Journal of Porphyrins and Phthalocyanines J. Porphyrins Phthalocyanines 2010; 14: 832–845 DOI: 10.1142/S108842461000263X Published at http://www.worldscinet.com/jpp/ Copyright © 2010 World Scientific Publishing Company INTRODUCTION Modern medicine is increasingly concerned with treat- ment strategies that specifically target only the diseased tissue, protecting as much as possible viable tissues. Pho- todynamic therapy (PDT) has thus evolved, combining focused light illumination with photodynamic action. In the presence of a photosensitizer (sens), visible light and molecular oxygen, which have low intrinsic toxicity, may lead to localized damage of diseased tissues. Dam- age can occur by two mechanisms: types I and II. Type I refers to the transfer of electrons from sens to other molecules, generating reactive oxygen species (ROS) and radical species (R.) [1, 2], culminating in damage to biomolecules. On the other hand, singlet oxygen ( 1 O 2 ) may induce cellular damage through mechanism type II [3, 4], whereby the energy of the triplet state of sens is transferred to molecular oxygen in the fundamental state, generating singlet oxygen, 1 O 2 , which is capable of dam- aging membranes, proteins and DNA, either directly or by formation of R. [5–8]. Whichever the mechanism, the overall result is the possibility of destruction of diseased tissues, such as Relationship between structure and photoactivity of porphyrins derived from protoporphyrin IX Adjaci F. Uchoa* a , Carla S. Oliveira b and Mauricio S. Baptista* a a Instituto de Química, Departamento de Bioquímica e Departmamento de Química, Universidade de São Paulo, Av. Prof. Lineu Prestes 748, São Paulo SP 05508-900, Brazil b Department of Morphophysiology, Center of Biological Sciences and of Health, Biochemistry Laboratory, Universidade do Mato Grosso do Sul, Cidade Universitária, Campo Grande MS 79070-900, Brazil Received 11 February 2010 Accepted 23 July 2010 ABSTRACT: Protoporphyrin (Pp IX) derivatives were prepared to study the relationship between photosensitizer structure and photoactivity, with an emphasis on understanding the role of membrane interactions in the efficiency of photosensitizers used in photodynamic therapy (PDT). The synthetic strategies described here aimed at changing protoporphyrin periferic groups, varying overall charge and oil/water partition, while maintaining their photochemical properties. Three synthetic routes were used: (1) modification of Pp IX at positions 3 1 and 8 1 by addition of alkyl amine groups of different lengths (compounds 2–5), (2) change of Pp IX at positions 13 3 and 17 3 , generating alkyl amines (compounds 6 and 7), a phosphate amine (compound 8), and quarternary ammonium compounds (compounds 9 and 10), and (3) amine-alkylation of Hematoporphyrin IX (Hp IX) at positions 3 1 , 8 1 , 13 3 and 17 3 (compound 12). Strategy 1 leads to hydrophobic compounds with low photocytotoxicity. Strategy 2 leads to compounds 6–10 that have high levels of binding/incorporation in vesicles, mitochondria and cells, which are indicative of high bioavailability. Addition of the phosphate group (compound 8), generates an anionic compound that has low liposome and cell incorporation, plus low photocytotoxicity. Compound 12 has intermediate incorporation and photocytotoxic properties. Compound modification is also associated with changes in their sub-cellular localization: 30% of 8 (anionic) is found in mitochondria as compared to 95% of compound 10 (cationic). Photocytotoxicity was shown to be highly correlated with membrane affinity, which depends on the asymmetrical and amphiphilic characters of sens, as well as with sub-cellular localization. KEYWORDS: photodynamic therapy, PDT, synthesis, membrane, logP, singlet oxygen, photosensitizer, bioavailability, mitochondria, organelle targeting, sub-cellular distribution.  SPP full member in good standing *Correspondence to: Adjaci F. Uchoa, email: adjaci@usp.br and Mauricio S. Baptista, email: baptista@iq.usp.br, tel: +55 11-3091-3815, fax: +55 11-3815-5579 J. Porphyrins Phthalocyanines 2010.14:832-845. Downloaded from www.worldscientific.com by DOT. LIB INFORMATION LLC on 01/20/15. For personal use only.