Synthesis of new tripyridyl amphiphilic porphyrins for use in photodynamic therapy

Fotodinamička terapija je selektivna metoda liječenja tumora i ostalih bolesti koja kombinira elektromagnetsko zračenje određene valne duljine i fotosenzibilizator, tvar osjetljivu na navedeno zračenje, uz prisutnostost kisika kako bi uništila ciljane stanice bez nepovoljnih sistemskih učinaka na organizam pacijenta. Dobar fotosenzibilizator uz niz fotofizičkih treba imati i povoljan omjer hidrofilnih i lipofilnih svojstava kako bi se mogao administrirati u vodenom mediju i ne stvarati agregate, a istovremeno prelaziti staničnu membranu i nakupljati se u tumorskim stanicama. Poznato je kako porfirini imaju većinu poželjnih svojstava dobrih fotosenzibilizatora, a studije ukazuju kako trikationski porfirini s 3-piridilnim supstituentima uz jednu slobodnu meso poziciju za daljnju funkcionalizaciju čine dobar temelj strukture fotosenzibilizatora. Također, konjugacija s masnim kiselinama može povećati fotodinamičku aktivnost i selektivnost za tumorske stanice. Kako bi nastavili istraživanje u navedenom pravcu u ovom su radu sintetizirani novi 3- i 4-piridilni derivati porfirina. Konjugati su pripremljeni pomoću asimetričnog tripiridilnog porfirina dobivenog modificiranom Adler - Longo sintezom i njegovim daljnjim modifikacijama; konjugacijom sa stearoil- i oleoil-kloridom te kvaternizacijom piridinskih dušika jodmetanom i meta-klorperbenzojevom kiselinom. Tako su pripravljeni amfifilni kationski i zwitterionski spojevi s dugim alifatskim lancima koji bi mogli imati odgovarajuću ravnotežu hidrofilnih i lipofilnih svojstava u molekuli za potencijalnu primjenu u fotodinamičkoj terapiji. Svi novo pripravljeni spojevi izolirani su u čistom stanju, a strukture su potvrđene i okarakterizirane 1H i 13C NMR, UV/VIS, fluorescentnim i masenim spektrima. Spojevi su namijenjeni daljnjem testiranju in vitro fotodinamičke aktivnosti u bakterijskim i tumorskim stanicama.Photodynamic therapy is a selective method for treating cancer and various other diseases which combines light of appropriate wavelength and photosensitizer sensitive to that light with oxygen to produce toxic effects on targeted cells in immediate surroundings without systemic adverse effects on a patient. Ideal photosensitizer, apart certain photophysical properties, also needs to have appropriate ratio between hydrophilic and lipophilic properties in order to be administered in aqueous medium without aggregating, to traverse cell membranes through lipid layers, and accumulate in tumor cells. Porphyrins are known to possess many of the desired properties of a good photosensitizer and studies have shown that tricationic porphyrins with 3-pyridyl substituents with one free meso position for further functionalization make a good photosensitizer basis. Moreover, conjugation with fatty acids has shown to increase compound's photodynamic activity and selectivity for tumor cells. In order to further investigate the effects of different modifications, in this research new 3- and 4-pyridyl derivatives of porphyrins were synthesized. Conjugates were prepared from asymmetric tripyridyl porphyrins made in modified Adler – Longo synthesis and their further modifications; bonding with long alkyl chains of stearic and oleic acid in reactions with their chlorides and quaternization of pyridyl nitrogens with iodomethane and meta-chloroperbenzoic acid. Thus, final amphiphilic cationic and zwitterionic compounds with long alkyl chains are prepared that might have the required balance between hydrophilic and lipophilic properties for potential use in photodynamic therapy. All new compounds were isolated pure and their structures were confirmed and analyzed by 1H and 13C NMR, UV/VIS, fluorescence spectroscopy and mass spectrometry. Future work involves testing these products for in vitro photodynamic activity in bacterial and tumor cells