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

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.

Synthesis of Novel Tryptamine Derivatives and Their Biological Activity as Antitumor Agents

“…Based on literature reports on the biological activity of compounds bearing different heterocyclic moieties bound to an azelayl chain through an amide bond [ 17 , 18 ], we planned to synthesize compounds 13 and 14 , bearing a tryptamine group.…”

“…The azelayl moiety recalls part of 9-hydroxystearic acid, a cellular lipid showing antiproliferative activity toward cancer cells with HDAC as the molecular target [ 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 ]. Actually, we found that some derivatives belonging to series in Figure 2 B–D behave as selective histone deacetylase inhibitors (HDACi): benzothiazole-based series ( Figure 2 B) is active against HT29 human colon cancer cells line [ 17 ] whereas, among the series containing pyridinyl (or piperidinyl, benzimidazolyl, benzotriazolyl) groups ( Figure 2 C,D), two aminopyrimidinyl and the benzimidazolyl derivatives showed specific activity on osteosarcoma cells [ 18 ]. The two latter moieties, aminopyrimidyl- and imidazolyl- one are also present in Apcin, ( Figure 2 E) a small molecule that blocks the interaction between APC/C and Cdc20 [ 19 ].…”

Uncovering New Drug Properties in Target-Based Drug–Drug Similarity Networks

“…(Instead, they bond to other amino acid residues than Abiraterone [ 91 ].) In a recent paper, Gabriele Micheletti et al reported results of biological and docking evaluations of some hybrid aza-heterocycles compounds, which bound azelayl moiety through an amide bond that act as histone deacetylase inhibitors; this suggests the anticancer potential for three of their Azelaic acid derivatives in osteosarcoma among the five tumor cell lines tested [ 92 ].…”

Design and Synthesis of Organic Molecules as Antineoplastic Agents

“…In most cases [2][3][4][5][6][7][8][9][10][11], the structural skeleton of these molecules contain a heterocyclic scaffold, and biological investigations were supported by docking calculations to identify and predict the possible molecular targets.…”

“…Docking calculation of complexes with each protein allowed the selection of some molecules to be subjected to screening on a panel of 60 human cancer cell lines. In the context of molecular hybridization, a synthesis of molecules containing azaheteroaromatics bound to azelaic acid fragments has been planned, owing to their analogous structure with some histone deacetylase inhibitors [8]. Cell lines included in the evaluation of toxicity profiles were: malignant U2OS, HT29, PC3, IGROV1, and normal human adult fibroblast HDFa cells.…”