Design, Synthesis and Mechanistic Study of New Dual Targeting HDAC/Tubulin Inhibitors

Abstract

Aim:

The purpose of this work is to create and synthesize a new class of chemicals: 3-cyano-2-substituted pyridine compounds with expected multitarget inhibition of histone deacetylase (HDAC) and tubulin.

Materials & methods:

The target compounds (3a–c, 4a–c and 5a–c) were synthesized utilizing 6-(4-methoxyphenyl)-2-oxo-4-(3,4,5-trimethoxyphenyl)-3-cyanopyridine, with various linkers and zinc-binding groups (ZBGs).

Results:

Most of the tested compounds showed promising growth inhibition, and hydroxamic acid-containing hybrids possessed higher HDAC inhibition than other ZBGs. Compound 4b possessed the highest potency; however, it showed the most tubulin polymerization inhibition. Docking studies displayed good binding into HDAC1 and six pockets and tubulin polymerization protein.

Conclusion:

Compound 4b could be considered a good antitumor candidate to go further into in vivo and clinical studies.

Graphical abstract

Keywords::

• capping
• cyanopyridine
• docking
• HDAC
• multitargeting
• tubulin

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at: www.tandfonline.com/doi/suppl/10.4155/fmc-2023-0336

Acknowledgments

The authors extend their appreciation to the co-author Dr Hanan A Al-Ghulikah who provided them with the publication fees through Princess Nourah bint Abdulrahman University Researchers Supporting Project number (PNURSP2024R95), Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia.

Financial disclosure

The work was supported by Princess Nourah bint Abdulrahman University Researchers Supporting Project no. PNURSP2024R95. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Competing interests disclosure

The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Writing disclosure

No writing assistance was utilized in the production of this manuscript.

Additional information

Funding

The authors extend their appreciation to the co-author Dr Hanan A Al-Ghulikah who provided them with the publication fees through Princess Nourah bint Abdulrahman University Researchers Supporting Project number (PNURSP2024R95), Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia.