BINOL-amino acid conjugates as triggerable carriers of DNA-targeted potent photocytotoxic agents.
Mild photoactivation of new BINOL-amino acid and -amino ester conjugates (BINOLAMs) yielded alkylating and DNA cross-linking agents with high photoefficiency and superior cytotoxicity. Detection of the transient electrophile, by laser flash photolysis (LFP), suggests that BINOL-quinone methides (QMs) are key intermediates in the process. QMs trapping by water, monitored in a time-dependent product distribution analysis, demonstrated that the phototriggered reactivity of BINOLAMs as bis-alkylating agents is the result of a two-step process involving sequential photogeneration of monoalkylating QMs. Light activation of the BINOL-L-amino esters produced cytotoxic QMs very effective against human tumor LoVo cells with EC50 in the 130-230 nM range. Trimethylpsoralen (PS) is about 4 times less potent than our newly tested compounds. BINOL-L-proline methyl ester showed notable photoselectivity because it displayed cytotoxic effects upon irradiation only and was able to efficiently reach the target DNA inside the cells, where it forms both alkylated and cross-linked species.
Doria
Filippo
F
Dipartimento di Chimica Organica, Università di Pavia, Italy.
Richter
Sara N
SN
Nadai
Matteo
M
Colloredo-Mels
Stefano
S
Mella
Mariella
M
Palumbo
Manlio
M
Freccero
Mauro
M
D000596:Amino Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018906:Antineoplastic Agents, Alkylating / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D020552:Comet Assay; D003432:Cross-Linking Reagents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004247:DNA / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D004952:Esters; D006801:Humans; D008027:Light; D017319:Photosensitizing Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011392:Proline / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011809:Quinones / Q000138:chemical synthesis / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000596:Amino Acids; D018906:Antineoplastic Agents, Alkylating; D003432:Cross-Linking Reagents; D004952:Esters; D017319:Photosensitizing Agents; D011809:Quinones; D004247:DNA; D011392:Proline