Conjugation of porphyrins with DL-buthionine sulfoximine and D-erythro sphingosine

Fotodinamička terapija (PDT) se sve više upotrebljava u liječenju raka, ali i mnogih drugih bolesti. Da bi PDT bila uspješna, potrebne su tri komponente; fotosenzibilizator (PS), izvor svjetla i kisik. Najčešći PS-i su porfirini, tetrapirolni aromatski spojevi. Do danas su u upotrebi 3 generacije PS-a. Prvu čine prirodni spojevi, drugu sintetski, dok treću generaciju predstavljaju PS-i sintetskog porijekla konjugirani s biološki aktivnim molekulama. Biološki aktivne molekule predstavljene u ovom radu su DL-butioninsulfoksimin (BSO) i D-eritrosfingozin. BSO pripada skupini sulfoksiimina, a glavna uloga ove molekule je inhibicija glutationa (GSH), jednog od najvažnijih antioksidansa stanice. D-eritrosfingozin je produkt raspada ceramida i vrlo je potentan inhibitor enzima protein kinaze C (PKC) i sfingozin kinaze koji su potencijalne mete u liječenju raka. U ovom radu je Adler-Longo metodom sintetiziran 5-(4-aminofenil)-10,15,20-tris(3-piridil)porfirin koji je korišten za daljnje modifikacije i konjugacije. Uspješno izvedenim reakcijama sa sukcinanhidridnom odnosno 1,1'-tiokarbonildi-2(1H)-piridonom (TDP) dobivena je reaktivna skupina porfirina na kojoj su se odvijale konjugacije s D-eritrosfingozinom i BSO. Iako su željene konjugacije izvršene, u ovom radu, dobiveni konjugati nisu do kraja pročišćeni zbog niskih iskorištenja u početnim reakcijama sinteze porfirina. Međutim, stvaranje novih konjugata je spektroskopski potvrđeno i otvara put prema optimizaciji sintetskih puteva i dobivanju čistih konačnih produkata u budućim sintezama.Photodynamic therapy (PDT) is increasingly used in cancer treatment, as well as in treatment of other diseases. For PDT to be efficient, there is a need for three components: photosensitizer (PS), source of light and oxygen. The most common PSs are porphyrins, tetrapirole aromatic compounds. Nowadays, there are three generations of PS that are being used. They are: natural compounds, synthetic compounds and synthetic compounds that are conjugated with biologically active molecules. Biologically active molecules that are part of this paper are DL-buthionine sulfoximine (BSO) and D-erythro sphingosine. BSO belongs to the group of sulfoximines and its main role is inhibition of glutathione (GSH), which is one of the most important cell antioxidant. D-erythro sphingosine is a product of ceramide breakup and it is very potent inhibitor of enzymes protein kinase C (PKC) and sphingosine kinase which are potential target in cancer treatment. In this paper, 5-(4-aminophenyl)-10,15,20-tris(3-pyridyl)porphyrin is synthesized by using Adler-Longo method and used for further modifications and conjugations. Successfully performed reactions with succinic anhydride, and with 1,1′-thiocarbonyldi-2(1H)-pyridone (TDP), yielded a reactive group of porphyrins that are used for conjugations of porphyrins with D-erythrophingosine and BSO. Although the desired conjugations have been performed, new conjugates have not been completely purified due to low yielding condensation reaction in early synthetic steps. However, the formation of new conjugates was confirmed by spectroscopy and it paves the way toward optimisation of the synthetic pathway that will allow the preparation of the purified final products in future synthesis.