Probing cytochrome P450 bioactivation and fluorescent properties with morpholinyl-tethered anthraquinones

• Published in: Bioorganic & medicinal chemistry letters Vol. 28; no. 8; pp. 1274 - 1277
• Main Authors: Errington, Rachel J., Sadiq, Maria, Cosentino, Laura, Wiltshire, Marie, Sadiq, Omair, Sini, Marcella, Lizano, Enric, Pujol, Maria D., Morais, Goreti R., Pors, Klaus
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.05.2018; Elsevier
• Subjects: Anthraquinone; Anthraquinones - chemical synthesis; Anthraquinones - chemistry; Anthraquinones - metabolism; Anthraquinones - toxicity; Cancer; Cell Line, Tumor; Chemistry; Chemistry, Medicinal; Chemistry, Organic; CYP1A2; Cytochrome P-450 Enzyme System - metabolism; Cytochrome P450; DRAQ5; Fluorescence; Fluorescent Dyes - chemical synthesis; Fluorescent Dyes - chemistry; Fluorescent Dyes - metabolism; Fluorescent Dyes - toxicity; Fluorophore; Humans; Hydroxylation; Life Sciences & Biomedicine; MMDX; Morpholines - chemical synthesis; Morpholines - chemistry; Morpholines - metabolism; Morpholines - toxicity; Nemorubicin; Pharmacology & Pharmacy; Physical Sciences; Science & Technology; MMDX; Anthraquinone; DRAQ5; Nemorubicin; Fluorophore; Cytochrome P450; CYP1A2; Cancer; RESISTANT OVARIAN-CANCER; CELLS; ACTIVATION; AZINOMYCIN ANALOG; TUMOR; ANTITUMOR-ACTIVITY; ALCHEMIX; FCE-23762; BLADDER
• ISSN: 0960-894X; 1464-3405; 1464-3405
• DOI: 10.1016/j.bmcl.2018.03.040

[Display omitted] Structural features from the anticancer prodrug nemorubicin (MMDX) and the DNA-binding molecule DRAQ5™ were used to prepare anthraquinone-based compounds, which were assessed for their potential to interrogate cytochrome P450 (CYP) functional activity and localisation. 1,4-disubstituted anthraquinone 8 was shown to be 5-fold more potent in EJ138 bladder cancer cells after CYP1A2 bioactivation. In contrast, 1,5-bis((2-morpholinoethyl)amino) substituted anthraquinone 10 was not CYP-bioactivated but was shown to be fluorescent and subsequently photo-activated by a light pulse (at a bandwidth 532–587 nm), resulting in punctuated foci accumulation in the cytoplasm. It also showed low toxicity in human osteosarcoma cells. These combined properties provide an interesting prospective approach for opto-tagging single or a sub-population of cells and seeking their location without the need for continuous monitoring.