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Despite the large number of peptidomimetics with incorporated heteroannularly functionalized ferrocenes, few studies have investigated their bioactivity. Here, we report the biological evaluation and conformational analysis of enantiomeric dipeptides derived from 1′-aminoferrocene-1-carboxylic acid (Fca) and hydrophobic amino acids (AA = Val, Leu, Phe). The conformational properties of Y-AA-Fca-OMe (Y = Ac, Boc) were elucidated by experimental (IR, NMR, CD, and X-ray) and theoretical (DFT) methods. The prepared dipeptides were screened for their antimicrobial activity against selected Gram-positive and Gram-negative bacteria, lactic acid bacteria and yeasts, while their antioxidant activity was tested by DPPH and FRAP methods. Of all compounds tested, dipeptide d-2a showed the best antibacterial properties against S. aureus, B. subtilis, and P. aeruginosa at a concentration of 2 mM. The time–kill curves showed that antibacterial activity was concentration- and time-dependent. Chirality (d-) and a more polar-protecting group (Ac) were found to affect the biological activity, both antimicrobial and antioxidant. All investigated peptides are considered to be highly hydrophobic and chemically stable in both acidic and buffer media. Dipeptides d-1a–3a, which showed biological activity, were subjected to the determination of proteolytic activity, revealing very good resistance to proteolysis in the presence of chymotrypsin.

Strukturne različitosti aminokiselina, a samim time i peptida te proteina, omogućuju brojne biološki važne funkcije proteina u stanici. Budući da je mogućnost korištenja peptida i proteina u terapeutske svrhe ograničena, njihova svojstva moguće je poboljšati ugradnjom ferocenskog kalupa u strukturu peptida, što omogućuje tvorbu vodikove veze između peptidnih lanaca kao glavni preduvjet za tvorbu sekundarnih struktura, a samim time i za biološku aktivnost i funkciju peptida. U ovom je radu opisana sinteza i konformacijska analiza tripeptida 2 i 3 (Boc-L(D)-Ala-D-Pro-NH-Fn-COOMe) te 4 i 5 (Ac-L(D)-Ala-D-Pro-NH-Fn-COOMe), izvedenih iz 1ʼ-aminoferocen-1-karboksilne kiseline (Fca) i Pro-Ala peptidne sekvence. Provedena je IR-, NMR- i CD-spektroskopska analiza dobivenih biokonjugata, s ciljem ispitivanja utjecaja kiralnosti i zaštitnih skupina (Boc/Ac) aminokiselina na mogućnost tvorbe intramolekulskih vodikovih veza te u konačnici i sekundarnih peptidnih struktura The structural differences of amino acids, and consequently of peptides and proteins, enable numerous biologically important functions of proteins in the cell. Since the possibility of using peptides and proteins for therapeutic purposes is limited, their properties can be improved by incorporating certain ferrocene templates into the peptide structure. Formation of hydrogen bond is main prerequisite for the formation of secondary structures, and thus for the biological activity and function of the peptides. This paper describes the synthesis and conformational analysis of tripeptides 2 and 3 (Boc-L(D)-Ala-D-Pro-NH-Fn-COOMe), as well as the tripeptides 4 and 5 (Ac-L(D)-Ala-D-Pro-NH-Fn-COOMe), derived from 1ʼ-aminoferrocene-1-carboxylic acid (Fca) and Pro-Ala peptide sequence. IR-, NMR- and CD-spectroscopic analysis of the obtained bioconjugates was carried out, with the aim of examining the influence of chirality and protective groups (Boc/Ac) of amino acids on the possibility of intramolecular hydrogen bond formation, and ultimately secondary peptide structures.

Konformacijska analiza obuhvaća široko područje istraživanja molekularnih struktura, a uz izračun odgovarajućih termodinamičkih veličina može se dobiti opis stabilnosti sustava i objašnjenje njegovih kemijskih svojstava te reaktivnosti. U okviru ovog istraživanja određeni su potpuni konformacijski prostori odabranih skupova cikličkih i acikličkih molekula metodom sustavnog pretraživanja koristeći postojeći algoritam za rigidno pretraživanje (engl. rigid scan) i novorazvijeni algoritam za prilagodljivo relaksirano pretraživanje (engl. adaptive relaxed scan) te metodom pretrage reduciranog prostora trajektorija molekularnih dinamika određenog komponentama dekompozicije tenzora drugoga i trećeg reda. Trajektorije molekularne dinamike sadrže sve steričke informacije o kemijskim strukturama molekula u istraživanom sustavu no teškoću predstavlja ogroman broj struktura koje je potrebno uzorkovati za potpunu konformacijsku analizu. Algoritam za prilagodljivo relaksirano pretraživanje omogućuje dobivanje potpunih konformacijskih prostora molekula u manje koraka čime su omogućene pretrage na znatno višim razinama teorije Conformational analysis covers a wide area of research of molecular structures, and by calculating thermodynamic parameters, a description of the stability of the system and an explanation of its chemical properties can be obtained. Within this research, complete conformational spaces for selected sets of cyclic and acyclic molecules were examined through a systematic search method using rigid scan and newly developed adaptive relaxed scan algorithm as well as dimensionality reduction method of molecular dynamics trajectories by the 2nd- and 3rd-order tensor decomposition. Molecular dynamics trajectories contain all steric information about the chemical structures of molecules in the system, but the difficulty is the large number of structures that need to be sampled for a complete conformational analysis. The adaptive relaxed scan algorithm makes it possible to obtain complete conformational spaces in fewer steps, thus enabling searches at higher levels of theory.

Considering the enormous importance of protein turns as participants in various biological events, such as protein–protein interactions, great efforts have been made to develop their conformationally and proteolytically stable mimetics. Ferrocene-1,1′-diamine was previously shown to nucleate the stable turn structures in peptides prepared by conjugation with Ala (III) and Ala–Pro (VI). Here, we prepared the homochiral conjugates of ferrocene-1,1′-diamine with l-/d-Phe (32/35), l-/d-Val (33/36), and l-/d-Leu (34/37) to investigate (1) whether the organometallic template induces the turn structure upon conjugation with amino acids, and (2) whether the bulky or branched side chains of Phe, Val, and Leu affect hydrogen bonding. Detailed spectroscopic (IR, NMR, CD), X-ray, and DFT studies revealed the presence of two simultaneous 10-membered interstrand hydrogen bonds, i.e., two simultaneous β-turns in goal compounds. A preliminary biological evaluation of d-Leu conjugate 37 showed its modest potential to induce cell cycle arrest in the G0/G1 phase in the HeLa cell line but these results need further investigation.

Aldoksimi su skupina organskih spojeva strukturne formule RCH=NOH (oksimi aldehida) čiju primjenu nalazimo u medicini kao reaktivatore enzima acetil- i butirilkolinesteraze nakon izloženosti organofosfornim spojevima te kao potencijalne agense s antimikrobnim djelovanjem. U sklopu ovog rada istraživana su prethodno sintetizirana dva nova aldoksima, (E)-N-benzilimidazol-2-karbaldoksim i (E)-N-benzil-2-hidroksiiminometil-3-metilimidazolijev bromid, korištenjem transmisijske infracrvene spektroskopije i Ramanove spektroskopije. Za oba spoja provedena su teorijska istraživanja koja su uključivala potpunu konformacijsku analizu spojeva metodom holističkog pretraživanja na višedimenzijskoj koordinatnoj hiperrešetki te kvantno-kemijske izračune harmoničkih i anharmoničkih infracrvenih i Ramanovih spektara. Proračuni su provedeni za najzastupljenije konformere korištenjem teorije funkcionala gustoće na B3LYP-D3/6-311++G(d,p) razini teorije. Na temelju tih rezultata određeni su potpuni konformacijski prostori, a usporedbom i analizom teorijskih te eksperimentalnih vibracijskih spektara asignirane su najvažnije vibracijske vrpce u vibracijskim spektrima. Aldoximes are a group of organic compounds with structural formula RCH=NOH (oximes of aldehydes) which are used in medicine as reactivators of the acetyl- and butyrylcholinesterase enzymes after exposure to organophosphorus compounds and as potential antimicrobial agents. In this thesis two previously synthesized aldoximes, (E)-N-benzylimidazole-2-carbaldoxime and (E)-N-benzyl-2-hydroxyiminomethyl-3-methylimidazolium bromide, were investigated using Infrared transmission spectroscopy and Raman spectroscopy. For both coumpounds a computational study involving conformational analysis using grid search method on multidimensional hyper grid and quantum-chemical calculations of anharmonic and hamornic Infrared and Raman spectra were performed. Calculations were performed for conformers with most significant content using density functional theory at the B3LYP-D3/6-311++G(d,p) level of theory. Based on these results complete conformational spaces were determined, and by comparison and analysis of theoretical and experimental vibrational spectra, most important vibrational bands in vibrational spectra were assigned.

Sekundarna struktura proteina ima bitnu ulogu u konačnoj strukturi proteina, stabilnosti, presavijanju, biološkim procesima i u samoj funkciji proteina, te se stoga pokušava predvidjeti i usmjeriti, kako bi proteini postali konformacijski fleksibilniji, stabilniji i time terapeutski primjenjiviji. U ovom je radu opisana sinteza i konformacijska analiza biokonjugata Boc-D-Val-NH-Fn- COOMe (1) i Ac-D-Val-NH-Fn-COOMe (2) (Ac = acetil, Boc = tert-butoksikarbonil) koji su pripravljeni iz voluminozne aminokiseline valina i ferocenske aminokiseline. S ciljem utvrđivanja mogućeg steričkog utjecaja valinskog bočnog ogranaka na uspostavu sekundarne strukture rezultirajućih peptida, provedena je konformacijska analiza (IR-, NMR- i CD-spektroskopija). The secondary structure of a protein plays an important role in the final structure of the protein, stability, folding, biological processes and in the function of the protein itself. Therefore, scientific researches are made to predict and direct proteins to be more conformationally flexible, stable and therapeutically applicable. This paper describes the synthesis and conformational analysis of the bioconjugates Boc-D-Val-NH-Fn-COOMe (1) and Ac-D-Val-NH-Fn-COOMe (2) (Ac = acetyl, Boc = tert-butoxycarbonyl) which are prepared from the voluminous amino acid valine and the ferrocene amino acid. In order to determine the possible steric influence of the valine backbone on the formation of the secondary structure of the resulting peptides, conformational analysis (IR, NMR and CD spectroscopy) was performed.

U okviru ove doktorske disertacije provedena je sinteza i konformacijska analiza peptidnih konjugata aminoferocena [Boc–(AA)n–NH–Fc, Fc = ferocenil, AA = D(L)–Pro, D(L)–Ala, Boc (tert–butoksikarbonil), Aib (α–aminoizobutirična kiselina), n = 2–4] kao i dinuklearnih ferocenskih derivata [Fc–CO–(AA)2–NH–Fc, AA = D(L)–Pro, D(L)–Ala] kako bi se istražio utjecaj nabiranja aminokiselinskog slijeda na kirooptička svojstva organometalnog kromofora. Konformacijskom analizom (IR–spektroskopija, spektroskopija NMR i CD, kristalografska analiza, računalno modeliranje) utvrđeno je da su pripravljeni spojevi, u otopini i u čvrstom stanju, stabilizirani unutarmolekulskim vodikovim vezama koje podržavaju okrete i uzvojnice slične onima u prirodnim peptidima. Kombiniranim teorijskim i eksperimentalnim pristupom pokazano je kako kiralno uređenje peptidnog segmenta inducira Cottonov efekt u blizini UV/Vis apsorpcijskog maksimuma ferocena čiji je predznak u korelaciji s diedarskim kutom koji opisuje rotaciju oko veze između ferocenskog kromofora i peptidnog segmenta. In this PhD thesis peptide derivatives of aminoferrocene [Boc–(AA)n–NH–Fc, Fc = ferrocenyl, AA = D(L)–Pro, D(L)–Ala, Aib, Boc (tert–butoxycarbonyl), Aib (α– aminoisobutyric acid), n = 2–4] as well as the dinuclear ferrocene derivatives [Fc–CO– (AA)2–NH–Fc, AA = D(L)–Pro, D(L)–Ala] were synthesized. The novel compounds were subjected to conformational analysis in order to investigate the influence of folding of amino acid sequence on the chiroptical properties of organometallic chromophore. Conformational analysis (IR, NMR, and CD spectroscopy, crystallographic analysis, computational modeling) of the prepared compounds revealed that they are stabilized by intramolecular hydrogen bonds, that support turns and helices similar to those in natural peptides, in solution as well as in solid state. The combined theoretical and experimental approach has shown that the chiral arrangement of the peptide segment induces Cotton effect near the UV/Vis absorption maximum of ferrocene, whose sign is in correlation with dihedral angle which describes rotation around ferrocene–peptide linkage.

Najveća zapreka za korištenje biološki aktivnih peptida u terapeutske svrhe je njihova konformacijska fleksibilnost koja može izazvati nuspojave uslijed vezanja na neželjene receptore. Kako bi se uz spomenuto prevladala i ostala ograničenja za terapeutsku primjenu peptida, dizajnirani su peptidomimetici. Ferocenski peptidomimetici građeni su iz ferocenskog kalupa na koji su vezane aminokiselinske sekvence, a svrha kalupa je indukcija elemenata sekundarne strukture i ''zaključavanje'' peptida u biološki aktivnoj konformaciji. U ovom radu opisana je konformacijska analiza homokiralnog tetrapeptida Ac-L-Ala-L-Pro-NH-Fn-NH-L-Pro-L-Ala-Boc (1) i njegovog dijastereomera, heterokiralnog peptida Ac-D-Ala-L-Pro-NH-Fn-NH-L-Pro-D-Ala-Boc (2). Kao kalup, na kojeg su vezani Pro-Ala peptidi koji se međusobno razlikuju u kiralnosti alaninskog ostatka, upotrijebljen je ferocen-1,1'-diamin (Fcda). Strukturna analiza tih peptidomimetika provedena je mjerenjem IR-spektara (ovisno o koncentraciji), te NMR-spektara (ovisno o koncentraciji, temperaturi i otapalu) i CD-spektara. Cilj ovog rada jest prikazati upotrebu spektroskopskih metoda u konformacijskoj analizi ferocenskih peptida te ukazati na utjecaj kiralnosti peptidne okosnice na njihova konformacijska svojstva. The greatest obstacle for clinical usage of peptides is their conformational flexibility capable to cause side effects due to the binding to undesired receptors. To overcome all the limitations for the therapeutic application of peptides, peptidomimetics have been designed. Ferrocene peptidomimetic is composed of a ferrocene scaffold equipped with peptide strands, aimed to induce secondary structure elements and to lock peptide in a biologically active conformation. Herein, a conformational analysis of the homochiral tetrapeptide Ac-L-Ala-L-Pro-NH-Fn-NH-L-Pro-L-Ala-Boc (1) and its diastereomeric heterochiral peptide Ac-D-Ala-L-Pro-NH-Fn-NH-L-Pro-D-Ala-Boc (2) is described. Ferrocene-1,1'-diamine (Fcda) was used as the scaffold for attachment of Pro-Ala sequences which differ in the chirality of alanine unit Structural analysis of these peptidomimetics was performed by measuring of IR (concentration-dependent), NMR (concentration-, temperature- and solvent-dependent) and CD spectra. The goal of this work is to present the application of the spectroscopic methods in the conformational analysis of ferrocene peptides and to point out the impact of the peptide backbone chirality on its conformational properties.

Biološka primjena prirodnih peptida ograničena je njihovim nepoželjnim svojstvima (konformacijska fleksibilnost, niska stabilnost) zbog čega se intenzivno istražuje područje peptidomimetika. Ferocenski konjugati s aminokiselinama često se koriste kao peptidomimetici jer su se 1, n-disupstituirani ferocenski biokonjugati pokazali dobrim kalupom za tvorbu intramolekulskih vodikovih veza. Sekvence bogate alaninom i prolinom pokazuju brojna poželjna svojstva (visoka topljivost, stabilnost i biodostupnost), dok ferocenski diamin inducira tvorbu intramolekulskih vodikovih veza koje su stabilizirane 14-članim prstenovima. U ovom Diplomskom radu opisana je sinteza i konformacijska analiza ferocenskih tripeptida 12-15 [Ac-L(D)-Ala-D-Pro-NH-Fn-NH-L(D)-Pro-Boc, Fn = ferocenilen, Ac = acetil, Boc = tert-butoksikarbonil] kao i njihovih prekursora 2-5 [Boc(Ac)-L(D)-Ala-D-Pro-NH-Fca-COOMe], izvedenih iz ferocen-1,1'-diamina i peptidne sekvence Ala-Pro. Utjecaj kiralnosti pojedinih aminokiselina u peptidnom lancu, kao i N-terminalnih zaštitnih skupina (Boc, Ac) ispitani su spektroskopskom analizom (IR-, NMR- i CD-spektroskopija) te potkrijepljeni DFT-računima. Pokazalo se da promjenom kiralnosti aminokiselina dolazi do promjene u obrascima vodikovih veza, dok zaštitne skupine nemaju utjecaj na tvorbu istih. The biological application of natural peptides is limited by their undesirable properties (conformational flexibility, low stability), therefore the field of peptidomimetics is being intensively investigated. As the 1, n-disubstituted ferrocene bioconjugates have been established as good motif for the formation of intramolecular hydrogen bonds, ferrocene conjugates with amino acids are often used as peptidomimetics. Regarding to that alanine- and proline-rich sequences exhibit a number of desirable properties (high solubility, stability, and bioavailability), as well as the ferrocene diamine induces the formation of intramolecular hydrogen bonds that are stabilized by forming 14-membered rings we have decided to prepare new type of peptidomimetics. This Graduate Thesis describes the synthesis and conformational analysis of ferrocene tripeptides 12-15 [Ac-L(D)-Ala-D-Pro-NH-Fn-NH-L(D)-Pro-Boc, Fn = ferrocenylene, Ac = acetyl, Boc = tert-butoxycarbonyl] as well as their precursors 2-5 [Boc(Ac)-L(D)-Ala-D-Pro-NH-Fca-COOMe], derived from ferrocene-1,1'-diamine and Ala-Pro peptide sequences. The influence of chirality of individual amino acids in the peptide chain, as well as N-terminal protecting groups (Boc, Ac) were examined by spectroscopic analysis (IR-, NMR- and CD-spectroscopy) and supported by DFT-calculations. It has been shown that change in the chirality of amino acids leads to change in the hydrogen bond patterns, while the protecting groups have no effect on their formation.

Butadienski kromofori sintetizirani su Wittigovom reakcijom kao smjese (E) i (Z) izomera te podvrgnuti intramolekulskoj fotokemijskoj reakciji u cilju dobivanja fotoprodukata s reaktivnom slobodnom dvostrukom vezom. Na fotoproduktima je provedena epoksidacija te otvaranje epoksidnog prstena s ciljem da se priprave odgovarajući alkoholi. Računalnim modeliranjem posebno je istražena Wittigova reakcija za dobivanje butadienskih kromofora. Reakcija o-ksililen-a,a'-difosfonijevog bromida s cimetnim aldehidom i njegovim derivatima ima općenito nisku diastereoselektivnost pa nastaju (E/Z) smjese supstituiranih butadiena. Stereokemija bifunkcionalnog reagensa je slabo istražena. U slučaju dva neovisna propelerska stereocentra, očekuju se homokiralni (P,P)/(M,M) par i heterokiralna (P,M) meso-forma. Konformacijska analiza ilid-fosfonijeve vrste kvantno-kemijskim računima na temelju teorije funkcionala gustoće (DFT) pokazuje da je heterokiralna (P,M) meso-forma za 5,2 kcal/mol stabilnija od homokiralne (M,M)-forme. Intramolekulsko transilidiranje modelirano je na meso-obliku. Prijelazno stanje za translokaciju karbaniona putem prijenosa protona lokalizirano je na plohi potencijalne energije te su njegova geometrija, kao i geometrije odgovarajućih minimuma, optimizirane. Karakteriziranje kratkih kontakata omogućuje identifikaciju nekonvencionalnih C–H···p i C–H···C− intramolekulskih vodikovih veza koje određuju konformacije ilida. Struktura prijelaznog stanja za cikloadiciju dobivena računalnim modeliranjem pokazuje da prisutnost zaostale trifenilfosfonijeve soli u ključnom stereogenom stupnju Wittigove reakcije utječe na osobito nisku selektivnost u ovom redu polustabiliziranih ilida. Piramidalizacija karbaniona i unutarnja rotacija oko ilid-arilne veze važne su karakteristike. Gauche interakcija između fenilnoga o-položaja i atoma fosfora određuje preferiranu konformaciju benzilida (torzijski ∠P+CH−CiCo 110 – 140°) u prijelaznom stanju [2+2]-cikloadicije. Ova strukturna značajka vrijedi i za različite slučajeve opisane u literaturi. Sterička zapriječenost gauche usmjerenim fenilnim prstenom u neposrednoj blizini C–C veza koje tek počinju nastajati dobro objašnjava stereokemijski tijek reakcija. Butadiene chromophores prepared by Wittig reaction as mixtures of (E) and (Z) isomers were subjected to an intramolecular photochemical reaction with the intention to prepare products containing a reactive free double bond. The photoproducts were epoxidized and converted to the corresponding alcohols by ring opening. The synthesis of butadiene chromophores was thoroughly examined by computational modeling. Wittig reaction of o-xylylene-a,a'- diphosphonium bromide with cinnamaldehyde and related aldehydes generally proceeds with low diastereoselectivity to give an (E/Z) mixture of substituted butadienes. Stereochemistry of the bifunctional reagent has received little attention. For two independent propeller-shaped stereocenters, a homochiral (P,P)/(M,M) pair and heterochiral (P,M) meso-form, are to be expected. Conformational analysis of the ylide-phosphonium species by quantum-chemical calculations based on density functional theory (DFT) reveals that the heterochiral (P,M) mesoform is 5.2 kcal/mol more stable than the homochiral (M,M)-form. Computational modeling of intramolecular transylidation was performed on the meso-form. The transition state involved in carbanion translocation via proton transfer is localized on the potential energy surface, and its geometry, as well as geometries of corresponding minima, are optimized. Characterization of short contacts aids identification of unconventional C–H···p and C–H···C− intramolecular hydrogen bonds that control the ylide conformations. Computationally obtained structures of the cycloaddition transition states show that the presence of the residual triphenylphosphonium salt in the key stereogenic stage of the Wittig reaction may be responsible for the particularly low selectivity in this series of semi-stabilized ylides. Carbanion pyramidalization accompanied by an internal rotation about the ylide-aryl bond are noteworthy features. The gauche interaction between the phenyl o-carbon and phosphorus atoms in benzylide exerts a control over the molecular conformation (torsion ∠P+CH−CiCo 110 – 140°) in [2+2] cycloaddition transition states. This structural trend holds true for various cases described in the literature. The steric hindrance in the region close to the incipient C–C bond formation by the gauche exposed phenyl moiety nicely accounts for the stereocourse of the reactions.

Diamantoidi su policikličke alkanske molekule sa strogo definiranim, kavezastim strukturama zbog čega njihovi derivati imaju svojstva koja se mogu iskoristiti u razvoju različitih materijala s potencijalnom primjenom u medicini, elektrotehnici, nanotehnologiji, itd. U tu svrhu su pripravljeni i analizirani do sada slabo istraženi diamantoidni eteri koji se sastoje od kombinacije adamantanske i diamantanske podjedinice. U sklopu ovog rada cilj je bio pripraviti di(adamant-1-il)-eter i adamant-1-il-diamant-1-il-eter kondenzacijom odgovarajućih alkohola i metansulfonata kao polaznih reaktanta. Također je provedena konformacijska analiza ciljnih etera kako bi se utvrdila mogućnost rotacije eterske veze u ovisnosti o prisutnom diamantoidnom supstituentu. Di(adamant-1-il)-eter je uspješno sintetiziran reakcijom adamantan-1-ola i adamant-1-il-metansulfonata, dok eter koji se sastoji od adamantanske i diamantanske podjedinice nije izoliran iz analogne reakcije kondenzacije diamantan-1-ola i adamant-1-il-metansulfonata, najvjerojatnije zbog steričkih razloga. Diamondoids are polycyclic alkane molecules with strictly defined cage structures and their derivatives possess properties useful in the development of different materials applicable in medicine, electronics, nanotechnology, etc. Therefore diamondoid ethers, unexplored compounds consisting of a combination of adamantane and diamantane subunits, were prepared and analyzed. The goal of this study was to prepare di(adamant-1-yl) ether and adamant-1-yl-diamant-1-yl ether by means of condensing the corresponding alcohol and mesylate precursors. A conformational analysis of the target ethers was also performed in order to determine the possibility of rotation of the ether bond in dependence of the present diamondoid substituent. Di(adamant-1-yl) ether was successfully synthesized in a reaction between adamantan-1-ol and adamant-1-yl methanesulfonate, while the ether composed from the adamantane and diamantane subunit could not be isolated from the analogous condensation reaction between diamantan-1-ol and adamant-1-yl methanesulfonate, probably due to sterical reasons.

Jednostavni konjugati aminoferocena i peptida mogu tvoriti uređene sekundarne strukturne elemente, a pritom homo- odnosno heterokiralnost aminokiselinske sekvencije uvjetuje tvorbu β- odnosno γ-okreta. U ovom radu opisana je priprava i konformacijska analiza homokiralnih bis-ferocenskih derivata VI [Fc-CO- L-Pro-L-Ala-NH-Fc; (8) i Fc-CO-D-Pro-D-Ala-NH-Fc; (9)]. Iscrpna spektroskopska analiza (CD-, IR-, 1H- i 2D NMR), u kombinaciji s molekulskim modeliranjem i kristalografskom analizom, pokazala je kako se u najstabilnijim konformacijama 8 i 9 javljaju, vodikovim vezama podržani, 10-člani prstenovi (β-okreti). Cottonovi efekti opaženi u blizini UV/Vis apsorpcijskog maksimuma ferocena u CD-spektrima 8 i 9 proizlaze iz prijenosa kiralne informacije iz lokalne sekundarne strukture do akiralnog ferocenskog kromofora. Simple conjugates of aminoferocene and peptides are able to form ordered secondary structural elements, while homo- or heterocirality of the amino acid sequence determines the formation of β- or γ-turns. This thesis describes the synthesis and conformational analysis of homochiral bis-ferrocene derivatives VI [Fc-CO-L-Pro-L-Ala-NH-Fc; (8) and Fc-CO-D-Pro-D-Ala-NH-Fc; (9)]. Thorough spectroscopic analysis (CD-, IR-, 1H- and 2D NMR), in combination with molecular modelling and X-ray diffraction, revealed the presence of 10-membered rings (β-turns), supported by hydrogen bonds, in the most stable conformations of 8 and 9. Cotton effects observed near the UV/Vis absorption maximum of ferrocene in CD spectra of 8 and 9 originate from the transfer of chiral information from the local secondary structure to the achiral ferrocene chromophore.

Da bi se spriječila ili potaknula aktivnost nekog proteina, potencijalni lijek mora ući u stanicu gdje se taj protein nalazi. Permeabilnost predstavlja mjeru sposobnosti lijeka da prođe kroz staničnu membranu. Neki makrociklički lijekovi mogu povećati svoju permeabilnost mijenjajući konformaciju u ovisnosti o sredini u kojoj se nalaze. Jedan od takvih „kameleonskih“ makrocikala je ciklosporin A. U ovom radu istraživani su utjecaj temperature i iona kalcija na konformaciju dva odabrana makrociklička lijeka (rifampicin i fidaksomicin), te su dobiveni rezultati uspoređivani s rezultatima dobivenim za ciklosporin A. Spektroskopija nuklearne magnetske rezonancije i molekulsko modeliranje korišteni su za generiranje najvjerojatnijih konformacijskih stanja in silico. Kompleksiranje metalnih iona s odabranim makrociklima dodatno je potvrđeno spektrometrijom masa. In order to influence the activity of a target protein, the potential drug needs to enter the cell where that protein is located. Ability of a drug to penetrate cell membranes is called permeability. Some of the macrocyclic drugs can increase their permeability through change in their conformation triggered by different surroundings. One of the macrocycles for which it has been proven to have this “chameleonic” ability is Cyclosporin A. In this research, conformational changes caused by temperature increase and addition of metal ions were investigated for two other macrocyclic drugs (Rifampicin and Fidaxomicin). Final results were compared to the ones of Cyclosporin A. Experiments were performed using nuclear magnetic resonance spectroscopy and molecular modelling to generate most probable conformations in silico. Additionally, mass spectrometry was used to confirm the complexation of macrocycles with metal ions.

U sklopu ovog rada provedena je sinteza, karakterizacija i konformacijska analiza novih derivata aromatskih trinitrozo i azo spojeva. Aromatski trinitrozo spoj pripravljen je reakcijom redukcije iz odgovarajućeg trinitro spoja te su IR spektroskopijom proučene fototermičke reakcije polimernog oblika u čvrstom stanju pri kriogenim uvjetima. Kinetika polimerizacije monomernog oblika trinitrozo spoja u čvrstom stanju, pripravljenog kriogenom fotodisocijacijom polimera, praćena je vremenski razlučenom IR spektroskopijom. Aromatski azo spojevi priređeni su Millsovom reakcijom između aromatskog trinitrozo spoja i aromatskih diamino spojeva te aromatskog triamino spoja i aromatskih dinitrozo spojeva. Pripravljeni spojevi karakterizirani su IR spektroskopijom te difrakcijom rentgenskih zraka na praškastom uzorku. Dobiveni produkti proučavani su metodama računalne kemije. Na modelnim spojevima s azodioksidnom i azo vezom odabrane su molekularno i kvantno-mehaničke metode koje dobro reproduciraju njihove eksperimentalno određene geometrije. Provedena je pretraga konformacijskog prostora pretpostavljenih modela novosintetiziranih spojeva kojom su analizirane njihove optimizirane geometrije. Dane su smjernice za daljnji dizajn sličnih spojeva. Synthesis, characterization and conformational analysis of new derivatives of aromatic trinitroso and azo compounds was performed. Aromatic trinitroso compound was prepared by reduction of trinitro derivative, and solid-state cryogenic photothermal reactions of polymeric form were studied by IR spectroscopy. Kinetics of solid-state polymerization of monomeric trinitroso compound, produced by cryogenic photodissociation of polymer, was monitored by time-resolved IR spectroscopy. Aromatic azo compounds were synthesized by Mills reaction between aromatic trinitroso compound and aromatic diamino derivatives, and aromatic triamino compound and aromatic dinitroso derivatives. Compounds were characterized by IR spectroscopy and powder X-ray diffraction. The products were investigated by computational chemistry methods. Models with azodioxide and azo bonds were used to find molecular and quantum-mechanical methods enabling reproduction of the experimentally determined geometries. Conformational space search of the assumed models of new compounds was performed and the obtained geometries were analyzed. Guidelines for future design of similar compounds were provided.

U prvom dijelu rada opisana je sinteza i konformacijska svojstva biokonjugata 21-32 [izvedenih kondenzacijom ferocen-1,1-diamina (Fcda) i prirodnih peptida Ala-Pro i Pro-Ala] i njihovih prekursora 1-14. Pripravljeni spojevi podvrgnuti su spektroskopskoj analizi (IR-, NMR- i CD-spektroskopija) i DFT-modeliranju da bi se ispitao utjecaj slijeda i kiralnosti prirodnih aminokiselina te N-terminalnih zaštitnih skupina na njihov konformacijski prostor. Pokazalo se da (i) peptidi 21-32 [Y-(AA) n-NH-Fn-NH-(AA)m-Y, Fn = ferocenilen, AA = D(L)-Pro, D(L)-Ala, Y = Ac (acetil), Boc (tert-butoksikarbonil), m,n = 1, 2] uspostavljaju interlančane intramolekulske vodikove veze (IHB) kojima se induciraju ß- i -okreti te (ii) da se promjena kiralnosti i slijeda prirodnih aminokiselina kao i zaštitnih skupina odražava na IHB-obrasce. U drugom dijelu disertacije, posvećenom konjugatima ferocenâ s ugljikohidratima, opisana je sinteza ferocenskih muropeptida N-Ac-(izo)Mur-NH-Fn-R, (44-48, Mur = muraminska kiselina, R = H, COOMe, NHAc) te konjugata N-Ac-Mur-L(D)-Ala-Fca-OMe (49-52), analoga muramildipeptida (MDP, N-Ac-Mur-Ala-izoGln). Spektroskopskom analizom potkrijepljenom DFT-računima utvrđen je utjecaj organometalnog fragmenta na konformacijska svojstva rezultirajućih konjugata. Nadalje, opisana je sinteza esterskih (61-66) i amidnih konjugata ferocenâ i manoze (67-72) koji su se pokazali inhibitorima hemaglutinacije Escherichie coli. In the first part of this dissertation the synthesis and conformational analysis of bioconjugates 21-32 [derived by condensation of ferrocene-1,1-diamine (Fcda) with natural peptides Ala-Pro and Pro-Ala] and their precursors 1-14 are described. In order to explore the impact of chirality and sequence of amino acids, as well as effect of N-protecting groups on conformational space of prepared compounds, the detailed conformational analysis (IR, NMR and CD spectroscopy, DFT calculations) was performed. It was demonstrated that (i) peptides 21-32 [Y-(AA) n -NH-Fn-NH-(AA)-Y, Fn = ferrocenylene, AA = D(L)-Pro, D(L)-Ala, Y = Ac(acetyl), Boc (tert-butoxycarbonyl), m,n = 1, 2] form ß- and -turns through intermolecular m hydrogen bonding (IHB) and (ii) chirality and sequence of amino acids as well as protecting groups affect the IHB motifs. In the second part of this dissertation, dealing with bioconjugates of ferrocenes and carbohydrates, the synthesis of ferrocene muropeptides N-Ac-(iso)Mur-NH-Fn-R, (44-48, Mur = muramic acid, R = H, COOMe, NHAc) and conjugates N-Ac-Mur-L(D)-Ala-Fca-OMe (49-52), an analogues of muramyl dipeptide (MDP, N-Ac-Mur-Ala-isoGln), was desribed. The influence of an organometallic moiety on the conformational properties of the synthesized compounds was examined by spectroscopic analysis corroborated with DFT modeling. Furthermore, the synthesis and inhibitory potency of ester and amide conjugates of ferrocene and mannose (67-72) toward Escherichia coli were presented.

Tiosemikarbazoni mogu postojati u nekoliko tautomernih oblika i konformacija, s mogućnošću stvaranja intra- i intermolekulskih vodikovih veza. Detaljna strukturna karakterizacija tiosemikarbazona, kao spojeva koji se povezuju sa širokim spektrom bioloških aktivnosti, preduvjet je za bolje razumijevanje njihove bioaktivnosti, kao i dobivanje molekula s poboljšanim farmakološkim svojstvima. Primjenom višenuklearne spektroskopije NMR (1H, 13C i 15N) u čvrstom stanju i otopini istražen je utjecaj supstituenata, prirode otapala (različitih polarnosti, odnosno različitih proton-donorskih i proton-akceptorskih svojstava) i temperature na molekulsku konformaciju, tautomeriju i prirodu vodikovih veza (intra- i intermolekulskih) derivata salicilaldehid i 2-metoksibenzaldehid tiosemikarbazona. Kombinacija poznate kristalne strukture te izmjerenih kemijskih pomaka 13C i 15N u čvrstom stanju, korištena je kao temelj za detekciju strukturnih promjena u otopini. Eksperimentalni rezultati upotpunjeni su računalnim istraživanjem konformacijskog prostora odabranih spojeva u vakuumu, i organskim otapalima (PCM pristup), kombinacijom molekulsko- i kvantno-mehaničkih metoda. Najstabilnije strukture, dobivene molekulskom mehanikom, reoptimirane su u vakuumu, CHCl3 i DMSO primjenom računskog modela B3LYP-D3/6- 311++G(2df,2p). Metodom populacijske analize QTAIM, korištenjem Koch-Popelierovih kriterija, okarakterizirane su intramolekulske vodikove veze u najstabilnijim konformerima istraživanih spojeva. Thiosemicarbazones can exist in several tautomeric forms and conformations, with the possibility of intra- and intermolecular hydrogen bonding. Detailed structural characterization of thiosemicarbazones, as compounds that are associated with a wide spectrum of biological activities, is a prerequisite for better understanding of their bioactivity and for obtaining molecules with improved pharmacological properties. Solid and solution state multinuclear NMR spectroscopy (1H, 13C i 15N) was emloyed to explore the influence of the substituents, the nature of the solvent (different polarity and different proton-donor and proton-acceptor abbilities) and temperature on the molecular conformation, tautomerism and the nature of hydrogen bonding (intra- and intermolecular) of salicylaldehyde and 2-methoxybenzaldehyde thiosemicarbazone derivatives. The combination of known crystal structures and observed 13C and 15N chemical shifts in the solid state, was used as a basis for the detection of structural changes in solution. The experimental results were complemented with computational research of conformational space of selected compounds in a vacuum, and organic solvents (PCM approach), by combination of molecular- and quantum-mechanical methods. The most stable structures, obtained by molecular mechanics, were reoptimized in vacuum, CHCl3 and DMSO with B3LYP-D3/6-311++G(2df,2p) computational model. QTAIM population analysis method, together with Koch-Popelier criteria, was used for characterization of intramolecular hydrogen bonds in most stable conformers of investigated compounds.