Novel methyl helianthrones as photosensitizers: synthesis and biological evaluation.
A combination of light, oxygen and a photosensitizer is used to induce death of cancer cells by photodynamic therapy. In this study, we have synthesized several new methyl helianthrone derivatives and compared their phototoxicity with that of hypericin. In contrast to hypericin, methyl helianthrones are soluble in aqueous solutions and have a broad range of light absorbance, which allows the use of polychromatic light. Structural modifications of methyl helianthrone demonstrated that substitution of hydrogen atoms of methyl helianthrone at Positions 2 and 5 with Br atoms or methylation of its phenolic hydroxyls, significantly increases the corresponding singlet oxygen quantum yield and their phototoxicity toward alphaT3-1, M2R and LNCaP cells. The phototoxicity of some of these compounds was similar to that of hypericin. Methyl helianthrones, like hypericin, accumulated mainly in the perinuclear region as evident by confocal microscopy. Irradiation of cells pretreated with methyl helianthrone derivatives generates intracellular reactive oxygen species and lipid free radicals, as shown by a fluorescentic probe and electron paramagnetic resonance methods, respectively. The phototoxicity of these methyl helianthrones as well as their ability to oxidize membrane lipids were significantly decreased on addition of specific Type-II inhibitors, suggesting the involvement of singlet oxygen as the main oxidant.
Rahimipour
Shai
S
Department of Organic Chemistry, Weizmann Institute of Science, Rehovot, Israel. coshai@scripps.edu
Litichever-Coslovsky
Naomi
N
Alaluf
Moran
M
Freeman
Dalia
D
Ehrenberg
Benjamin
B
Weiner
Lev
L
Mazur
Yehuda
Y
Fridkin
Mati
M
Koch
Yitzhak
Y
D000818:Animals; D000873:Anthracenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D004354:Drug Screening Assays, Antitumor; D005609:Free Radicals / Q000378:metabolism / Q000528:radiation effects; D006639:Histidine / Q000494:pharmacology; D006801:Humans; D008027:Light; D051379:Mice; D015394:Molecular Structure; D010569:Perylene / Q000031:analogs & derivatives / Q000494:pharmacology; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism / Q000528:radiation effects; D026082:Singlet Oxygen / Q000378:metabolism / Q000528:radiation effects; D013997:Time Factors; D014810:Vitamin E / Q000494:pharmacology
D000873:Anthracenes; D005609:Free Radicals; D017319:Photosensitizing Agents; D017382:Reactive Oxygen Species; D014810:Vitamin E; D026082:Singlet Oxygen; D006639:Histidine; D010569:Perylene; C004965:hypericin