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Structure-activity relationships of natural quinone vegfrecine analogs with potent activity against VEGFR-1 and -2 tyrosine kinases

The Journal of Antibiotics volume 74, pages 734–742 (2021)Cite this article

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Abstract

A series of analogs of vegfrecine, a natural quinone vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor, was synthesized via oxidative amination of 2,5-dihydroxybenzamide with functionalized arylamine followed by ammonolysis and substitution of the quinone ring. The inhibitory activities of the analogs against the VEGFR-1 and -2 tyrosine kinases were assayed in vitro with the aim to identify a compound suitable to treat cancer and inflammatory diseases. Alterations of the functionality of the phenyl group, substitution of the quinone ring, and oxidative cyclization of the 1-carboxamide-2-aminoquinone moiety to form an isoxazole quinone ring were examined. Introduction of halo- and alkyl-substituents at the 5′-position of the phenyl ring resulted in potent inhibition of the VEGFR-1 and -2 tyrosine kinases. In particular, structural modification at C-5′ on the phenyl ring was shown to significantly affect the selectivity of the inhibition between the VEGFR-1 and -2 tyrosine kinases. Compound 8, 5′-methyl-vegfrecine, showed superior selectivity toward the VEGFR-2 tyrosine kinase over the VEGFR-1 tyrosine kinase.

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Acknowledgements

We thank Dr. Masatomi Iijima and Dr. Isao Momose for mass spectral determinations.

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Authors and Affiliations

  1. Institute of Microbial Chemistry (BIKAKEN), Shizuoka, Japan

    Hayamitsu Adachi

  2. Institute of Microbial Chemistry (BIKAKEN), Tokyo, Japan

    Chisato Nosaka, Sonoko Atsumi, Koichi Nakae, Yoji Umezawa, Ryuichi Sawa, Yumiko Kubota, Chie Nakane & Yoshio Nishimura

  3. Jobu University, Gunma, Japan

    Masabumi Shibuya

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  1. Hayamitsu Adachi
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Correspondence to Hayamitsu Adachi.

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Adachi, H., Nosaka, C., Atsumi, S. et al. Structure-activity relationships of natural quinone vegfrecine analogs with potent activity against VEGFR-1 and -2 tyrosine kinases. J Antibiot 74, 734–742 (2021). https://doi.org/10.1038/s41429-021-00445-y

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  • DOI: https://doi.org/10.1038/s41429-021-00445-y

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