Water-soluble, core-modified porphyrins as novel, longer-wavelength-absorbing sensitizers for photodynamic therapy.
Water-soluble, core-modified 5,10,15, 20-tetrakis(4-sulfonatophenyl)-21,23-dithiaporphyrin (1) and 5,10,15, 20-tetrakis(4-sulfonatophenyl)-21,23-diselenaporphyrin (2) were prepared as the tetrasodium salts by the sulfonation of 5,10,15, 20-tetraphenyl-21,23-dithiaporphyrin (3) and -21, 23-diselenaporphyrin (4), respectively, with sulfuric acid. Compounds 3 and 4 were prepared by the condensation of pyrrole with either 2,5-bis(phenylhydroxymethyl)thiophene (5) or 2, 5-bis(phenylhydroxymethyl)selenophene (6) in propionic acid. The addition of benzaldehyde to 2,5-dilithiothiophene or 2, 5-dilithioselenophene gives 5 or 6, respectively, as a nearly equimolar mixture of meso- and d,l-diastereomers. Careful crystallization of 5 gives a single diastereomer by removing the crystalline product from the equilibrating mixture of diastereomers in solution. Photodynamic therapy (PDT) with 1 has an LD(50) of less than 25 microg/mL against Colo-26 cells in culture and exhibits a lethal dose for 90% or more at concentrations greater than 50 microg/mL. In contrast, PDT with 5,10,15, 20-tetrakis(4-sulfonatophenyl)porphyrin (TPPS(4)) requires concentrations of greater than 100 microg/mL to achieve LD(50). Neither 1 nor TPPS(4) shows significant photoactivity against the murine T-cell line, MOLT-4, above the dark toxicity. Sensitizer 1 shows no toxicity or side effects in BALB/c mice observed for 30 days following a single intravenous injection of 10 mg (9.1 micromol)/kg. Distribution studies show that sensitizer 1 accumulates in the tumors of BALB/c mice bearing Colo-26 or EMT-6 tumors with sensitizer concentration roughly doubling as the dosage of 1 increased from 5 to 10 mg/kg. In vivo studies show that PDT with sensitizer 1 at both 3.25 and 10 mg/kg with 135 J cm(-2) of 694-nm light is effective against Colo-26 tumors in BALB/c mice.
Stilts
C E
CE
Departments of Chemistry and Medicinal Chemistry, State University of New York at Buffalo, Buffalo, New York 14260, USA.
Nelen
M I
MI
Hilmey
D G
DG
Davies
S R
SR
Gollnick
S O
SO
Oseroff
A R
AR
Gibson
S L
SL
Hilf
R
R
Detty
M R
MR
D000818:Animals; D002460:Cell Line; D003576:Electron Transport Complex IV / Q000037:antagonists & inhibitors; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D020128:Inhibitory Concentration 50; D051379:Mice; D008807:Mice, Inbred BALB C; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D011166:Porphyrins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D012995:Solubility; D014867:Water
C410940:5,10,15,20-tetrakis(4-sulfonatophenyl)-21,23-dithiaporphyrin; D004791:Enzyme Inhibitors; D017319:Photosensitizing Agents; D011166:Porphyrins; D014867:Water; D003576:Electron Transport Complex IV