Structure-Function Study of Symmetrically Substituted Pyridine Derivatives Based on the Iron binding Site of Bleomycin

Masami Otsuka; Mikako Fujita

doi:10.1055/a-2921-9657

August 14, 2026Synlett

Structure-Function Study of Symmetrically Substituted Pyridine Derivatives Based on the Iron binding Site of Bleomycin

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Key Points

To synthesize and evaluate symmetrical pyridine derivatives modeled after the iron-binding site of bleomycin and assess their activity against zinc finger proteins and disease phenotypes.
Designed and synthesized symmetrical pyridine compounds based on the bleomycin iron-binding core to generate the zinc-binding parent molecule SN-1.
Evaluated SN-1 and its chemical library for regulatory and inhibitory effects against zinc finger proteins including HIV-EP1, farnesyltransferase, APOBEC3G, TRAF6, and ADAM17.
Performed phenotypic screening of the SN-1 derivative library by assessing fibroblast morphological changes during epithelial-mesenchymal transition.
Discovered that symmetrical pyridine molecule SN-1 unexpectedly binds zinc and regulates multiple zinc finger proteins and related regulatory enzymes.
Identified lead compound HPH-15, defined structurally by thioamide and S-tert-butyl side chains, as an inhibitor of fibroblast phenotypic transition.
Demonstrated qualitative therapeutic efficacy for HPH-15 against diabetes, fatty liver disease, and both skin and liver fibrosis.

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Implication

Preclinical screening demonstrates therapeutic efficacy of zinc-binding pyridine derivative HPH-15 in models of fibrosis, diabetes, and fatty liver, suggesting novel multi-target drug potential.

Abstract

Symmetrical molecules were designed based on the bleomycin iron-binding site leading to an unexpected finding of a zinc-binding molecule SN-1. SN-1 and its derivatives inhibited/regulated zinc finger proteins HIV-EP1, farnesyltransferase, APOBEC3G, TRAF6, and ADAM17. HPH-15 was identified by a phenotype screening of a library of SN-1 derivatives, judging based on the cell morphological changes during epithelial mesenchymal transition of fibroblast. Structural characteristics of HPH-15 are side chains containing a thioamide and a S-tert-butyl group. HPH-15 was found to be effective against diabetes, fatty liver, and skin/liver fibrosis.

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Otsuka et al. (2026) studied this question.

synapsesocial.com/papers/6a8179abf2fb91fc834acf22 https://doi.org/10.1055/a-2921-9657

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Structure-Function Study of Symmetrically Substituted Pyridine Derivatives Based on the Iron binding Site of Bleomycin

Key Points

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Abstract

Discussion

Cite This Study

Structure-Function Study of Symmetrically Substituted Pyridine Derivatives Based on the Iron binding Site of Bleomycin

Key Points

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

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