Oksidacije 1-benzotiofena (tianaftena)

Aromatski heterociklički spoj 1-benzotiofen, oksidacijom se prevodi iz sulfida u odgovarajući sulfon, 1 -benzotiofen-1,1-dioksid. U ovom radu 1 -benzotiofen je oksidiran u 1-benzotiofen-1,1-dioksid korištenjem vodene otopine vodikova peroksida i ledene octene kiseline kao otapala, uz refluksiranje i to u vrlo dobrom iskorištenju od 71 %. Oksidacija 1- benzotiofena je provedena i uz oksidirajući reagens H2O2-P2O5 i acetonitril kao otapalo, sa ili bez refluksiranja. Ovisno o metodi, iskorištenja su bila 3-48%. Korištenje H2O2-P2O5 reagensa je ekološki prihvatljivo i pokazalo se kao dosta dobro oksidacijsko sredstvo, koje se može primjeniti i za druge heterocikličke spojeve koji sadrže sumpor, a u slučaju 1 - benzotiofena osobito onda kada sadrži elektron-akceptorske skupine (EWG).The aromatic heterocyclic compound 1-benzothiophene can be oxidized from its sulfide functional group into a sulfone, 1-benzothiophene-1,1-dioxide. In this work 1- benzothiophene is oxidized into 1 -benzothiophene-1,1-dioxide by heating an aqueous solution of hydrogen peroxide and glacial acetic acid as a solvent at reflux, with a very good yield of 71 %. Oxidation of 1-benzothiophene was carried out with H2O2-P2O5 reagent and acetonitrile as solvent, with and without reflux. Depending on the method, yields were ranging from 3-48%. The use of H2O2-P2O5 reagent is environmentally acceptable and it has been demonstrated to be a good oxidation agent which can be applied for other heterocyclic compound that contain sulfur, especially for 1-benzothiophenes that contain electron-withdrawing groups (EWG)

Oksidacije 1-benzotiofena (tianaftena)

Aromatski heterociklički spoj 1-benzotiofen, oksidacijom se prevodi iz sulfida u odgovarajući sulfon, 1 -benzotiofen-1,1-dioksid. U ovom radu 1 -benzotiofen je oksidiran u 1-benzotiofen-1,1-dioksid korištenjem vodene otopine vodikova peroksida i ledene octene kiseline kao otapala, uz refluksiranje i to u vrlo dobrom iskorištenju od 71 %. Oksidacija 1- benzotiofena je provedena i uz oksidirajući reagens H2O2-P2O5 i acetonitril kao otapalo, sa ili bez refluksiranja. Ovisno o metodi, iskorištenja su bila 3-48%. Korištenje H2O2-P2O5 reagensa je ekološki prihvatljivo i pokazalo se kao dosta dobro oksidacijsko sredstvo, koje se može primjeniti i za druge heterocikličke spojeve koji sadrže sumpor, a u slučaju 1 - benzotiofena osobito onda kada sadrži elektron-akceptorske skupine (EWG).The aromatic heterocyclic compound 1-benzothiophene can be oxidized from its sulfide functional group into a sulfone, 1-benzothiophene-1,1-dioxide. In this work 1- benzothiophene is oxidized into 1 -benzothiophene-1,1-dioxide by heating an aqueous solution of hydrogen peroxide and glacial acetic acid as a solvent at reflux, with a very good yield of 71 %. Oxidation of 1-benzothiophene was carried out with H2O2-P2O5 reagent and acetonitrile as solvent, with and without reflux. Depending on the method, yields were ranging from 3-48%. The use of H2O2-P2O5 reagent is environmentally acceptable and it has been demonstrated to be a good oxidation agent which can be applied for other heterocyclic compound that contain sulfur, especially for 1-benzothiophenes that contain electron-withdrawing groups (EWG)

Endiinski spojevi u višekomponentnim reakcijama

Trokomponentna Passerinijeva i četverokomponentna Ugijeva reakcija pripadaju skupini višekomponentnih reakcija koje uključuju izocijanidnu komponentu. Do sada u literaturi nije opisana primjena ovih reakcija u sintezi spojeva s endiinskim motivom. Stoga je cilj istraživanja provedenih u okviru ove doktorske disertacije bio primjena Passerinijeve i Ugijeve reakcije u sintezi endiinskih peptidomimetika. Pripravljena su četiri aldehida s različitom duljinom alkilne razmaknice u iskorištenju 78 - 96 %. Dobiveni aldehidi korišteni su u Passerinijevoj i Ugijevoj reakciji te je sintetiziran dvadeset jedan Passerinijev produkt u iskorištenju 29 - 92 % i trideset dva Ugijeva produkta u iskorištenju 13 - 93 %. Dokazana je mogućnost postmodifikacija Passerinijevih i Ugijevih produkata. Pripravljen je jedan postmodificirani Passerinijev produkt u 50%-tnom iskorištenju te dvadeset pet Sonogashirinih produkata u iskorištenju 34 - 99 %. Ciklizacijom Sonogashirinih produkata dobiveno je šesnaest makrocikličkih spojeva s endiinskim motivom i esterskom vezom u iskorištenju 9 - 68 %

Synthesis and Anion Binding Assessment of Novel Adamantane Amidopyrroles

Two new adamantane anion receptors with amidopyrrole side arms were prepared and their anion binding ability in DMSO solutions with TBA salts (Cl–, AcO– and H2PO4–) was investigated by UV/Vis spectroscopy. After calculating the corresponding association constants of receptor-anion complexes, it became apparent that only one amidopyrrole side arm was engaged in complexation. These experimental findings were rationalized using computational tools and the binding mode was proposed. In addition to the found 1 : 1 stoichiometry, we showed that the studied receptors bind oxo-anions (H2PO4– and AcO–) more strongly than spherical halogenide (Cl–) anions

Enediyne compounds in multicomponent reactions

Trokomponentna Passerinijeva i četverokomponentna Ugijeva reakcija pripadaju skupini višekomponentnih reakcija koje uključuju izocijanidnu komponentu. Do sada u literaturi nije opisana primjena ovih reakcija u sintezi spojeva s endiinskim motivom. Stoga je cilj istraživanja provedenih u okviru ove doktorske disertacije bio primjena Passerinijeve i Ugijeve reakcije u sintezi endiinskih peptidomimetika. Pripravljena su četiri aldehida s različitom duljinom alkilne razmaknice u iskorištenju 78 - 96 %. Dobiveni aldehidi korišteni su u Passerinijevoj i Ugijevoj reakciji te je sintetiziran dvadeset jedan Passerinijev produkt u iskorištenju 29 - 92 % i trideset dva Ugijeva produkta u iskorištenju 13 - 93 %. Dokazana je mogućnost postmodifikacija Passerinijevih i Ugijevih produkata. Pripravljen je jedan postmodificirani Passerinijev produkt u 50%-tnom iskorištenju te dvadeset pet Sonogashirinih produkata u iskorištenju 34 - 99 %. Ciklizacijom Sonogashirinih produkata dobiveno je šesnaest makrocikličkih spojeva s endiinskim motivom i esterskom vezom u iskorištenju 9 - 68 %.Isocyanide-based multicomponent reactions (IMCRs) include a three-component Passerini and a four-component Ugi reaction. To the best of our knowledge, multicomponent reactions haven't been utilized in the synthesis of compounds with enediyne motif. Therefore, the aim of studies carried out within the frame of this doctoral thesis was utilizing Passerini and Ugi reaction in the synthesis of enediyne peptiodmimetics. Four aldehydes with different alkyl chains were prepared in 78 - 96 % yield. The aldehydes were utilizing in the Passerini and Ugi reaction and twenty one Passerini products in 29 - 92 % yield were prepared along with thirty two Ugi products obtained in 13 - 93 % yield. The possibility of post-condensation modifications was proved. One post-modificated Passerini product in 50 % yield and twenty five Sonogashira products in 34 - 99 % yield were prepared. Cyclisation of Sonogashira products gave sixteen macrocyclic lactones with endiyne motif in 9 - 68 % yield

Enediyne compounds in multicomponent reactions

Trokomponentna Passerinijeva i četverokomponentna Ugijeva reakcija pripadaju skupini višekomponentnih reakcija koje uključuju izocijanidnu komponentu. Do sada u literaturi nije opisana primjena ovih reakcija u sintezi spojeva s endiinskim motivom. Stoga je cilj istraživanja provedenih u okviru ove doktorske disertacije bio primjena Passerinijeve i Ugijeve reakcije u sintezi endiinskih peptidomimetika. Pripravljena su četiri aldehida s različitom duljinom alkilne razmaknice u iskorištenju 78 - 96 %. Dobiveni aldehidi korišteni su u Passerinijevoj i Ugijevoj reakciji te je sintetiziran dvadeset jedan Passerinijev produkt u iskorištenju 29 - 92 % i trideset dva Ugijeva produkta u iskorištenju 13 - 93 %. Dokazana je mogućnost postmodifikacija Passerinijevih i Ugijevih produkata. Pripravljen je jedan postmodificirani Passerinijev produkt u 50%-tnom iskorištenju te dvadeset pet Sonogashirinih produkata u iskorištenju 34 - 99 %. Ciklizacijom Sonogashirinih produkata dobiveno je šesnaest makrocikličkih spojeva s endiinskim motivom i esterskom vezom u iskorištenju 9 - 68 %.Isocyanide-based multicomponent reactions (IMCRs) include a three-component Passerini and a four-component Ugi reaction. To the best of our knowledge, multicomponent reactions haven't been utilized in the synthesis of compounds with enediyne motif. Therefore, the aim of studies carried out within the frame of this doctoral thesis was utilizing Passerini and Ugi reaction in the synthesis of enediyne peptiodmimetics. Four aldehydes with different alkyl chains were prepared in 78 - 96 % yield. The aldehydes were utilizing in the Passerini and Ugi reaction and twenty one Passerini products in 29 - 92 % yield were prepared along with thirty two Ugi products obtained in 13 - 93 % yield. The possibility of post-condensation modifications was proved. One post-modificated Passerini product in 50 % yield and twenty five Sonogashira products in 34 - 99 % yield were prepared. Cyclisation of Sonogashira products gave sixteen macrocyclic lactones with endiyne motif in 9 - 68 % yield

Enediyne compounds in multicomponent reactions

Trokomponentna Passerinijeva i četverokomponentna Ugijeva reakcija pripadaju skupini višekomponentnih reakcija koje uključuju izocijanidnu komponentu. Do sada u literaturi nije opisana primjena ovih reakcija u sintezi spojeva s endiinskim motivom. Stoga je cilj istraživanja provedenih u okviru ove doktorske disertacije bio primjena Passerinijeve i Ugijeve reakcije u sintezi endiinskih peptidomimetika. Pripravljena su četiri aldehida s različitom duljinom alkilne razmaknice u iskorištenju 78 - 96 %. Dobiveni aldehidi korišteni su u Passerinijevoj i Ugijevoj reakciji te je sintetiziran dvadeset jedan Passerinijev produkt u iskorištenju 29 - 92 % i trideset dva Ugijeva produkta u iskorištenju 13 - 93 %. Dokazana je mogućnost postmodifikacija Passerinijevih i Ugijevih produkata. Pripravljen je jedan postmodificirani Passerinijev produkt u 50%-tnom iskorištenju te dvadeset pet Sonogashirinih produkata u iskorištenju 34 - 99 %. Ciklizacijom Sonogashirinih produkata dobiveno je šesnaest makrocikličkih spojeva s endiinskim motivom i esterskom vezom u iskorištenju 9 - 68 %.Isocyanide-based multicomponent reactions (IMCRs) include a three-component Passerini and a four-component Ugi reaction. To the best of our knowledge, multicomponent reactions haven't been utilized in the synthesis of compounds with enediyne motif. Therefore, the aim of studies carried out within the frame of this doctoral thesis was utilizing Passerini and Ugi reaction in the synthesis of enediyne peptiodmimetics. Four aldehydes with different alkyl chains were prepared in 78 - 96 % yield. The aldehydes were utilizing in the Passerini and Ugi reaction and twenty one Passerini products in 29 - 92 % yield were prepared along with thirty two Ugi products obtained in 13 - 93 % yield. The possibility of post-condensation modifications was proved. One post-modificated Passerini product in 50 % yield and twenty five Sonogashira products in 34 - 99 % yield were prepared. Cyclisation of Sonogashira products gave sixteen macrocyclic lactones with endiyne motif in 9 - 68 % yield

Vasopressin and Its Analogues: From Natural Hormones to Multitasking Peptides

Human neurohormone vasopressin (AVP) is synthesized in overlapping regions in the hypothalamus. It is mainly known for its vasoconstricting abilities, and it is responsible for the regulation of plasma osmolality by maintaining fluid homeostasis. Over years, many attempts have been made to modify this hormone and find AVP analogues with different pharmacological profiles that could overcome its limitations. Non-peptide AVP analogues with low molecular weight presented good affinity to AVP receptors. Natural peptide counterparts, found in animals, are successfully applied as therapeutics; for instance, lypressin used in treatment of diabetes insipidus. Synthetic peptide analogues compensate for the shortcomings of AVP. Desmopressin is more resistant to proteolysis and presents mainly antidiuretic effects, while terlipressin is a long-acting AVP analogue and a drug recommended in the treatment of varicose bleeding in patients with liver cirrhosis. Recently published results on diverse applications of AVP analogues in medicinal practice, including potential lypressin, terlipressin and ornipressin in the treatment of SARS-CoV-2, are discussed

Dipeptides Containing Pyrene and Modified Photochemically Reactive Tyrosine: Noncovalent and Covalent Binding to Polynucleotides

Dipeptides 1 and 2 were synthesized from unnatural amino acids containing pyrene as a fluorescent label and polynucleotide binding unit, and modified tyrosine as a photochemically reactive unit. Photophysical properties of the peptides were investigated by steady-state and time-resolved fluorescence. Both peptides are fluorescent (Φf = 0.3–0.4) and do not show a tendency to form pyrene excimers in the concentration range −5 M, which is important for their application in the fluorescent labeling of polynucleotides. Furthermore, both peptides are photochemically reactive and undergo deamination delivering quinone methides (QMs) (ΦR = 0.01–0.02), as indicated from the preparative photomethanolysis study of the corresponding N-Boc protected derivatives 7 and 8. Both peptides form stable complexes with polynucleotides (log Ka > 6) by noncovalent interactions and similar affinities, binding to minor grooves, preferably to the AT reach regions. Peptide 2 with a longer spacer between the fluorophore and the photo-activable unit undergoes a more efficient deamination reaction, based on the comparison with the N-Boc protected derivatives. Upon light excitation of the complex 2·oligoAT10, the photo-generation of QM initiates the alkylation, which results in the fluorescent labeling of the oligonucleotide. This study demonstrated, as a proof of principle, that small molecules can combine dual forms of fluorescent labeling of polynucleotides, whereby initial addition of the dye rapidly forms a reversible high-affinity noncovalent complex with ds-DNA/RNA, which can be, upon irradiation by light, converted to the irreversible (covalent) form. Such a dual labeling ability of a dye could have many applications in biomedicinal sciences

Synthesis of Novel Arginine Building Blocks with Increased Lipophilicity Compatible with Solid-Phase Peptide Synthesis

Arginine, due to the guanidine moiety, increases peptides’ hydrophilicity and enables interactions with charged molecules, but at the same time, its presence in a peptide chain might reduce its permeability through biological membranes. This might be resolved by temporary coverage of the peptide charge by lipophilic, enzyme-sensitive alkoxycarbonyl groups. Unfortunately, such a modification of a guanidine moiety has not been reported to date and turned out to be challenging. Here, we present a new, optimized strategy to obtain arginine building blocks with increased lipophilicity that were successfully utilized in the solid-phase peptide synthesis of novel arginine vasopressin prodrugs