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Residual Complexity Does Impact Organic Chemistry and Drug Discovery: The Case of Rufomyazine and Rufomycin

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posted on 10.02.2022, 21:19 by Mary P Choules, Larry KleinLarry Klein, David C Lankin, James B McAlpine, Sang Hyun ChoSang Hyun Cho, Jinhua Cheng, Hanki Lee, Joo-Won Suh, Birgit JakiBirgit Jaki, Scott FranzblauScott Franzblau, Guido PauliGuido Pauli
Residual complexity (RC) involves the impact of subtle but critical structural and biological features on drug lead validation, including unexplained effects related to unidentified impurities. RC commonly plagues drug discovery efforts due to the inherent imperfections of chromatographic separation methods. The new diketopiperazine, rufomyazine (6), and the previously known antibiotic, rufomycin (7), represent a prototypical case of RC that (almost) resulted in the misassignment of biological activity. The case exemplifies that impurities well below the natural abundance of 13C (1.1%) can be highly relevant and calls for advanced analytical characterization of drug leads with extended molar dynamic ranges of >1:1,000 using qNMR and LC-MS. Isolated from an actinomycete strain, 6 was originally found to be active against Mycobacterium tuberculosis with a minimum inhibitory concentration (MIC) of 2 μg/mL and high selectivity. As a part of lead validation, the dipeptide was synthesized and surprisingly found to be inactive. The initially observed activity was eventually attributed to a very minor contamination (0.24% [m/m]) with a highly active cyclic peptide (MIC ∼ 0.02 μM), subsequently identified as an analogue of 7. This study illustrates the serious implications RC can exert on organic chemistry and drug discovery, and what efforts are vital to improve lead validation and efficiency, especially in NP-related drug discovery programs.

Funding

900MHz NMR For Structural Biology In Chicago | Funder: National Institutes of Health (National Institute of General Medical Sciences) | Grant ID: P41GM068944

Development of A Transformative Approach To The Rapid Detection, Isolation and Identification Of Anti-Tuberculosis Natural Products | Funder: National Institutes of Health (National Institute of Allergy and Infectious Diseases) | Grant ID: R21AI093919

Research Training in Natural Product Complementary and Alternative Medicine | Funder: National Institutes of Health (National Center for Complementary and Integrative Health) | Grant ID: T32AT007533

Center for Natural Product Technologies at UIC | Funder: National Institutes of Health (National Center for Complementary and Integrative Health) | Grant ID: U41AT008706

History

Citation

Choules, M. P., Klein, L. L., Lankin, D. C., McAlpine, J. B., Cho, S. -H., Cheng, J., Lee, H., Suh, J. -W., Jaki, B. U., Franzblau, S. G.Pauli, G. F. (2018). Residual Complexity Does Impact Organic Chemistry and Drug Discovery: The Case of Rufomyazine and Rufomycin. The Journal of Organic Chemistry, 83(12), 6664-6672. https://doi.org/10.1021/acs.joc.8b00988

Publisher

American Chemical Society (ACS)

Language

en

issn

0022-3263