In Vivo Mutagenicity Testing of Arylboronic Acids and Esters.
Animals
Bone Marrow
/ drug effects
Boronic Acids
/ toxicity
Comet Assay
/ methods
Duodenum
/ drug effects
Erythrocytes
/ drug effects
Esters
/ toxicity
Liver
/ diagnostic imaging
Male
Micronucleus Tests
/ methods
Mutagenesis
/ drug effects
Mutagenicity Tests
/ methods
Mutagens
/ toxicity
Rats
Rats, Sprague-Dawley
Rats, Wistar
Reticulocytes
/ drug effects
Pig-a
comet
impurity
micronucleus
Journal
Environmental and molecular mutagenesis
ISSN: 1098-2280
Titre abrégé: Environ Mol Mutagen
Pays: United States
ID NLM: 8800109
Informations de publication
Date de publication:
12 2019
12 2019
Historique:
received:
25
03
2019
revised:
09
07
2019
accepted:
15
07
2019
pubmed:
25
7
2019
medline:
18
12
2019
entrez:
24
7
2019
Statut:
ppublish
Résumé
Arylboronic acids and esters (referred to collectively as arylboronic compounds) are commonly used intermediates in the synthesis of pharmaceuticals but pose a challenge for chemical syntheses because they are often positive for bacterial mutagenicity in vitro. As such, arylboronic compounds are then typically controlled to levels that are acceptable for mutagenic impurities, that is, the threshold of toxicological concern (TTC). This study used ICH M7 guidance to design and conduct a testing strategy to investigate the in vivo relevance of the in vitro positive findings of arylboronic compounds. Eight arylboronic compounds representing a variety of chemical scaffolds were tested in Sprague Dawley and/or Wistar rats in the in vivo Pig-a (peripheral blood reticulocytes and mature red blood cells) and/or comet assays (duodenum and/or liver). Five of the eight compounds were also tested in the micronucleus (peripheral blood) assay. The arylboronic compounds tested orally demonstrated high systemic exposure; thus the blood and bone marrow were adequately exposed to test article. One compound was administered intravenously due to formulation stability issues. This investigation showed that arylboronic compounds that were mutagenic in vitro were not found to be mutagenic in the corresponding in vivo assays. Therefore, arylboronic compounds similar to the scaffolds tested in this article may be considered non-mutagenic and managed in accordance with the ICH Q3A/Q3B guidelines. Environ. Mol. Mutagen. 2019. © 2019 Wiley Periodicals, Inc.
Substances chimiques
Boronic Acids
0
Esters
0
Mutagens
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
766-777Commentaires et corrections
Type : ErratumIn
Informations de copyright
© 2019 Wiley Periodicals, Inc.
Références
Callan JGA, Lad A, Stannard L, Howe J, Kenny J. 2013. Mutagenicity of Aryl Boronic Acids in the Mouse Lymphoma Assay. Poster at the International Conference on Environmental Mutagens.
Custer L. 2012. Impact of New Mutagenicity Data on Marketed Drugs: A Case Study. Presentation at the Genetic Toxicology Association Meeting.
Dertinger SD, Phonethepswath S, Franklin D, Weller P, Torous DK, Bryce SM, Avlasevich S, Bemis JC, Hyrien O, Palis J, et al. 2010. Integration of mutation and chromosomal damage endpoints into 28-day repeat dose toxicology studies. Toxicol Sci 115(2):401-411.
Galloway SM, Vijayaraj Reddy M, McGettigan K, Gealy R, Bercu J. 2013. Potentially mutagenic impurities: Analysis of structural classes and carcinogenic potencies of chemical intermediates in pharmaceutical syntheses supports alternative methods to the default TTC for calculating safe levels of impurities. Regul Toxicol Pharmacol 66(3):326-335.
Gollapudi BB, Lynch AM, Heflich RH, Dertinger SD, Dobrovolsky VN, Froetschl R, Horibata K, Kenyon MO, Kimoto T, Lovell DP, et al. 2015. The in vivo pig-a assay: A report of the international workshop on Genotoxicity testing (IWGT) workgroup. Mutat Res Genet Toxicol Environ Mutagen 783:23-35.
Hall DG, editor. 2011. Boronic Acids: Preparation and Applications in Organic Synthesis and Medicine, 2nd ed. Weinheim: Wiley-VCH.
Hansen MM, Jolly RA, Linder RJ. 2015. Boronic acids and derivatives-probing the structure-activity relationships for mutagenicity. Org Process Res Dev 19(11):1507-1516.
International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. 2006. ICH Harmonised Tripartite Guideline. Impurities in New Drug Substances Q3A(R2). Available at: https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q3A_R2/Step4/Q3A_R2__Guideline.pdf. Accessed October 25, 2006.
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. 2017. ICH Harmonised Guideline. Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk M7(R1). Available at: https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Multidisciplinary/M7/M7_R1_Addendum_Step_4_2017_0331.pdf. Accessed March 31, 2017.
Kenyon M. 2018. Genotoxicity of Aryl Boronic Acids in vitro in Mammalian Cells. Presentation at the Genetic Toxicology Association, Newark, DE.
Lennox AJ, Lloyd-Jones GC. 2014. Selection of boron reagents for Suzuki-Miyaura coupling. Chem Soc Rev 43(1):412-443.
Magano J, Dunetz JR. 2011. Large-scale applications of transition metal-catalyzed couplings for the synthesis of pharmaceuticals. Chem Rev 111(3):2177-2250.
National Research Council. 2011. The Guide for the Care and Use of Laboratory Animals, 8th ed. Washington DC: National Academies Press.
O'Donovan MR, Mee CD, Fenner S, Teasdale A, Phillips DH. 2011. Boronic acids-a novel class of bacterial mutagen. Mutat Res 724(1-2):1-6.
Organisation for Economic Co-operation and Development (OECD). 2016a. OECD Guideline for the Testing of Chemicals 474: Mammalian Erythrocyte Micronucleus Test. Available at: https://www.oecd-ilibrary.org/deliver/9789264264762-en.pdf?itemId=/content/publication/9789264264762-en&mimeType=application/pdf. Accessed July 29, 2016.
Organisation for Economic Co-operation and Development (OECD). 2016b. OECD Guideline for the Testing of Chemicals 489: in vivo Mammalian Alkaline Comet Assay. Available at: https://www.oecd-ilibrary.org/deliver/9789264264885-en.pdf?itemId=/content/publication/9789264264885-en&mimeType=application/pdf. Accessed July 29, 2016.
Patel I, Venkatramani CJ, Stumpf A, Wigman L, Yehl P. 2017. Trace analysis of potentially mutagenic boronic acids and esters in drug substance by ICP-MS. Org Process Res Dev 21(2):182-186.
Pellizzaro ML, Covey-Crump EM, Fisher J, Werner A-LD, Williams RV. 2015. Investigating a relationship between the mutagenicity of arylboronic acids and 11B NMR chemical shifts. Chem Res Toxicol 28(7):1422-1426.
Stannard L, Giddings A, Lad A, Munoz-Muriedas J. 2012. Can lowest unoccupied molecular orbital (LUMO) energies predict the mutagenicity of boronic acids. Mutagenesis 27(6):807-808.
Torborg C, Beller M. 2009. Recent applications of palladium-catalyzed coupling reactions in the pharmaceutical, agrochemical, and fine chemical industries. Adv Syn Catal 351(18):3027-3043.
United Kingdom. 1986. Animals (Scientific Procedures) Act, Legislation, United Kingdom.
Williams R. 2015. Arylboronic Acid Genotoxicity: Summary of Data and Knowledge. Lhasa Limited, United Kingdom.