Probing cytochrome P450-mediated activation with a truncated azinomycin analogue

Vinader, V.; Sadiq, Muhammad; Sutherland, Mark; Huang, Mengying; Loadman, Paul M.; Elsalem, Lina; Shnyder, Steven D.; Cui, Hongjuan; Afarinkia, K.; Searcey, Mark; Patterson, Laurence H.; Pors, Klaus

doi:10.1039/c4md00411f

Cited by 4 publications

(6 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This represents valuable mechanistic information for the Passerini reaction, which most likely proceeds with the concerted formation of the imidate α-adduct rather than having a true nitrilium ion as intermediate . Furthermore, the trityl substituent can be readily removed yielding primary α-acyloxyamides 7 , which are useful building blocks for the synthesis of natural products and bioactive compounds. ,, …”

mentioning

confidence: 99%

Brønsted Acid-Catalyzed Cyanotritylation of Aldehydes by Trityl Isocyanide

et al. 2016

View full text Add to dashboard Cite

Cyanohydrins are versatile intermediates toward valuable organic compounds like α-hydroxy carboxylic acids, α-amino acids, and β-amino alcohols. Numerous protocols are available for synthesis of (O-protected) cyanohydrins, but all procedures invariably rely on the use of toxic cyanide sources. A novel cyanide-free synthesis of O-trityl protected cyanohydrins via a catalytic Passerini-type reaction involving aldehydes and trityl isocyanide is reported. The feasibility of a catalytic asymmetric reaction is demonstrated using chiral phosphoric acid catalysis.

show abstract

mentioning

confidence: 99%

Brønsted Acid-Catalyzed Cyanotritylation of Aldehydes by Trityl Isocyanide

et al. 2016

View full text Add to dashboard Cite

show abstract

“…Such counterscreens could be established using primary human hepatocytes, transfected cell lines, or a panel of recombinant CYP enzymes. 22,35 In summary, KLE cells have been shown to exclusively express appreciable levels of CYP1B1. Additionally, a KLE cell-based screening model has been characterized using two probe prodrugs and thus proposed as a relevant drug discovery model that can be potentially developed to screen chemical libraries to discover novel CYP1B1-targeted anticancer prodrugs.…”

Section: Discussionmentioning

confidence: 91%

“…Such counterscreens could be established using primary human hepatocytes, transfected cell lines, or a panel of recombinant CYP enzymes. 22,35…”

Section: Discussionmentioning

confidence: 99%

“…21 Recently, rationally designed prodrugs have also been shown to be bioactivated by CYP1B1, although cytotoxic metabolites were also generated by CYP1A1 and CYP3A4. 22 The discovery of new CYP1B1-activated prodrugs has been hindered by the lack of a relevant drug discovery model to enable screening of large chemical libraries. The human uterus adenocarcinoma cell line KLE, derived from a poorly differentiated endometrial cancer with a defective estrogen receptor, possesses tumorigenic activity in nude mice.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Development of an In Vitro Model to Screen CYP1B1-Targeted Anticancer Prodrugs

et al. 2016

View full text Add to dashboard Cite

Cytochrome P450 1B1 (CYP1B1) is an anticancer therapeutic target due to its overexpression in a number of steroid hormone-related cancers. One anticancer drug discovery strategy is to develop prodrugs specifically activated by CYP1B1 in malignant tissues to cytotoxic metabolites. Here, we aimed to develop an in vitro screening model for CYP1B1-targeted anticancer prodrugs using the KLE human endometrial carcinoma cell line. KLE cells demonstrated superior stability of CYP1B1 expression relative to transiently transfected cells and did not express any appreciable amount of cognate CYP1A1 or CYP1A2, which would have compromised the specificity of the screening assay. The effect of two CYP1B1-targeted probe prodrugs on KLE cells was evaluated in the absence and presence of a CYP1B1 inhibitor to chemically "knock out" CYP1B1 activity (CYP1B1 inhibited). Both probe prodrugs were more toxic to KLE cells than to CYP1B1-inhibited KLE cells and significantly induced G0/G1 arrest and decreased the S phase in KLE cells. They also exhibited pro-apoptotic effects in KLE cells, which were attenuated in CYP1B1-inhibited KLE cells. In summary, a KLE cell-based model has been characterized to be suitable for identifying CYP1B1-targeted anticancer prodrugs and should be further developed and employed for screening chemical libraries.

show abstract

“…We evaluated these in the EJ138 bladder cancer cell line (identical to the T24 cell line 27 ) due to its very low levels of CYPs. 6 Using previously published methodology, 28 metabolites were generated via incubation of compounds 7 and 8 with 20 pmol CYP bactosomes in 50 mM Tris-HCl buffer (2 mM NADPH, 1 mM MgCl 2 , pH 7.4). Generally, none of the extracted metabolite incubates were shown to exert increased antiproliferative activity over their parental compounds 7 and 8 using the MTT assay ( Table 1).…”

Section: Nemorubicinmentioning

confidence: 99%

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

Errington

Sadiq

Cosentino

et al. 2018

Bioorganic & Medicinal Chemistry Letters

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Probing cytochrome P450-mediated activation with a truncated azinomycin analogue

Cited by 4 publications

References 22 publications

Brønsted Acid-Catalyzed Cyanotritylation of Aldehydes by Trityl Isocyanide

Brønsted Acid-Catalyzed Cyanotritylation of Aldehydes by Trityl Isocyanide

Development of an In Vitro Model to Screen CYP1B1-Targeted Anticancer Prodrugs

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

Contact Info

Product

Resources

About