U ovom doktorskom radu sintetizirani su Cu(II) molekulski kompleksi Cu(1-TsC-N3)2Cl2 i Cu(1-MsC-N3)2Cl2 biološki aktivnih N-sulfonilcitozinskih (C) liganada s tosilom (Ts) i mezilom (Ms) te novi ...ciklam-TsC konjugati. Mannichova reakcija TsC liganda, paraformaldehida i ciklama u prisutnosti octene kiseline daje C-aminometilirani konjugat u kojem je ciklam vezan preko metilenskog mosta na C5 položaj citozina. Ista reakcija sa zaštićenim ciklamom daje C4 aminometilirani produkt. Pomoću ESI-MS metode provedena je studija stabilnosti i utjecaja biološki važnih metalnih iona (Na+, K+, Ca2+, Mg2+, Zn2+, Cu2+) na ligande, Cu(II) komplekse, te na poliaza makrocikličke konjugate. U interakciji s ligandima i Cu(II) kompleksima alkalijski metali uslijed elektrostatskih interakcija stvaraju klastere, dok je nastanak bis i tris te miješanih kompleksa uočen u interakciji s Ca2+ i Mg2+. Interakcija Zn2+ s ligandima i Cu(II) kompleksima rezultira nastankom monometalnih kompleksa kao i dimetalnih kompleksa zbog afniteta Zn2+ prema atomima kisika i dušika koji u strukturu uključuju molekule vode. Novi poliaza makrociklički konjugati u interakciji s CuCl2 stvaraju molekulske komplekse u kojima je CuCl2 u ciklamskom prstenu, a u interakciji s ZnSO4 nastaju ionski kompleksi u kojima je Zn2+ smješten u ciklamskom prstenu.
Abstract In this doctoral thesis, Cu (II) molecular complexes Cu(1-TsC-N3)2Cl2 and Cu(1-MsC-N3)2Cl2 of biologically active N-sulfonylcytosine ligands (C) with tosyl (Ts) and mesyl (Ms) and new cyclame-TsC conjugates were synthesized. The Mannich reaction of TsC, paraformaldehyde and cyclame in the presence of acetic acid yields C-aminomethylated konjugate in which the cyclame was introduced through a methylene bridge at C5 position of cytosine. The same reaction with protected cyclame gives C4 aminomethylated product. Using ESI-MS method was conducted stability studies and the influence of biologically important metal ions (Na+, K+, Ca2+, Mg2+, Zn2+, Cu2+) to ligands, Cu (II) complexes, and polyaza macrocyclic conjugates. The interaction of ligands and Cu (II) complexes with biologically important metal ions results with formation of various metal complex. Alkali metals Na+ and K+ formed clusters due to the electrostatic inetractions. Bis, tris and mixed ligand complexes were observed upon mixing with Ca2+ or Mg2+ salt. Interaction with Zn2+ sieed monometal Zn2+ complexes and mixed ligand dimetal complexes that includ water molecules in the structures of the complexes because of affinity of Zn2+ for both O and N atoms. Both ions Cu2+ and Zn2+ were located within the cyclamic ring upon their interaction with polyaza macrocyclic conjugates. Newly formed Cu2+complexes were molecular while the ionic complexes were formed with zinc ions.
Peptidi i proteini imaju ključnu ulogu u nizu bioloških i fizioloških procesa; međutim, njihova primjena kao terapeutika je ograničena slabom stabilnošću i biodostupnošću. Stoga je razvoj ...peptidomimetika, spojeva koji oponašaju strukturu i/ili funkciju proteina od velikog značaja za akademsku zajednicu i farmaceutsku industriju. Cilj istraživanja predloženih u okviru doktorske disertacije je priprava peptidomimetika korištenjem hidrazino-derivata -aminokiselina. Istraživanja će uključivati: razvoj metodologije za pripravu optički čistih hidrazino-derivata -aminokiselina te razvoj metodologije za pripravu hidrazino-peptidomimetika postupnom sintezom u otopini i primjenom u višekomponentnim reakcijama. Istraživanja bi trebala rezultirati optimiranim uvjetima priprave hidrazino-derivata -aminokiselina i hidrazino-peptidomimetika te potpuno novom skupinom peptidomimetika s ugrađenom hidrazino-jedinicom.
Peptides and proteins have a crucial role in a number of biological and physiological processes; however, their use as therapeutics is limited by poor stability and bioavailability. Therefore, the development of peptidomimetics, compounds that mimic structure and/or function of proteins is of great importance for the academic community and the pharmaceutical industry. The objective of the research proposed in this doctoral thesis is the preparation of peptidomimetics using hydrazino derivatives of -amino acids. Therefore, studies include: development of methodologies for the preparation of optically pure hydrazino derivatives of -amino acids; development of methodology for the preparation of hydrazino peptidomimetics by stepwise synthesis in solution and by multicomponent reactions. Expected results are: optimized conditions for the preparation of hydrazino derivatives of -amino acids and hydrazino peptidomimetics and a new class of peptidomimetics comprising hydrazino moiety. Item Type: Thesis (Doctoral thesis)
Na temelju prethodno konstruirane ljestvice elektrofugalnosti, temeljene na benzhidrilnome
sustavu, te izmjerenih konstanti brzine solvolize, a prema LFER jednadžbi reaktivnosti log k
= sf(Nf + Ef), ...određene su nukleofugalnosti raznih izlaznih skupina. Pri tome parametar
elektrofugalnosti, Ef, definira heterolitičku reaktivnost kationskog dijela supstrata, a parametri
nukleofugalnosti, Nf i sf, definiraju reaktivnost izlazne skupine u kombinaciji s otapalom u
kojem se provodi solvoliza. Različito supstituiranim fenolatima, benzoatima i alifatskim
karboksilatima određena je nukleofugalnost u raznim otapalima, čime je nadopunjena
postojeća ljestvica nukleofugalnosti novim izlaznim skupinama.
Nadalje, istraženi su utjecaji strukturnih i solvatacijskih efekata na reaktivnost izlaznih
skupina. Tako je utvrđeno da supstituenti utječu na solvolitičku reaktivnost benzoata
induktivnim efektom i efektom polja te da polarnost otapala može uvjetovati relativne
doprinose ovih elektronskih efekata za različita mjesta supstitucije na prstenu.
Unatoč razlikama u strukturama i stabilizacijskim efektima koji utječu na solvolitičku
reaktivnost istraženih supstrata, ovaj LFER model pokazuje održivost i konzistentnost u
koreliranju solvolitičke reaktivnosti i strukture.
Uz eksperimentalne metode pokazana je i mogućnost proširenja ljestvice nukleofugalnosti na
temelju korelacije eksperimentalnih i kvantno-kemijskih podataka reaktivnosti.
On the basis of the established electrofugality scale developed for the benzhydrylium system
and measured solvolytic rate constants, it is possible to define nucleofugalities of various
leaving groups according to the LFER equation log k = sf(Nf + Ef). Electrofugality parameter
(Ef) defines heterolytic reactivity of the cationic part of substrates, whereas nucleofugality
parameters (Nf and sf) define the reactivity of a leaving group in the combination with
employed solvent.
Following syntheses of benzhydrylium derivates, nucleofugalities of variously substituted
phenolates, benzoates and other carboxylates in combinations with different solvents have
been determined. Hereby, the existing nucleofugality scale is supplemented with new leaving
groups different in type and structure.
In addition, impacts of structural and solvation effects on both nucleofugalities of leaving
groups and overall heterolytic reactivities of substrates undergoing solvolysis have been
investigated. Despite the differences in the structures and stabilization effects that govern the
solvolytic reactivities of invastegated substrates, this LFER model demonstrates both
sustainability and consistency in relating the solvolytic reactivity with a structure.
In order to supplement the nucleofugality scale with new data, the possibilities of correlating
the experimental free energies of activation with activation energies afforded by quantumchemical
models have been investigated.
