A cationic chalcogenoxanthylium photosensitizer effective in vitro in chemosensitive and multidrug-resistant cells.
Pentacyclic thio- (1) and seleno- (2) analogues of tetramethylrosamine (TMR) were prepared with a julolidyl fragment replacing the 3-dimethylamino substituent in the xanthylium core. The pentacylic structure increases the lipophilicity of 1 and 2 relative to TMR-S and TMR-Se and locks the lone-pair of electrons on the julolidyl N atom into conjugation with the xanthylium core. This conformational rigidization leads to longer wavelengths of absorption, but has little impact on other photophysical properties such as quantum yields for fluorescence and singlet-oxygen generation and fluorescence lifetimes in 1 and 2 relative to TMR-S and TMR-Se. Both 1 and 2 are effective photosensitizers against chemosensitive AUXB1 cells in vitro at 1x10(-7)M and compound 2 is an effective photosensitizer against multidrug-resistant CR1R12 cells in vitro at 1x10(-7)M. While the uptake TMR-S into CR1R12 cells as measured by fluorescence is significantly lower than uptake into chemosensitive AUXB1 cells, there is no significant difference in the uptake of 1 into either AUXB1 or CR1R12 cells. The addition of 2x10(-4)M verapamil to the cells prior to treatment with 1 had no significant effect on the uptake of 1 into either AUXB1 or CR1R12 cells. Treating lipid-activated, purified Pgp with 2 and light gave complete inhibition of Pgp ATPase activity.
Holt
Jason J
JJ
Department of Chemistry, University at Buffalo, The State University of New York, Buffalo, NY 14260-3000, USA.
Gannon
M K
MK
Tombline
Gregory
G
McCarty
Taylor A
TA
Page
Phillip M
PM
Bright
Frank V
FV
Detty
Michael R
MR
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002478:Cells, Cultured / Q000187:drug effects; D018011:Chalcogens / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006224:Cricetinae; D003412:Cricetulus; D018432:Drug Resistance, Multiple; D005260:Female; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008027:Light; D051379:Mice; D015394:Molecular Structure; D010053:Ovary / Q000187:drug effects; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018036:Selenium Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D026082:Singlet Oxygen / Q000378:metabolism; D013329:Structure-Activity Relationship; D014700:Verapamil / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002121:Calcium Channel Blockers; D018011:Chalcogens; D006575:Heterocyclic Compounds, 3-Ring; D017319:Photosensitizing Agents; D018036:Selenium Compounds; C493770:tetramethylrosamine selenium; C493769:tetramethylrosamine sulfur; D026082:Singlet Oxygen; D014700:Verapamil; D000251:Adenosine Triphosphatases