A selenopyrylium photosensitizer for photodynamic therapy related in structure to the antitumor agent AA1 with potent in vivo activity and no long-term skin photosensitization.
Cationic chalcogenopyrylium dyes 5 were synthesized in six steps from p-aminophenylacetylene (9), have absorption maxima in methanol of 623, 654, and 680 nm for thio-, seleno-, and telluropyrylium dyes, respectively, and generate singlet oxygen with quantum yields [Phi((1)O(2))] of 0.013, 0.029, and 0.030, respectively. Selenopyrylium dye 5-Se was phototoxic to cultured murine Colo-26 and Molt-4 cells. Initial acute toxicity studies in vivo demonstrate that, at 29 mg (62 micromol)/kg, no toxicity was observed with 5-Se in animals followed for 90 days under normal vivarium conditions. In animals given 10 mg/kg of 5-Se via intravenous injection, 2-8 nmol of 5-Se/g of tumor was found at 3, 6, and 24 h postinjection. Animals bearing R3230AC rat mammary adenocarcinomas were treated with 10 mg/kg of 5-Se via tail-vein injection and with 720 J cm(-2) of 570-750-nm light from a filtered tungsten lamp at 200 mW cm(-2) (24 h postinjection of 5-Se). Treated animals gave a tumor-doubling time of 9 +/- 4 days, which is a 300% increase in tumor-doubling time relative to the 3 +/- 2 days for untreated dark controls. Mechanistically, the mitochondria appear to be a target. In cultured R3230AC rat mammary adenocarcinoma cells treated with 0.1 and 1.0 microM 5-Se and light, mitochondrial cytochrome c oxidase activity was inhibited relative to cytochrome c oxidase activity in untreated cells. Irradiation of isolated mitochondrial suspensions treated with 10 microM dye 5-Se inhibited cytochrome c oxidase activity. The degree of enzyme inhibition was abated in a reduced oxygen environment. Superoxide dismutase, at a final concentration of 30 U, did not alter the photosensitized inhibition of mitochondrial cytochrome c oxidase by dye 5-Se. The data suggest that singlet oxygen may play a major role in the photosensitized inhibition of mitochondrial cytochrome c oxidase.
Leonard
K A
KA
Departments of Chemistry and Medicinal Chemistry, State University of New York at Buffalo, Buffalo, New York 14260, USA.
Hall
J P
JP
Nelen
M I
MI
Davies
S R
SR
Gollnick
S O
SO
Camacho
S
S
Oseroff
A R
AR
Gibson
S L
SL
Hilf
R
R
Detty
M R
MR
D000230:Adenocarcinoma / Q000188:drug therapy; D000814:Aniline Compounds / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D003576:Electron Transport Complex IV / Q000037:antagonists & inhibitors; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D015674:Mammary Neoplasms, Animal / Q000188:drug therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D000442:Octanols; D009942:Organometallic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016566:Organoselenium Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D012643:Selenium; D012867:Skin / Q000187:drug effects / Q000528:radiation effects*; D012995:Solubility; D013053:Spectrophotometry; D013876:Thiophenes / Q000737:chemistry*; D023382:Toxicity Tests, Acute; D014407:Tumor Cells, Cultured; D014867:Water; D023041:Xenograft Model Antitumor Assays
C416654:2-(4-aminophenyl)-4-(4-N,N-dimethylanilino)-6-phenylselenopyrylium; D000814:Aniline Compounds; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D000442:Octanols; D009942:Organometallic Compounds; D016566:Organoselenium Compounds; D017319:Photosensitizing Agents; D013876:Thiophenes; D014867:Water; C086431:2,6-bis(4-aminophenyl)-4-(4-(dimethylamino)phenyl)thiopyrylium; D003576:Electron Transport Complex IV; D012643:Selenium