Synthesis of Novel Structural Hybrids between Aza-Heterocycles and Azelaic Acid Moiety with a Specific Activity on Osteosarcoma Cells.

Gabriele Micheletti,Silvia Bordoni,Giulia Frisco,Carla Boga,Vincenzo Palmacci,Dario Telese,Giovanna Farruggia,Giovanna Farruggia,Elena Strocchi,Natalia Calonghi

doi:10.3390/molecules25020404

Gabriele Micheletti, Silvia Bordoni + Show 8 more

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https://doi.org/10.3390/molecules25020404

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Abstract

Nine compounds bearing pyridinyl (or piperidinyl, benzimidazolyl, benzotriazolyl) groups bound to an azelayl moiety through an amide bond were synthesized. The structural analogy with some histone deacetylase inhibitors inspired their syntheses, seeking new selective histone deacetylase inhibitors (HDACi). The azelayl moiety recalls part of 9-hydroxystearic acid, a cellular lipid showing antiproliferative activity toward cancer cells with HDAC as a molecular target. Azelayl derivatives bound to a benzothiazolyl moiety further proved to be active as HDACi. The novel compounds were tested on a panel of both normal and tumor cell lines. Non-specific induction of cytotoxicity was observed in the normal cell line, while three of them induced a biological effect only on the osteosarcoma (U2OS) cell line. One of them induced a change in nuclear shape and size. Cell-cycle alterations are associated with post-transcriptional modification of both H2/H3 and H4 histones. In line with recent studies, revealing unexpected HDAC7 function in osteoclasts, molecular docking studies on the active molecules predicted their proneness to interact with HDAC7. By reducing side effects associated with the action of the first-generation inhibitors, the herein reported compounds, thus, sound promising as selective HDACi.

Highlights

Nitrogen-containing heterocycles are an important class of compounds of wide interest toward many applied fields, such as material, agrochemical, and medicinal chemistry
1), by reacting chloride of the methyl azelate synthesized from oxalyl chloride(Scheme and mono methyl esteracyl of azelaic acid)
2a–c synthesized from oxalyl chloride and mono methyl ester of azelaic acid)

Summary

Introduction

Nitrogen-containing heterocycles are an important class of compounds of wide interest toward many applied fields, such as material, agrochemical, and medicinal chemistry. One of the simplest aza-heteroaromatics is pyridine (1, Figure 1), first isolated by Anderson in 1851 [1], which plays a key role both in organic chemistry (as solvent and reactant) and in biological systems, since its nucleus belongs to many coenzymes and vitamins. Insertion of a further aza-moiety within the six-membered pyridine structure gives 1,2-diazines, 1,3-diazines, or 1,4-diazines, whose ancestors are pyridazine (2), pyrimidine (3), and pyrazine (4), respectively (Figure 1). Molecules 2020, 25, 404; doi:10.3390/molecules25020404 www.mdpi.com/journal/molecules 25, xx FOR FOR PEER PEER REVIEW REVIEW Molecules of 18. 22 of Structures of of pyridine pyridine (1), Figure 1.

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