the group that all the children will be equally pleased to be part of the group, is an imperative in kindergarten teacher’s inclusion work within a kindergarten institution.

Low targeting efficiency and fast metabolism of antineoplastic drugs are hindrances to effective chemotherapies and there is an ongoing search for better drugs, but also better carriers. Steroid derivatives, 3β-hydroxy-16-hydroxymino-androst-5-en-17-one (A) and 3β,17β-dihydroxy-16-hydroxymino-androst-5-ene (B) as cancer growth inhibitors were chemically synthesized and captured in a carrier composed of hydroxyapatite (HAp) nanoparticles coated with chitosan oligosaccharide lactate (ChOLS). The only difference between the two derivatives is that A has a carbonyl group at the C17 position of the five-membered ring and B has a hydroxyl. This small difference in the structure resulted not only in different physicochemical properties of the A- and B-loaded HAp/ChOSL, but also in different biological activities. The morphology of drug-loaded HAp/ChOSL particles was spherical, but the size depended on the drug identity: d50 = 138 nm for A-loaded HAp/ChOSL and d50 = 223 nm for B-loaded HAp/ChOSL. Cell-selective toxicity was tested against human breast carcinoma (MCF7 and MDA-MB-231), human lung carcinoma (A549) and human lung fibroblasts (MRC-5). The small selectivity of pure derivatives A and B toward breast cancer cells became drastically increased when they were delivered using HAp/ChOSL particles. Whereas the ratio of the cytotoxicity imposed onto breast cancer cells and the cytotoxicity imposed onto healthy MRC-5 fibroblasts ranged from 1.5 to 1.7 for pure A and from 1.5 to 2.3 for pure derivative B depending on the concentration, it increased to 5.4 for A-loaded HAp/ChOSL and 5.1 for B-loaded HAp/ChOSL. FACS analysis demonstrated poor uptake of HAp/ChOSL particles by MCF7 cells, suggesting that the drug release occurs extracellularly. The augmented activity of the drugs was most likely due to sustained release, although the favorable positive charge of the carrier, allowing it to adhere to the negatively charged plasma membrane and release the drugs steadily and direc

The applicative potential of synthetic calcium phosphates, especially hydroxyapatite (HAp), has become intensely broadened in the past 10 years, from bone tissue engineering to multiple other fields of biomedicine. Hybrid systems based on nano hydroxyapatites (HAp) are the subject of numerous studies in preventive and regenerative medicine. HAp nanoparticles coated with bioresorbable polymers have been successfully used as fillers, carriers of antibiotics, vitamins and stem cells in bone tissue engineering, etc. In this study we utilize an emulsification process and freeze drying to load the hybrid system made of nano HAp particles coated with chitosan oligosaccharide lactate (ChOSL) with two different but similar steroid derivatives: 3β-hydroxy- 16-hydroxymino-androst-5-ene-17-one (A), C19H27NO3 and 3β, 17β-dihydroxy-16-hydroxyminoandrost- 5-ene (B), C19H29NO3. The cell-selective toxicity of HAp particles coated with of A- or B-loaded ChOSL was examined simultaneously on the following cell lines: human breast carcinoma (MCF-7, MDA-MB-231), human lung carcinoma (A549) and human lung fibroblasts (MRC-5), using dye exclusion (DET) and MTT assays. 1H NMR, 13C NMR and high-resolution time-of-flight mass spectrometry (MS) techniques confirmed the intact structure of the derivatives A or B. FT-IR, XRD, DTA, TGA and DSC techniques confirmed the drug loading process of steroide (A or B) in core–shell particles based on nano hydroxyapatite. Atomic force microscopy and particle size analyses were used to confirm that the particles were spherical with sizes between 80 and 240 nm. The measured values of electrokinetic parameters (zeta potential, electrophoretic mobility and conductivity) were significantly different for the steroid free carrier (HAp/ChOLS) and A- or B-loaded ChOSL. The value of the topological molecular polar surface area (TPSA, the sum of the surfaces of polar atoms and groups in the molecule), were also different for drug free carrier and A- or BHAp/ ChOLS. H

У раду су истражене релације између садржаја у наставним програмима и уџбеницима наставе природе и друштва у односу на ставове учитеља различите етничке припадности. У склопу тако реализованог истраживања, утврђена је структура садржаја у програмима разредне наставе, који се односе на област природе и друштва у Србији, Хрватској и Босни и Херцеговини. Након тога, анализирани су ставови учитеља о другим (суседним) народима, не само у паралели са наставним садржајима и коришћеним уџбеницима, већ и на нивоу њихове кореспонденције са практично коришћеним наставним методама и дидактичко-методичким принципима. Посебна истраживачка пажња посвећена је поступцима, који пружају могућност учитељима да у важнијим аспектима доживљаја националног идентитета формирају став о одређеним садржајима наставе природе и друштва везаним за свој народ и друге народе из региона. Овако постављен дијагностички приступ био је неопходан, нарочито због тога што је омогућио да се идентификују важнији елементи на пољу мишљења и социјалног опажања, на шта ставови директно утичу, а у сврху побољшања васпитно-образовног рада са ученицима. Преиспитани су односи и међусобно разумевање култура српског, хрватског и бошњачког народа. Циљ емпиријског дела био је да се утврде ставови и утицаји учитеља различите етничке припадности према реализацији друштвених садржаја наставе природе и друштва. Резултатима истраживања констатовано је да етничка припадност учитеља не утиче на реализацију садржаја наставе природе и друштва. Резултати говоре и у прилог основне претпоставке истраживања да се учитељи, припадници сваког испитиваног ентитета, статистички значајно разликују у ставовима иначину реализације друштвених садржаја наставе природе и друштва. Закључује се да извор за ослобађање од многих предрасуда, пре свега етничких, треба тражити у адекватном васпитнообразовном процесу, у коме су главни актери васпитања и образовања учитељи., U radu su istražene relacije između sadržaja u nastavnim programima i udžbenicima nastave prirode i društva u odnosu na stavove učitelja različite etničke pripadnosti. U sklopu tako realizovanog istraživanja, utvrđena je struktura sadržaja u programima razredne nastave, koji se odnose na oblast prirode i društva u Srbiji, Hrvatskoj i Bosni i Hercegovini. Nakon toga, analizirani su stavovi učitelja o drugim (susednim) narodima, ne samo u paraleli sa nastavnim sadržajima i korišćenim udžbenicima, već i na nivou njihove korespondencije sa praktično korišćenim nastavnim metodama i didaktičko-metodičkim principima. Posebna istraživačka pažnja posvećena je postupcima, koji pružaju mogućnost učiteljima da u važnijim aspektima doživljaja nacionalnog identiteta formiraju stav o određenim sadržajima nastave prirode i društva vezanim za svoj narod i druge narode iz regiona. Ovako postavljen dijagnostički pristup bio je neophodan, naročito zbog toga što je omogućio da se identifikuju važniji elementi na polju mišljenja i socijalnog opažanja, na šta stavovi direktno utiču, a u svrhu poboljšanja vaspitno-obrazovnog rada sa učenicima. Preispitani su odnosi i međusobno razumevanje kultura srpskog, hrvatskog i bošnjačkog naroda. Cilj empirijskog dela bio je da se utvrde stavovi i uticaji učitelja različite etničke pripadnosti prema realizaciji društvenih sadržaja nastave prirode i društva. Rezultatima istraživanja konstatovano je da etnička pripadnost učitelja ne utiče na realizaciju sadržaja nastave prirode i društva. Rezultati govore i u prilog osnovne pretpostavke istraživanja da se učitelji, pripadnici svakog ispitivanog entiteta, statistički značajno razlikuju u stavovima inačinu realizacije društvenih sadržaja nastave prirode i društva. Zaključuje se da izvor za oslobađanje od mnogih predrasuda, pre svega etničkih, treba tražiti u adekvatnom vaspitnoobrazovnom procesu, u kome su glavni akteri vaspitanja i obrazovanja učitelji., The paper examines the relations between the content in curricula and the content in textbooks of teaching natural and social studies with respect to the attitudes of the teachers of different ethnic backgrounds. Within the framework of this research the content structure in the class teaching curricula, which is related to the field of natural and social studies in Serbia, Croatia and Bosnia and Herzegovina, was determined. After that, the teachers’ attitudes were analyzed, not only in parallel with the teaching contents and the textbooks used, but also at the level of their correspondence with practically used teaching methods and didactical-methodical principles. Special research attention is devoted to the procedures that provide teachers with the opportunity to formulate a view on certain contents of teaching natural and social studies related to their nation and other nations from the region in the most important aspects of the experience of national identity. The diagnostic approach outlined in this way would be necessary, especially because it enables the identification of more important elements in the field of thinking and social perception, which are directly influenced by the attitudes, and with the aim of improving educational work with students. Relations and mutual understanding of the cultures of the Serbian, Croatian and Bosniak peoples are reviewed. The aim of the empirical work is to determine the attitudes and influences of teachers of different ethnic backgrounds on the realization of social contents of teaching natural and social studies. It has been found that the ethnicity of a teacher does not influence the realization of the content of teaching natural and social studies. The results also speak in favour of the basic assumption of the research, which is that the teachers, the members of each examined ethniciity, significantly differ in the attitudes and the manners of realization of social contents of teaching natural and social studies fro

U ovom radu ostvarene su sinteze C19-derivatizovanih steroidnih D-homo laktona. Takođe, sintetisani su i 5,6-halogeni derivati, 5,6-supstituisani kiseonični derivati, kao i 6,19-epoksi steroidi. Za sva sintetisana jedinjenja je utvrđen antitumorski potencijal ispitivanjem njihove oralne bioraspoloživosti, antiproliferativne aktivnosti na šest ćelijskih linija kancera, vezivanja za odabrane steroidne receptore i inhibitorne aktivnosti na enzim AKR1C3., In this paper, a synthesis of C19-derivatized steroidal D-homo lactones has been conducted. 5,6-Halogen derivatives, 5,6-substituted oxygen derivatives and 6,19-epoxy steroids were also synthesized. Antitumor potential was determined for all synthesized compounds by examining their oral bioavailability, antiproliferative activity on six cancer cell lines, binding to selected steroid receptors and inhibitor activity on the AKR1C3 enzyme.

Low targeting efficiency and fast metabolism of antineoplastic drugs are hindrances to effective chemotherapies and there is an ongoing search for better drugs, but also better carriers. Steroid derivatives, 3-hydroxy-16-hydroxymino-androst-5-en-17-one (A) and 3,17-dihydroxy-16-hydroxymino-androst-5-ene (B) as cancer growth inhibitors were chemically synthesized and captured in a carrier composed of hydroxyapatite (HAp) nanoparticles coated with chitosan oligosaccharide lactate (ChOLS). The only difference between the two derivatives is that A has a carbonyl group at the C17 position of the five-membered ring and B has a hydroxyl. This small difference in the structure resulted not only in different physicochemical properties of the A- and B-loaded HAp/ChOSL, but also in different biological activities. The morphology of drug-loaded HAp/ChOSL particles was spherical, but the size depended on the drug identity: d(50) = 138 nm for A-loaded HAp/ChOSL and d(50) = 223 nm for B-loaded HAp/ChOSL. Cell-selective toxicity was tested against human breast carcinoma (MCF7 and MDA-MB-231), human lung carcinoma (A549) and human lung fibroblasts (MRC-5). The small selectivity of pure derivatives A and B toward breast cancer cells became drastically increased when they were delivered using HAp/ChOSL particles. Whereas the ratio of the cytotoxicity imposed onto breast cancer cells and the cytotoxicity imposed onto healthy MRC-5 fibroblasts ranged from 1.5 to 1.7 for pure A and from 1.5 to 2.3 for pure derivative B depending on the concentration, it increased to 5.4 for A-loaded HAp/ChOSL and 5.1 for B-loaded HAp/ChOSL. FACS analysis demonstrated poor uptake of HAp/ChOSL particles by MCF7 cells, suggesting that the drug release occurs extracellularly. The augmented activity of the drugs was most likely due to sustained release, although the favorable positive charge of the carrier, allowing it to adhere to the negatively charged plasma membrane and release the drugs steadily and dire

Low targeting efficiency and fast metabolism of antineoplastic drugs are hindrances to effective chemotherapies and there is an ongoing search for better drugs, but also better carriers. Steroid derivatives, 3-hydroxy-16-hydroxymino-androst-5-en-17-one (A) and 3,17-dihydroxy-16-hydroxymino-androst-5-ene (B) as cancer growth inhibitors were chemically synthesized and captured in a carrier composed of hydroxyapatite (HAp) nanoparticles coated with chitosan oligosaccharide lactate (ChOLS). The only difference between the two derivatives is that A has a carbonyl group at the C17 position of the five-membered ring and B has a hydroxyl. This small difference in the structure resulted not only in different physicochemical properties of the A- and B-loaded HAp/ChOSL, but also in different biological activities. The morphology of drug-loaded HAp/ChOSL particles was spherical, but the size depended on the drug identity: d(50) = 138 nm for A-loaded HAp/ChOSL and d(50) = 223 nm for B-loaded HAp/ChOSL. Cell-selective toxicity was tested against human breast carcinoma (MCF7 and MDA-MB-231), human lung carcinoma (A549) and human lung fibroblasts (MRC-5). The small selectivity of pure derivatives A and B toward breast cancer cells became drastically increased when they were delivered using HAp/ChOSL particles. Whereas the ratio of the cytotoxicity imposed onto breast cancer cells and the cytotoxicity imposed onto healthy MRC-5 fibroblasts ranged from 1.5 to 1.7 for pure A and from 1.5 to 2.3 for pure derivative B depending on the concentration, it increased to 5.4 for A-loaded HAp/ChOSL and 5.1 for B-loaded HAp/ChOSL. FACS analysis demonstrated poor uptake of HAp/ChOSL particles by MCF7 cells, suggesting that the drug release occurs extracellularly. The augmented activity of the drugs was most likely due to sustained release, although the favorable positive charge of the carrier, allowing it to adhere to the negatively charged plasma membrane and release the drugs steadily and dire

Hybrid systems based on nano hydroxyapatites (HAp) are the subject of numerous studies in preventive and regenerative medicine. Special interests are directed towards the creation of a system based on HAp for use in a nano-oncology. The main objective of this research is directed towards the creation of a system with cytotoxic properties towards the cancer cells with the same time, minimum side effects. Carriers base on core shell of HAp/chitosan-poly(D,L)-lactide-coglycolide (PLGA) loaded with androstane-based cancer inhibitor could be seen as promising drug delivery platforms for selective cancer therapies. In this study we utilize an emulsification process and freeze drying to load the composite particles based on HAp nanocarrier, chitosane (Ch), PLGA and chitosan oligosaccharide lactate (ChOL) with 17β-hydroxy-17α-picolyl-androst-5-en-3β-acetate (A) and 3β,17β-dihydroxy-16-hydroxymino-androst-5-en (B), a chemotherapeutic derivatives of androstane. The picolyl androstane derivatives showed high potency in the cell inhibitors of hormone-dependent cancers (lung, prostate and colon cancer; adeno and cervix carcinoma; etc.). 1H NMR, 13C NMR and high-resolution time-of-flight mass spectrometry (MS) techniques confirmed the intact structure of the derivatives A and B. The thermogravimetric and differential thermal analysis (TGA, DTA) coupled with mass spectrometry was used to qualitatively confirm the drug loading process. FT-IR, XRD, AFM and DSC techniques have confirmed the success of androstane (A and B) loading process in core shell particles base on nano hydroxyapatite. All the synthesized particles were found to be spherical in shape with a uniform size distribution from d50=167 to d50=231 nm. Highly selective anticancer activity was noted towards the human lung carcinoma (A549) by A loaded HAp/Ch-PLGA and towards the human breast adenocarcinoma (MDA-MB-231) by B loaded HAp/ChOL. The obtained results of the DET and MTT tests were in agreement.

Hybrid systems based on nano hydroxyapatites (HAp) are the subject of numerous studies in preventive and regenerative medicine. Special interests are directed towards the creation of a system based on HAp for use in a nano-oncology. The main objective of this research is directed towards the creation of a system with cytotoxic properties towards the cancer cells with the same time, minimum side effects. Carriers base on core shell of HAp/chitosan-poly(D,L)-lactide-coglycolide (PLGA) loaded with androstane-based cancer inhibitor could be seen as promising drug delivery platforms for selective cancer therapies.In this study we utilize an emulsification process and freeze drying to load the composite particles based on HAp nanocarrier, chitosane (Ch), PLGA and chitosan oligosaccharide lactate (ChOL) with 17β-hydroxy-17α-picolyl-androst-5-en-3β-acetate (A) and 3β,17β-dihydroxy-16-hydroxymino-androst-5-en (B), a chemotherapeutic derivatives of androstane. The picolyl androstane derivatives showed high potency in the cell inhibitors of hormone-dependent cancers (lung, prostate and colon cancer; adeno and cervix carcinoma; etc.).1H NMR, 13C NMR and high-resolution time-of-flight mass spectrometry (MS) techniques confirmed the intact structure of the derivatives A and B. The thermogravimetric and differential thermal analysis (TGA, DTA) coupled with mass spectrometry was used to qualitatively confirm the drug loading process. FT-IR, XRD, AFM and DSC techniques have confirmed the success of androstane (A and B) loading process in core shell particles base on nano hydroxyapatite. All the synthesized particles were found to be spherical in shape with a uniform size distribution from d50=167 to d50=231 nm. Highly selective anticancer activity was noted towards the human lung carcinoma (A549) by A loaded HAp/Ch-PLGA and towards the human breast adenocarcinoma (MDA-MB-231) by B loaded HAp/ChOL. The obtained results of the DET and MTT tests were in agreement.

Da bi se dobio sistem surfaktanata željenih osobina moguće je hemijski modifikovati već postojeće molekule površinski aktivnih supstanci, a druga mogućnost je konstrukcija binarnih smeša surfaktanata. U farmaceutskoj i prehrambenoj industriji uveliko se primenjuju binarne smeše površinski aktivnih molekula. Ukoliko je binarna mešovita micela termodinamički stabilnija od hipotetičke idealne binarne mešovite micele, onda je kritična micelarna koncentracija binarne smeše surfaktanata niža čak i od hidrofobnije gradivne jedinice mešovite micele, što znači da je za isti efekat površinske aktivnosti potrebna manja količina binarne smeše nego čistog surfaktanta. Različite gradivne jedinice binarne micele u micelarnoj pseudofazi mogu formirati specifične regije koje mogu vezivati lekove određenih strukturnih karakteristika. Pogodno je da jedna gradivna jedinica bude krute konformacije, npr. soli žučnih kiselina, dok je druga gradivna jedinica konformaciono pokretljiva (ugljovodonični nizovi iznad C10). Na taj način se povećava zapremina hidrofobne micelarne faze u odnosu na zapreminu hidrofobne micelarne faze monokomponentne micelle konformaciono krutog surfaktanta, što povećava solubilizacioni kapacitet mešovite micele u odnosu na monokomponentnu micelu krutog surfaktanta. Povećanjem dužine ugljovodoničnog niza konformaciono pokretnog surfaktanta povećava se stepen unutrašnje pokretljivosti u hidrofobnom domenu mešovite micele, što takođe povećava verovatnoću prihvatanja molekula gosta. Micelarni sistemi, kako monokomponentnih micela tako i binarnih mešovitih micela dodatno se mogu termodinamički stabilizovati povećanjem jonske jačine rastvora. Za hidrataciju katjona troše se molekuli vode iz sistema, što povećava efekat desolvatizacije hidrofobne površine surfaktanata, pa se zbog toga pospešuje samoasocijacija., To obtain the surfactant system with the desired properties it is possible to chemically modify existing molecules of surface active agents. The other possibility is the construction of binary mixtures of surfactants. Binary mixtures of surface active molecules are widely used In the pharmaceutical and food industry. If the binary mixture micelle is more thermodynamically stable than the hypothetical ideal binary mixed micelle, then the critical micellar concentration (CMC) of the binary mixture of surfactants is even lower than the CMC of the more hydrophobic building block of the binary mixture. That means that for the same effect of surface activity less the amount of the binary mixture than the pure surfactants is required. The different building blocks of binary micelles in micelar pseudophase can form specific regions that can bind drugs of certain structural characteristics. It is suitable that one building block is of a rigid conformation, i.e. bile acid salts, while the second building block is of a flexible conformation (above C10 hydrocarbon arrays). In this way the volume of the hydrophobic micellar phase is increased in relation to the volume of the hydrophobic micellar phase of the monocomponent micelles of conformationally rigid surfactant, which increases the capacity of solubilisation of the mixed micelles, compared to the mono-component surfactant micelle of the rigid conformation. By increasing the length of the hydrocarbon array of the the conformational flexible surfactant, the degree of internal mobility in the hydrophobic domain of mixed micelles is also increased, which also increases the likelihood of acceptance of guest molecules. Micellar systems, of both monocomponent micelles and mixed micelles can be additionally thermodynamically stabilized by increasing the ionic strength of the solution. The hydration of cations uses the molecules of water from the system, which increases the effect of desolvatisation of the hydrophobic surface of th

Uloga micela u razvoju farmaceutskih oblika zasniva se na njihovom potencijalu da kao transportni sistemi povećaju bioraspoloživost lekovite supstance i unaprede njen farmakokinetski profil. Micele mogu da modifikuju propustljivost biološkuh membrana, omoguće kontrolisano oslobađanje lekovite supstance iz farmaceutskog oblika, stabilizuju lekovitu supstancu, itd. Kombinovanje različitih surfaktanata kao gradivih jedinica omogućava konstruisanje micela sa poželjnim fizičko-hemijskim karakteristikama. Takođe, mešovite micele između čijih gradivnih jedinica postoje sinergističke interakcije se formiraju na nižim koncentracijama surfaktanata u poređenju sa monokomponentnim micelama. U doktorskoj disertaciji je ispitana termodinamička stabilnost binarnih mešovitih micela Brij S10 i Brij S20 surfaktanata sa polisorbatom 20, polisorbatom 60 i polisorbatom 80 kao kosurfaktantima. Analiziran je uticaj građe odabranih nejonskih surfaktanata na fizičko-hemijske parametre i stabilnost njihovih mešovitih micela. Vrednosti kritične micelarne koncentracije su dobijene spektrofluorimetrijskim merenjima. Da bi se analizirao uticaj temperature na termodinamičku stabilnost micela, merenja su vršena na sledećim temperaturama: 273.15 K, 283.15 K, 293.15 K, 303.15 K i 313.15 K. Rezultati su tumačeni sa aspekta teorije regularnih rastvora (regular solution theory – RST), uz primenu Porterove jednačine. Na osnovu rezultata istraživanja, predloženi su modeli monokomponentnih i binarnih mešovitih micela. Utvrđeno je da u svim analiziranim binarnim mešovitim sistemima postoji dodatna entropija. Može se doneti zaključak da pretpostavka RST o isključivo entalpijskoj prirodi dodatne Gibsove energije nije primenljiva na ispitivane binarne sisteme. Utvrđeno je da postojanje razlike u dužini hidrofobnih segmenata monomera dodatno stabilizuje mešovitu micelu. Sa porastom temperature, ovaj stabilizacioni efekat entropijskog porekla postaje izraženiji. Prisustvo dvostruke veze u ugljovodoničnom lancu, The role of the micelles in pharmaceutical formulation lies in their ability to, when used as drug delivery systems, increase the bioavailability of the drug and enhance its pharmacokinetic profile. Micelles may modify the permeability of biomembranes, enable controlled release from drug delivery systems, stabilize the drug, etc. By combining different surfactants as building units it is possible to engineer micelles with favorable physicochemical characteristics. Also, the mixed micelles between whose building units synergistic interactions exist are formed on lower concentrations of surfactants in comparison to single-component micelles. In the doctoral dissertation the thermodynamic stability of binary mixed micelles built of Brij S10 and Brij S20 with polysorbate 20, polysorbate 60 and polysorbate 80 as co-surfactants is examined. The influence of the structure of selected nonionic surfactants on physicochemical parameters and the stability of their mixed micelles is analyzed. Critical micelle concentration values were obtained by spectrofluorimetric measurements. In order to analyze the influence of the temperature on the micelles’ thermodynamic stability, measurements were conducted on following temperatures: 273.15 K, 283.15 K, 293.15 K, 303.15 K and 313.15 K. Obtained results were studied using regular solution theory (RST) and Porter’s equation. Based on the research results, models of both single-component and binary mixed micelles are introduced. It is deduced that in all analyzed binary mixed systems the excess entropy exists. A conclusion can be made that the assumption of RST regarding solely enthalpic nature of the excess Gibbs energy is not applicable to investigated binary systems. The difference in the length of the hydrophobic segments of monomers additionally stabilizes the mixed micelle. With the increase in the temperature, this stabilizing effect of the entropic nature is more noticeable. The existence of the double bond in polysorbate 80 hydr

U disertaciji je ostvarena sineza amida i oksazolina žučnih kiselina, kao i njihovih alkil i alkilidenskih derivata polazeći od holne kiseline. Ipitano je ponašanje različitih okso derivata žučnih kiselina u uslovima Grignard-ove i Wittig-ove reakcije. Ispitana je biološka aktivnost odabranih sintetizovanih jedinjenja, Synhesis of bile acid amide and oxazoline derivatives, and their alkyl and alkylidene derivatives was accomplished starting from cholic acid. Also, chemical behavior of different bile acid oxo derivatives in Grignard and Wittig reaction was investigated. Biological activity of selected synthesized compounds was evaluated.

U disertaciji je ostvarena sineza amida i oksazolina žučnih kiselina, kao i njihovih alkil i alkilidenskih derivata polazeći od holne kiseline. Ipitano je ponašanje različitih okso derivata žučnih kiselina u uslovima Grignard-ove i Wittig-ove reakcije. Ispitana je biološka aktivnost odabranih sintetizovanih jedinjenja, Synhesis of bile acid amide and oxazoline derivatives, and their alkyl and alkylidene derivatives was accomplished starting from cholic acid. Also, chemical behavior of different bile acid oxo derivatives in Grignard and Wittig reaction was investigated. Biological activity of selected synthesized compounds was evaluated.

U radu je ispitan uticaj odabranih modifikovanih steroida na proliferaciju ćelija humanih malignih tumora i zdravih ćelija, a zatim njihov uticaj na modifikaciju ćelijskog ciklusa, indukovanje apoptoze i genetskih oštećenja u tumorskim ćelijama najsenzitivnijim na ova jedinjenja (MDA-MB-231 ćelijska linija humanog adenokarcinoma dojke, ER-). Ispitana je in vitro citotoksičnost odabranih steroidnih derivata prema ćelijskim linijama MCF-7, MDA-MB-231, PC3, HeLa, HT-29, MRC-5, K562 i A549, i proučavan ćelijski mehanizam koji je u osnovi uočenog antiproliferativnog efekta svakog od ispitivanih derivata. Sva ispitivana jedinjenja indukuju apoptozu MDA-MB-231 ćelija, na različite načine i sa različitim potencijalom. Genotoksikološka studija upotpunjuje rezultate proučavanja efekta ispitivanih steroidnih jedinjenja na biološke sisteme, ukazujući na izostanak genotoksičnosti ovih jedinjenja i njihov biomedicinski potencijal., In this work the effect of selected modified steroids on proliferation of human malignant tumor and healthy cells, as well as their impact on the modification of cell cycle arrest, induction of apoptosis and genetic defects in tumor cells most sensitive to these compounds (MDA-MB-231 cell line of human breast adenocarcinoma, ER-) were examined. We examined the in vitro cytotoxicity of selected steroidal derivatives towards MCF-7, MDA-MB-231, PC-3, HeLa, HT-29, MRC-5, K562 and A549 cell lines, and studied the cellular mechanism that is underlying the antiproliferative activity expressed by these steroidal derivatives. All tested compounds induced apoptosis of MDA-MB-231 cells, in different ways and with different potential. Genotoxicological study complements the results of the study of the effect of tested steroidal compounds on biological systems, pointing out the lack of genotoxicity of these compounds and therefore their biomedical potential.

Binarne mešovite micele su značajne u farmaceutsko-farmakološkim primenama, u kojima lek kao površinska aktivna supstanca može da bude gradivna jedinica binarne micelle (promena bioraspoloživosti, mehanizam resorpcije itd.). Takođe su važne i mešovite micele kod kojih su gradivne jedinice biosurfaktanti (biokompatibilni solubilizatori lekova). U kozmetičkoj, prehrambenoj i industriji detergenata mešovite micele su uveliko zastupljene. Važno je nalaženje binarnih sistema surfaktanata koji u mešovitim micelama poseduju sinergističko međudelovanje (negativna vrednost interakcionog parametra). Takva binarna smeša surfaktanata ima nižu vrednost kritične micelarne koncentracije od hidrofobnije komponente smeše. U prvom delu rada je ispitivan uticaj dužine hidrofobnog segmenta homolognih Tween-ova iz mešovitih micela sa Triton-om X100 na interakcioni parametra ( i, j β ) i dodatnu Gibbs-ovu energiju (GE ), takođe ispitivao se i uticaj temperature na stabilnost proučavanih mešovitih micela (273,15-328,115 K). Kritične micelarne koncentracije čistih surfaktanata i njihovih binarnih smeša su određeni spektrofluorometrijski uz primenu pirena kao probnog molekula. Nađeno je da na svakoj ispitivanoj temperaturi povećanje dužine zasićenog alifatičnog niza polisorbata povećava stabilnost mešovite micele ( , 0 i j β < i GE < 0 ) u odnosu na idealnu mešovitu micelu. Prisustvo C9 dvostruke veze u ostatku oleinske kiseline Tween-a 80 umanjuje sinergistički efekat ovog polisorbata u odnosu na Tween 60, koji ima hidrofobni segment sa istim brojem C atoma, ali bez olefinske veze. Dodatna slobodna entalpija ispod temperature 298.15 K određena je entropijskim doprinosem, a iznad 298.15 K entalpijskim doprinosom. U drugom delu rada ispitivane su binarne smeše surfaktanata Tween 85/Triton X100 i Tween 85/Triton X165 u vodenom rastvoru u intervalu temperature od 273.15 K do 323.15 K. Pri temperaturama od 273.15 K i 283.15 K između različitih gradivnih jedinica binarnih mešovitih micela postoj, Binary micelles are important in pharmaceutical-pharmacological applications, in which drug as surface active substance can be building unit of binary micelle (influencing bioavailability change, change of resorption mechanism etc.). Mixed micelles in which building units are biosurfactants (biocompatible drug solubilizers) are also important. In cosmetics, food and detergent industry mixed micelles are widely present. It is important to find binary surfactant systems having synergistic interactions (negative value of interaction parameter). That binary surfactant mixture has lower critical micelle concentration value than more hydrophobic component of the mixture. In the first parth of this work, influence of hydrophobic segment length of homologues Tweens in mixed micelles with Triton X-100 on the interaction parameter value ( i, j β ) and an excess Gibbs energy (GE ) was investigated. Also, influence of temperature on the stability of investigated mixed micelles has been investigated (273.15-328.15 K). Critical micelle concentration values of pure surfactants and their binary mixtures were determined spectrofluorimetrically using pyrene as a probe molecule. It was found for every investigated temperature that increase in length of saturated aliphatic side chain of a polisorbate increases the stability of investigated mixed micelles (β < and GE < 0 ) compared to ideal mixed micelles. Presence of the C9 double bond in oleic acid residue of Tween 80 reduces synergistic effect of this polysorbate compared to Tween 60 which contains hydrophobic segment with the same number of C atoms but without olefin bond. Excess free enthalpy below the 298.15 K is determined with entropic contribution, but above 298.15 K with enthalpic contribution. In the second parth of this work, binary surfactant mixtures of Tween 85/Triton X100 and Tween 85/Triton X165 have been investigated in water solution in the temperature range from 273.15 K to 323.15 K. At the temperatures of 273.15 K a

U radu je ispitan uticaj odabranih modifikovanih steroida na proliferaciju ćelija humanih malignih tumora i zdravih ćelija, a zatim njihov uticaj na modifikaciju ćelijskog ciklusa, indukovanje apoptoze i genetskih oštećenja u tumorskim ćelijama najsenzitivnijim na ova jedinjenja (MDA-MB-231 ćelijska linija humanog adenokarcinoma dojke, ER-). Ispitana je in vitro citotoksičnost odabranih steroidnih derivata prema ćelijskim linijama MCF-7, MDA-MB-231, PC3, HeLa, HT-29, MRC-5, K562 i A549, i proučavan ćelijski mehanizam koji je u osnovi uočenog antiproliferativnog efekta svakog od ispitivanih derivata. Sva ispitivana jedinjenja indukuju apoptozu MDA-MB-231 ćelija, na različite načine i sa različitim potencijalom. Genotoksikološka studija upotpunjuje rezultate proučavanja efekta ispitivanih steroidnih jedinjenja na biološke sisteme, ukazujući na izostanak genotoksičnosti ovih jedinjenja i njihov biomedicinski potencijal., In this work the effect of selected modified steroids on proliferation of human malignant tumor and healthy cells, as well as their impact on the modification of cell cycle arrest, induction of apoptosis and genetic defects in tumor cells most sensitive to these compounds (MDA-MB-231 cell line of human breast adenocarcinoma, ER-) were examined. We examined the in vitro cytotoxicity of selected steroidal derivatives towards MCF-7, MDA-MB-231, PC-3, HeLa, HT-29, MRC-5, K562 and A549 cell lines, and studied the cellular mechanism that is underlying the antiproliferative activity expressed by these steroidal derivatives. All tested compounds induced apoptosis of MDA-MB-231 cells, in different ways and with different potential. Genotoxicological study complements the results of the study of the effect of tested steroidal compounds on biological systems, pointing out the lack of genotoxicity of these compounds and therefore their biomedical potential.

U radu su ostvarene višefazne sinteze većeg broja analoga prirodnih stiril-laktona (+)-goniofufurona i 7-epi-(+)-goniofufurona polazeći iz D-glukoze. Ispitana je in vitro citotoksičnost sintetizovanih analoga prema devet malignih i jednoj zdravoj ćelijskoj liniji. Uspostavljeni su korelacioni odnosi izmedju strukture i antiproliferati vne aktivnosti sintetizovanih proizvoda, pored toga uradjeni su i dodatni biološki testovi koji se odnose na dokazivanje mehanizma citotoksičnog dejstva pomenutih stiril-laktona i analoga., Multistep synthesis of a number of natural styryl lactones goniofufurone and 7-epi-goniofufurone analogues was achieved starting f rom D-glucose. In vitro cytotoxicity of newly synthetized analogues against nine human tumour cell lines and against a single normal cell line was evaluated. Structure-activity relationships were established for both natural products and analogues. Some additional biological tests related to the cell mechanisms underlying the cytotoxicity of the mentioned styryl lactones and analogues, were also carried out.

Surfaktanti imaju značajnu primenu u farmaciji i medicini. Ove supstance se primenjuju u farmakoterapiji, koriste se za solubilizaciju hidrofobnih lekova, a pojedina ispitivanja pokazuju da mogu unaprediti bioraspoloživost određenih aktivnih supstanci. U poslednje vreme se sve više pažnje posvećuje ispitivanju smeša surfaktanata, pošto je utvrđeno da sistemi dva ili više surfaktanta često pokazuju poželjnija svojstva od pojedinačnih surfaktanata za aplikaciju u farmaciji i medicini. U ovoj disertaciji su ispitivani binarni sistemi osam anjona žučnih kiselina i dva nejonska surfaktanta (polisorbat 40 i polisorbat 80). Ciljevi su određivanje vrednosti kritičnih micelarnih koncentracija ispitivanih smeša surfaktanta, utvrđivanje međudejstva između različitih surfaktanta u njihovim mešovitim micelama, kao i ispitivanje uticaja stukture ispitivanih surfaktanata na fizičko-hemijske karakteristike mešovitih micela. Rezultati pokazuju da ispitivane smeše imaju znatno niže vrednosti kritičnih micelarnih koncentracija od anjona žučnih kiselina. Smeše anjona žučnih kiselina i polisorbata 40 imaju manje vrednosti eksperimentalnih kritičnih micelarnih koncentracija, od izračunatih, idealnih, vrednosti, što ukazuje na postojanje sinergističkih interakcija u mešovitim micelama. Smeše anjona žučnih kiselina i polisorbata 80 imaju uglavnom veće vrednosti kritičnih micelarnih koncentracija od idealnih vrednosti, što može biti posledica postojanja antagonističkih interakcija između gradivnih jedinica mešovitih micela. Vrednosti interakcija, koje dovode do neidealnog ponašanja sistema surfaktanata, su određene računanjem vrednosti interakcionog parametra, β1,2, prema regular solution theory. Sistemi anjona žučnih kiselina i polisorbata 40 imaju negativne vrednosti interakcionog parametra, dok sistemi anjona žučnih kiselina i polisorbata 80 imaju uglavnom pozitivne vrednosti interakcionog parametra. Poređenjem fizičko-hemijskih parametara mešovitih micela je utvrđeno da postojanje privl, Surfactants have important application in pharmacy and medicine. These substances are applied in pharmacotherapy, they are used for hydrophobic drug solubilisation, and certain investigations indicate they can improve bioavailability of certain active substances. Lately, investigations of surfactant mixtures have gained a lot of attention, since it was found that systems of two or more surfactants often show more desirable properties than the individual surfactants, for application in pharmacy and medicine. In this dissertation, binary systems of eight bile acid anions and two nonionic surfactants (polysorbate 40 and polysorbate 80) were investigated. The aims were to determine values of critical micelle concentrations of investigated surfactant mixtures, interactions between different surfactants in their mixed micelles, and to investigate the influence of the structure of investigated surfactants on physico-chemical characteristics of mixed micelles. The results indicate that investigated mixtures have significantly lower values of critical micelle concentrations than bile acid anions. Mixtures of bile acid anions and polysorbate 40 have lower values of experimentally obtained critical micelle concentrations than the calculated, ideal, values, indicating the existence of synergistic interactions in mixed micelles. Mixtures of bile acid anions and polysorbate 80 have mainly higher values of critical micelle concentrations than the ideal values, what could be due to the existence of antagonistic interactions between building units of mixed micelles. The values of the interactions, attributing to the nonideal behaviour of the surfactant systems were obtained by calculating the values of the interaction parameter, β1,2 , according to the regular solution theory. Systems of bile acid anions and polysorbate 40 have negative values of the interaction parameter, while systems of bile acid anions and polysorbate 80 have mainly positive values of interaction parameter. By

U radu je ostvarena sinteza četiri prirodna proizvoda, goniobutenolida A i B, krasalaktona D i 3-deoksi-kardiobutanolida i 32 derivata i analoga polazeći iz D-glukoze. Sinteza prirodnog stiril-laktona, kardiobutanolida i njegova 4 derivata je izvedena polazeći iz D-ksiloze. Ispitan je uticaj sintetizovanih jedinjenja na inhibiciju rasta 10 tumorskih i jedne zdrave ćelijske linije. Uspostavljene su i korelacije izmedju strukture i antiproliferativne aktivnosti (SAR) i ispitan je mehanzam antitumorskog dejstva., Synthesis of four natural products: goniobutenolide A and B, crassalactone D, 3-deoxy-cardiobutanolide and their 32 analogues and derivatives is accomplished starting from D-glucose. Synthesis of natural styryl lactone cardiobutanolide and its four derivatives is achieved starting from D-xylose. Synthesized natural lactones, their analogues and derivatives were evaluated for their antiproliferative activity against ten malignant cell lines as well as against a single normal cell line. Influence of functional groups on antitumour activity was established by correlating structures of synthesized compounds with their biological activity (SAR). Also, mechanism of antitumour action was investigated.

U ovoj doktorskoj disertaciji ispitane su 1,3-dipolarne cikloadicione reakcije steroidnih azido-nitrila, nitrona i nitril-oksida, pri čemu su sintetizovana različita heterociklična steroidna jedinjenja androstanske i estranske serije. Utvrdjene su strukture novosintetizovanih jedinjenja. Ispitana je biološka aktivnost odabranih jedinjenja., In this PhD thesis 1,3-dipolar cycloadditions of steroidal azido-nitriles, nitrones and nitrile-oxide were examined. Various steroidal heterocyclic compounds in the androstane and estrane series were synthesised. The structural characterisation of newly synthesised compounds was done. Biological activity of selected compounds was examined.

Predviđena istraživanja u ovoj doktorskoj disertaciji su usmerena u pravcu modifikacije klasičnih metoda i postupaka za transformaciju karboksilne grupe prirodnih i sintetičkih karboksilnih kiselina. Modifikacije su rađene novim, savremenim, ekonomski i ekološki opravdanim metodama rada u mikrotalasnom reaktoru. Modifikovanim sintetskim postupcima u mikrotalasnom reaktoru urađena je sinteza amida, hidroksamskih derivata, kao i redukcija individualnih naftnih kiselina i smeše prirodnih naftnih kiselina „Velebit“ do alkohola. Prirodne naftne kiseline korišćene u ovom radu su prvo izolovane iz gasne frakcije (interval destilacije 168-290 °C) vojvođanske nafte „Velebit“ a potom prečišćene i razdvojene na uže frakcije na osnovu različite kiselosti. Nakon toga, izvršena je njihova karakterizacija GC-MS-EI analizom (čime je potvrđeno da dolazi do strukturne diferencijacije kiselina). U radu je takođe ispitana biološka aktivnost sintetizovanih derivata. Proučavan je uticaj prirodnih naftnih kiselina „Velebit“ i njenih derivata na rast pet sojeva Pseudomonas sp., kao i uticaj odabranih sintetisanih jedinjenja na proliferaciju četiri ćelijske linije humanih tumora pri čemu je kao kontrola služila jedna zdrava humana ćelijska linija., The investigation of this doctoral dissertation is directed toward the modification of the transformation of the carboxylic group of natural and synthetic carboxylic acids. The dissertation takes into consideration the classical methods and procedures of the reaction and modifies them using microwave reactor. The synthesis of amides, hydroxamic derivatives, as well as the reduction of individual petroleum acids and acid mixtures of natural oil "Velebit" to alcohol were achieved by the modifications made to the synthetic methods in the microwave reactor. The natural oil acids used within this study were first isolated from the gas fraction (distillation interval 168-290 °C) of the Vojvodina's crude oil "Velebit", and then purified and separated by the narrow fractions under the different acidity. After that, their characterisation was made by the GC-MS-EI analysis which confirmed that the structural differentiation of acids had been achieved. Also, the biological activity of the synthesized derivatives are analysed. The impact of natural petroleum acids "Velebit" and its derivatives on the growth of five strains of Pseudomonas sp. was studied, as well as the impact of selected synthesized compounds on the proliferation of four human tumor cell lines wherein one healthy human cell lines used as the control.

Cilj ove doktorske disertacije je bila sinteza novih steroidnih 16,17-seko-16,17a-dinitrila polazeći od dehidroepiandrosterona (1), odnosno estrona (14). U androstanskoj seriji su izvršene modifikacije 16,17-seko-16,17a-dinitrila 12 u A i/ili B prstenu steroidnog jezgra, pri čemu novosintetizovana jedinjenja sadrže 4-en-3-on, 1,4-dien-3-on ili 1,4,6-trien-3-on sistem, kao i supstituente u položajima C-4, odnosno C-6 (6-metilen, 6-keto i 6-oksimino). U radu je takođe proučavan uticaj odabranih novosintetizovanih jedinjenja na proliferaciju sedam ćelijskih linija humanih tumora, dok je kao kontrola služila jedna zdrava humana ćelijska linija., Starting from dehydroepiandrosterone (1) or estrone (14) new steroidal 16,17-seco-16,17a-dinitriles were synthesized. Modification of 16,17-seco-16,17a-dinitrile 12 afforded androstane derivatives containing 4-en-3-on, 1,4-dien-3-on or 1,4,6-trien-3-on system, with different substituents on position C-4 or C-6 (6-methylene, 6-keto i 6-oximino). Antiproliferative activity of some newly synthesized compounds were examined against seven human tumor cell lines, while healthy cells served as control.

U prvom delu ove doktorske disertacije je izvršena sinteza novih derivata androstana sa D-laktonskom funkcijom ili D-seko derivata, sa modifikacijama u Ai/ ili B-prstenovima. U drugom delu je ispitana antiproliferativna aktivnost odabranih novosintetizovanih jedinjenja prema humanim tumorskim ćelijskim linijama (MCF-7, MDA-MB-231, PC-3, HeLa, HT-29, K562) kao i prema zdravim ćelijama fetalnih fibroblasta pluća (MRC-5)., In first part of this work was achieved synthesis of some new androstane derivatives with D-lactone function and new D-seco derivatives with modification in A and/or B rings. In the second part the antiproliferative activity of selected newly synthesized compounds by human carcinoma cell lines (MCF-7, MDA-MB-231, PC-3, HeLa, HT-29, K562) and the healthy cells of fetal lung fibroblasts (MRC-5 ) was examined.

U prvom delu ove doktorske disertacije je izvršena sinteza novih 17α-pikolil i 17(E)-pikoliniliden androstanskih derivata, sa modifikacijama u A- i/ili B-prstenovima. U drugom delu rada je ispitana antiproliferativna aktivnost odabranih novosintetizovanih jedinjenja prema humanim tumorskim ćelijskim linijama (MCF-7, MDA-MB-231, PC-3, HeLa, HT-29 i A549) kao i prema zdravim ćelijama fetalnih fibroblasta pluća (MRC-5)., In the first part of this dissertation, the synthesis of new 17α-picolyl and 17(E)-picolinylidene androstane derivatives with modifications in A and/or B rings, were presented. The second part of the work consisted on investigation of antiproliferative activity of selected newly synthesized compounds toward human carcinoma cell lines (MCF-7, MDA-MB-231, PC-3, HeLa, HT-29 and A549), as well as the healthy fetal lung fibroblasts (MRC-5).

Ostvarene su višefazne sinteze prirodnih citotoksičnih laktona (+)-murikatacina (1), (–)-murikatacina (ent-1) i (+)-goniofufurona (2), kao i njihovih novih analoga (3a, 4, 5, 6, 7, 8, 9, ent-7 i ent-9), polazeći iz D-ksiloze ili iz D-glukoze. Ispitana je in vitro citotoksična aktivnost sintetizovanih prirodnih proizvoda i analoga prema odabranim humanim tumorskim ćelijskim linijama (K562, HL-60, Jurkat, Raji, HT-29, MDA-MB 231 i HeLa), kao i prema ćelijama fetalnih fibroblasta pluća (MRC-5)., Multiphase synthesis of natural cytotoxic lactones (+)-muricatacin (1), (–)-muricatacin (ent-1) and (+)-goniofufurone (2), as well as synthesis of their analogues (3a, 4, 5, 6, 7, 8, 9, ent-7and ent-9) was achived from D-xylose or D-glucose as starting compounds. In vitro cytotoxic activity of synthetized natural products and analogues against selected human tumour cell lines (K562, HL-60, Jurkat, Raji, HT-29, MDA-MB 231 and HeLa) and against cells of natural foetal lung fibroblasts (MRC-5) was examined.

U radu je ostvarena enantiodivergentna totalna sinteza oba enantiomera goniofufurona, 7-epi-goniofufurona i krasalaktona C polazeći iz D-glukoze. Ključne faze u sintezi 7-epi-(+)-goniofufurona bile su stereoselektivna adicija fenilmagnezijum bromida na aldehidnu grupu pogodno zaštićene dialdoze, i stereospecifično formiranje furano-laktonskog prstena ciklokondenzacijom odabranog hemiacetalnog derivata sa Meldrum-ovom kiselinom. Sinteza (+)-goniofufurona i (+)-krasalaktona C zahtevala je inverziju konfiguracije na C-5 u zajedničkom intermedijeru, koja je efikasno ostvarena u uslovima Mitsunobu-ove reakcije, ili alternativno oksidacijom benzilne hidroksilne grupe u prohiralni keton, uz naknadnu stereoselektivnu redukcijom sa borohidridom. Sličan pristup je zatim primenjen za sintezu neprirodnih (−)-enantiomera goniofufurona, 7-epi-goniofufurona i krasalaktona C, dva nova konformaciono ograničena analoga (+)- i (−)-goniofufurona (oksetani 36 i ent-36), kao i odgovarajućih 7-deoksigenovanih derivata (31 i ent-31). Takodje je razvijena i prva totalna sinteza prirodnog (+)-krasalaktona B (3) i alternativna sinteza (+)-krasalaktona C (4) polazeći iz D-glukoze. Selektivni pristup molekulima 3, odnosno 4 omogućen je promenom uslova za TBDPS deprotekciju u finalnom intermedijeru 53. Osnovna karakteristika pomenutih pristupa je njihova generalnost i fleksibilnost. Na taj način je omogućena sinteza serije analoga i derivata (+)-goniofufurona, ili 7-epi-goniofufurona, uključujući i do sada nepoznate 7-epi-(+)-krasalaktone B (6) i C (7), 5,7-di-O-cinamoil derivate 8 i 9, 5,7-di-O-izopropilidenske derivate 5 i 10, kao i više lipofilnih derivata (jedinjenja 26, 30, 33, 65, ent-30 i ent-33). Konačno, u drugom delu rada, ispitan je uticaj sintetizovanih stiril-laktona na rast odabranih tumorskih ćelijskih linija in vitro., Enantiodivergent total syntheses of both (+)- and (−)-enantiomers of goniofufurone, 7-epi-goniofufurone and crassalactone C have been accomplished starting from D-glucose. The key steps of the synthe-sis of 7-epi-(+)-goniofufurone were a stereo-selective addition of phenyl magnesium bromide to a protected dialdose, followed by a stereospecific furano-lactone ring formation by condensation of a partially protected lactole with Meldrum’s acid. The synthesis of (+)-goniofufurone and (+)-crassalactone C required a configurational inversion at C-5 in the common intermediate that was efficiently achieved under the standard Mitsunobu conditions, or alternatively through a sequential oxidation of the benzylic hydroxyl group followed by a stereo-selective reduction with borohydride. A similar approach was applied to the synthesis of the unnatural enantiomers of goniofufurone, 7-epi-goniofufurone and crassalactone C, two novel, conformationally constrained analogues of both (+)- and (−)-goniofufurone (oxetanes 34 and ent-34). as well as the corresponding 7-deoxygenated derivatives (31 and ent-31). We have also developed the first total synthesis of (+)-crassalactone B (2) and an alternative synthesis of (+)-crassalactone C (3) starting from D-glucose. Finally, the synthesized styryl-lactones were evaluated for their antiproliferative activity against a panel of human tumor cell lines.

Ostvarene su višefazne stereospecifične sinteze tiazolnih C-nukleozida, novih analoga, odnosno mimetika tiazofurina polazeći iz D-glukoze i D-ksiloze. Ispitana je in vitro citotoksična aktivnost sintetizovanih C-nukleozida prema odabranim humanim tumorskim ćelijskim linijama (K562, HL 60, Jurkat, Raji, PC 3, HT-29, MCF-7, MDA-MB-231, HeLa i Hs 294T) kao i prema ćelijama normalnih fetalnih fibroblasta pluća (MRC-5)., Multiphase stereospecific synthesis of thiazole C-nucleosides, new analogues and mimics of tiazofurin, has been achives starting from D-glucose and D-xylose. We examined the in vitrocytotoxic activity of synthesized C-nucleosides by selected human tumor cell lines (K562, HL 60, Jurkat, Raji, PC 3, HT-29, MCF-7, MDA-MB-231, HeLa and Hs 294T) and the cells of normal fetal lung fibroblasts (MRC-5).

Sintetisana su nova jedinjenja, 16- i 17-supstituisani 16,17-sekoestratrienski derivati i D-homoestranski derivati, polazeći od 3-benziloksi-17-hidroksi-16,17-sekoestra-1,3,5(10)-trien-16-nitrila. Ispitana je estrogena i antiestrogena aktivnost u eksperimentima in vivo, antiaromatazna aktivnost in vitro, antioksidantna aktivnost DPPH i TBA testom, kao i antiproliferativna aktivnost prema ćelijskim linijama MCF-7 ATCC, MDA-MB-231, HT-29 i MRC-5 novosintetisanih jedinjenja., Some new compounds, 16- and 17-substituted 16,17-secoestratriene derivatives, as well as D-homoestratriene derivatives, were synthesized, starting from 3-benzyloxy-17-hydroxy-16,17-secoestra-1,3,5 (10)-triene-16-nitrile. The newly synthesized compounds were tested for their in vivo estrogenic and antiestrogenic activity, in vitro antiaromatase activity, antioxidative activity by DPPH and TBA tests, as well as antiproliferative activity against MCF-7 ATCC, MDA-MB-231, HT-29 i MRC-5 cell lines.

Starting from dehydroepiandrosterone (1) 17-picolyl (2), 17-picolinylidene (7), 17-picolinylidene-16-one (10 and 11), and 17-picolyl-16-one (15) derivatives of androst-5-ene were synthesized in one, two, four and five steps respectively. By the Oppenauer oxidation or dehydration of 2, 7, 10, and 11 with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), the corresponding A and B ring modified derivatives 3, 5, 6, 8, 9, and 12-14 were obtained. The structure of 2 was unambiguously proved by the appropriate X-ray structural analysis. Compounds 3, 5, 9, 12-14 showed inhibitory activity against the enzyme aromatase. Antibacterial activity, toxicity to brine shrimp Artemia salina, antitumor activity against three tumor cell lines (human cervix carcinoma HeLa cells, human melanoma FemX cells, and human myelogenous leukemia K562 cells) and toxicity against peripheral blood mononuclear cells were evaluated. Three tested compounds, namely 11, 13, and 15, showed strong activity against all three cell lines, the IC50 values being in the range of 4-10 μM.