Title Priprema meso-(N, N-dietilaminofenil)porfirina i njihova N-oksidacija Title (english) Preparation of meso-(N, N-diethylaminophenyl)porphyrins and their N-oxidation Author Ivana Gvozdić Mentor Nela Malatesti (mentor)Committee member Duško Čakara (predsjednik povjerenstva)Committee member Nela Malatesti (član povjerenstva)Committee member Christian Andrew Reynolds (član povjerenstva)Granter University of Rijeka Defense date and country 2024-09-24, Croatia Scientific / art field, BIOTECHNICAL SCIENCES Abstract Fotodinamička terapija (PDT) je inovativni tretman koji selektivno cilja maligne stanice uz minimalnu štetu zdravom tkivu, čineći je učinkovitom za tumore i određene kožne bolesti. Postupak uključuje akumulaciju fotosenzibilizatora (PS) u tumorskom tkivu, osvjetljavanje zahvaćenog područja određenom valnom duljinom što rezultira stvaranjem reaktivnih kisikovih spojeva (ROS). Iako općenito neučinkovita protiv metastaza, PDT se može kombinirati s drugim terapijama kao što su kemoterapija ili radioterapija kako bi se poboljšala njezina učinkovitost i prevladali njeni nedostaci. Za učinkovitu terapiju ključno je odabrati optimalan fotosenzibilizator koji je dobro topiv u vodenim otopinama, netoksičan u mraku, učinkovito apsorbira u vidljivom dijelu spektra te učinkovito proizvodi singletni kisik i drugih ROS. Vrlo je bitan optimalan omjer lipofilnih i hidrofilnih dijelova u strukturi fotosenzibilizatora kako bi se olakšala akumulacija u tumorskim stanicama, što se postiže modifikacijama početnih struktura fotosenzibilizatora.
Simetrični meso-tetra-(4-dietilaminofenil)porfirin i njegovi asimetrični derivati u kombinaciji s 4-acetamidofenilnim supstituentima uspješno su izolirani za upotrebu kao fotosenzibilizatori u PDT-u. Sve nove strukture i njihova čistoća potvrđeni su 1H i 13C NMR spektroskopijom. Spojevi su pokazali apsorpciju u crvenom dijelu spektra, izuzetnu fotostabilnost i učinkovitu proizvodnju singletnog kisika, osobito 5-[4-(N-acetamido)fenil]-10,15,20-tri(4-(N,N-dietilamino)fenil)porfirin(A3B). Fototoksičnost sintetiziranih PS-ova ispitivana je MTT testom uz osvjetljavanje crvenim svjetlom (λ = 643 nm, 2 mW/cm2) na dvije tumorske stanične linije, MDA-MB 231 i HeLa, te na HFF kao normalnoj staničnoj liniji. Simetrični 5,10,15,20-tetra(N,N-dietil-4-aminofenil)porfirin (A4) zbog slabe topljivosti nije pokazao citotoksičan učinak, dok A3B, unatoč najefikasnijoj generaciji singletnog kisika, pokazao je smanjenu citotoksičnost u usporedbi sa 5,15-di[4-(N-acetamido)fenil]-10,20-di(4-(N,N-dietilamino)fenil)porfirin (trans-A2B2) i 5,10-di[4-(N-acetamido) fenil]-15,20-di(4-(N,N-dietilamino)fenil)porfirin (cis-A2B2) koji su pokazali najjaču citotoksičnost, ali ne i selektivnost prema tumorskim stanicama. Potrebne su daljnje modifikacije struktura dobivenih porfirina kako bi se poboljšala svojstva i postigli učinkovitiji fotosenzibilizatori.
Abstract (english) Summary
Photodynamic therapy (PDT) is an innovative treatment that selectively targets malignant cells while causing as little damage as possible to healthy tissue and it is, therefore, effective for tumors and certain skin diseases. The process involves the accumulation of photosensitizer (PS) in the tumor tissue, the illumination of the affected area with a specific wavelength and the generation of reactive oxygen species (ROS). Although PDT is generally ineffective against metastases, it can be combined with other therapies such as chemotherapy or radiotherapy to increase its effectiveness and overcome its limitations. For effective therapy, it is crucial to select an optimal PS that is highly soluble in aqueous solutions, non-toxic in the dark, has effective absorption in the visible spectrum, and efficiently generates singlet oxygen and ROS. The optimal ratio of lipophilic and hydrophilic parts in the structure of the PS is crucial for accumulation in tumor cells, which is achieved by various modifications of the original PS structure.
Symmetric meso-tetra-(4-diethylaminophenyl)porphyrin and its asymmetric derivatives with 4-acetamidophenyl substituents were successfully isolated for use as PSs in PDT. All new structures and their purity were confirmed by 1H and 13C NMR spectroscopy. They showed absorption in the red region of the spectrum, exceptional photostability and effective singlet oxygen production, especially the 5-[4-(N-acetamido)phenyl]-10,15,20-tri(4-(N,N-diethylamino) phenyl)porphyrin (A3B). The phototoxicity of the PSs was investigated using red light and MTT assay (λ = 643 nm, 2 mW/cm2) on two tumor cell lines, MDA-MB 231 and HeLa, and HFF as a normal cell line. Symmetric 5,10,15,20-tetra(N,N-diethyl-4-aminophenyl)porphyrin (A4) showed no cytotoxic effect due to its poor solubility, while A3B showed no cytotoxic effect despite its highly efficient production of singlet oxygen, in contrast to 5,15-di[4-(N-acetamido)phenyl]-10,20-di(4-(N,N-diethylamino)phenyl)porphyrin (trans-A2B2) and 5,10-di[4-(N-acetamido)phenyl]-15,20-di(4-(N,N-diethylamino) phenyl)porphyrin (cis-A2B2)which showed cytotoxic effects but no selectivity towards tumor cells. Further modifications of the obtained porphyrin structures are required to improve their properties and to develop more effective photosensitizers.
Keywords
Fotodinamička terapija (PDT)
fotosenzibilizator (PS)
reaktivni kisikovi spojevi
meso-tetra-(4-diethylaminophenyl)porfirin
singletni kiskik
citotoksični efekt
Keywords (english)
Photodynamic therapy (PDT)
photosensitizer (PS)
reactive oxygen species (ROS)
meso-tetra-(4-diethylaminophenyl)porphyrin
singlet oxygen
cytotoxic effect
Language croatian URN:NBN urn:nbn:hr:193:118255 Study programme Title: Medicinal chemistry Type of resource Text File origin Born digital Access conditions Embargoed access Terms of use Created on 2024-09-24 16:18:29
