Ring-Fused meso-Tetraarylchlorins as Auspicious PDT Sensitizers: Synthesis, Structural Characterization, Photophysics, and Biological Evaluation

Mafalda Laranjo; Nelson A M Pereira; Andreia S R Oliveira; Márcia Campos Aguiar; Gonçalo Brites; Bruno F O Nascimento; Beatriz Serambeque; Bruna D P Costa; João Pina; J Sérgio Seixas de Melo; Marta Pineiro; M Filomena Botelho; Teresa M V D Pinho E Melo

doi:10.3389/fchem.2022.873245

Ring-Fused meso-Tetraarylchlorins as Auspicious PDT Sensitizers: Synthesis, Structural Characterization, Photophysics, and Biological Evaluation

Front Chem. 2022 Apr 27:10:873245. doi: 10.3389/fchem.2022.873245. eCollection 2022.

Authors

Mafalda Laranjo^{1

2

3}, Nelson A M Pereira⁴, Andreia S R Oliveira⁴, Márcia Campos Aguiar^{1

4}, Gonçalo Brites¹, Bruno F O Nascimento⁴, Beatriz Serambeque^{1

2}, Bruna D P Costa⁴, João Pina⁴, J Sérgio Seixas de Melo⁴, Marta Pineiro⁴, M Filomena Botelho^{1

2

3}, Teresa M V D Pinho E Melo⁴

Affiliations

¹ Institute of Biophysics and Institute for Clinical and Biomedical Research (iCBR), Area of Environment Genetics and Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
² Centre of Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, Coimbra, Portugal.
³ Clinical and Academic Centre of Coimbra (CACC), Coimbra, Portugal.
⁴ Department of Chemistry, Coimbra Chemistry Centre-Institute of Molecular Sciences, University of Coimbra, Coimbra, Portugal.

Abstract

Novel 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-fused meso-tetraarylchlorins, with different degrees of hydrophilicity (with methyl ester, hydroxymethyl, and carboxylic acid moieties), have been synthesized and their photophysical characterization as well as in vitro photocytotoxicity assessment against human melanoma and esophageal and bladder carcinomas was carried out. An integrated analysis of the photosensitizers' performance, considering the singlet oxygen generation data, cell internalization, and intracellular localization, allowed to establish relevant structure-photoactivity relationships and the rationalization of the observed photocytotoxicity. In the diacid and monoalcohol series, chlorins derived from meso-tetraphenylporphyrin proved to be the most efficient photodynamic therapy agents, showing IC₅₀ values of 68 and 344 nM against A375 cells, respectively. These compounds were less active against OE19 and HT1376 cells, the diacid chlorin with IC₅₀ values still in the nano-molar range, whereas the monohydroxymethyl-chlorin showed significantly higher IC₅₀ values. The lead di(hydroxymethyl)-substituted meso-tetraphenylchlorin confirmed its remarkable photoactivity with IC₅₀ values below 75 nM against the studied cancer cell lines. Subcellular accumulation of this chlorin in the mitochondria, endoplasmic reticulum, and plasma membrane was demonstrated.

Keywords: cancer; chlorins; photodynamic therapy; photosensitizer; subcellular accumulation.