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A synthetic route to trans -A 2 B-corroles combining the macrocyclic core with a hydrazone moiety, based on the reactivity of azoalkenes toward dipyrromethanes, has been established with the aim of developing a new class of photosensitizers for photodynamic therapy of lung cancer. The study of the photophysical properties of the novel macrocycles allowed the identification of photosensitizers with absorption within the phototherapeutic window and high singlet oxygen quantum yield. Relevant structure-photodynamic activity correlations were established by studying the new corroles-based photodynamic therapy (PDT) in human lung cancer cell lines (A549 and H1299). The methyl-hydrazone corroles were more active than phenyl-hydrazone corroles, with the N -Boc and N -Ts groups being key structural features to ensure high activity. The lead photosensitizers, with IC 50 values below 100 nM and no cytotoxicity per se, were significantly more active than 5,10,15-triphenylcorrole, showing that the presence of the hydrazone functional group has a strong influence on PDT activity.

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 IC 50 values of 68 and 344 nM against A375 cells, respectively. These compounds were less active against OE19 and HT1376 cells, the diacid chlorin with IC 50 values still in the nano-molar range, whereas the monohydroxymethyl-chlorin showed significantly higher IC 50 values. The lead di(hydroxymethyl)-substituted meso -tetraphenylchlorin confirmed its remarkable photoactivity with IC 50 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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Laranjo, Pereira, Oliveira, Campos Aguiar, Brites, Nascimento, Serambeque, Costa, Pina, Seixas de Melo, Pineiro, Botelho and Pinho e Melo.)

Investigation of novel 4,5,6,7-tetrahydropyrazolo[1,5- a ]pyridine-fused chlorins, derived from 5,10,15,20-tetrakis(pentafluorophenyl)porphyrin, as PDT agents against melanoma and esophagus cancer is disclosed. Diol and diester fluorinated ring-fused chlorins, including derivatives with 2-(2-hydroxyethoxy)ethanamino groups at the phenyl rings, were obtained via a two-step methodology, combining S N Ar and [8π + 2π] cycloaddition reactions. The short-chain PEG groups at the para -position of the phenyl rings together with the diol moiety at the fused pyrazole ring promote a red-shift of the Soret band, a decrease of the fluorescence quantum yield and an increase of the singlet oxygen formation quantum yield, improving the photophysical characteristics required to act as a photosensitizer. Introduction of these hydrophilic groups also improves the incorporation of the sensitizers by the cells reaching cellular uptake values of nearly 50% of the initial dose. The rational design led to a photosensitizer with impressive IC 50 values, 13 and 27 nM against human melanoma and esophageal carcinoma cell lines, respectively., Competing Interests: The authors declare no personal, professional or financial conflicts of interest., (This journal is © The Royal Society of Chemistry.)