Twop olyamine derivatives of protoporphyrin IX (PPIX) were tested as photodynamic therapy (PDT) agents in HT29 colorectal cancer andH EP3Bl iver cancer cell lines.T hese compounds exhibit excellent singlet oxygen quantum yields and show strong in vitro PDT efficacy after 660 nm laser irradiation, whereas exogenous PPIX itself exhibits much weaker PDT effects. Confocalm icroscopy imaging studies revealt hat ap rotoporphyrin derivative with eight amine moieties has excellent water solubility,a nd localizes mainly in the mitochondria of both HT29 and HEP3B cells, whereas the cellular distribution of ap rotoporphyrin derivative with four amine moieties is not as specific.T his work demonstrates that polyamine moieties on macrocycles can enhance PDT efficacy by targeting mitochondria.

The synthesis of porphyrin–steroid conjugates is examined using the natural steroids oestradiol, oestrone, and lithocholic acid as precursors. Two strategies differing in the timing of formation of the steroid–porphyrin linkage leading to four different construction motifs are explored. Two approaches are based on a strategy of introduction of steroidal components in the porphyrin-forming reaction involving condensation of steroidal-alkylaldehydes and pyrrole to give 5,10,15,20-tetrakis(steroidal-alkyl)porphyrins and differ in the way in which the required aldehyde is introduced to the steroidal component. In the other strategy, a steroidal component is introduced by post-porphyrin synthesis reactions and here also two approaches were explored, one involving nucleophilic substitution and the other esterification. Of the four approaches investigated, the most efficient and most versatile one attaches the steroidal components late in the sequence to a 5,10,15,20-tetra(ω-haloalkyl)porphyrin by a nucleophilic substitution reaction. In this way, a 5,10,15,20-tetrakis[oestrone-linked-heptyl)porphyrin was obtained in 47 % yield.

The Front Cover shows photodynamic therapy (PDT) agents targeting and attacking mitochondria through their two polyamine linkers. Protoporphyrin IX derivatives tethering four‐ or eight‐amine moieties with rigid spacers have great potential for use in mitochondrial targeting, which was clearly visualized by confocal imaging studies. With light activation, these PDT agents can damage the cells. The molecules exhibit excellent singlet oxygen quantum yields and show strong in vitro PDT efficacy after 660 nm laser irradiation in HT29 colorectal cancer and HEP3B liver cancer cell lines. This work demonstrates that polyamine moieties on photosensitizers can enhance PDT efficacy by targeting mitochondria. More information can be found in the Communication by Fargol Taba, Akira Onoda, Takashi Hayashi et al. on page 15 in Issue 1, 2018 (DOI: 10.1002/cmdc.201700467).