Abstract
The synthesis and characterization of three aromatic oligoamides, constructed from the same pyridyl carboxamide core but incorporating distinct end groups of acetyl (Ac) 1, tert-butyloxycarbonyl (Boc) 2 and amine 3 is reported. Single crystal X-ray diffraction analysis of 1–3 and a dimethylsulfoxide (DMSO) solvate of 2 (2-DMSO), has identified the presence of a range of intra- and intermolecular interactions including N-H⋯N, N-H⋯O=C and N-H⋯O=S(CH3)2 hydrogen-bonding interactions, C-H⋯π interactions and off-set, face-to-face stacking π-π interactions that support the variety of slipped stack, herringbone and cofacial crystal packing arrangements observed in 1–3. Additionally, the cytotoxicity of this series of aromatic oligoamides was assessed against two human ovarian (A2780 and A2780cisR), two human breast (MCF-7 and MDA-MB-231) cancerous cell lines and one non-malignant human epithelial cell line (PNT-2), to investigate the influence of the terminal functionality of these aromatic oligoamides on their biological activity. The chemosensitivity results highlight that modification of the terminal group from Ac to Boc in 1 and 2 leads to a 3-fold increase in antiproliferative activity against the cisplatin-sensitive ovarian carcinoma cell line, A2780. The presence of the amine termini in 3 gave the only member of the series to display activity against the cisplatin-resistance ovarian carcinoma cell line, A2780cisR. Compound 2 is the lead candidate of this series, displaying high selectivity towards A2780 cancer cells when compared to non-malignant PNT-2 cells, with a selectivity index value >4.2. Importantly, this compound is more selective towards A2780 (cf. PNT-2) than the clinical platinum drugs oxaliplatin by > 2.6-fold and carboplatin by > 1.6-fold.
Highlights
The rise of cancer cell resistance towards clinical anticancer drugs, combined with the poor selectivity they can demonstrate for cancers over non-malignant tissue and the occurrence of adverse sideeffects, has driven the search for new compounds with increased antiproliferative activity and selectivity. (Mader et al, 1998; Winocur et al, 2006; Figaro et al, 2011; Tageja et al, 2011; Ward et al, 2021)
We report on the solid-state properties of 1–3 and solvatomorph 2-DMSO, and employ single-crystal X-ray diffraction analysis to identify the presence of a range of non-covalent interactions which support the diverse crystal packing behavior of these aromatic oligoamides
We have synthesized and characterized a series of aromatic oligoamides based on a common pyridyl carboxamide core but incorporating distinct end groups: acetyl (Ac) 1, tertbutyloxycarbonyl (Boc) 2 and amine 3
Summary
The rise of cancer cell resistance towards clinical anticancer drugs, combined with the poor selectivity they can demonstrate for cancers over non-malignant tissue and the occurrence of adverse sideeffects, has driven the search for new compounds with increased antiproliferative activity and selectivity. (Mader et al, 1998; Winocur et al, 2006; Figaro et al, 2011; Tageja et al, 2011; Ward et al, 2021). A crystallographic study of aromatic oligoamides by Nissinen and co-workers (Suhonen et al, 2012) showed that modification of the aromatic ring from benzene to pyridine results in marked changes in the folding behavior of these compounds resulting in the adoption of curved molecular structures. Gunnlaugsson and co-workers described a crystallographic analysis of a series of cytotoxic pyridine-based aromatic oligoamides, showing that they adopted curved molecular structures with a supramolecular arrangement that could potentially promote interaction with DNA. To probe the influence of the terminal group on the solid-state structure and antiproliferative activity of these aromatic oligoamides, we undertook the synthesis, crystallographic analysis and cytotoxicity studies of three aromatic oligoamides based on the same pyridyl carboxamide core but including different end groups; acetyl (Ac) 1, tertbutyloxycarbonyl (Boc) 2 and amine 3 (Figure 1). The results show that the most promising compound, a Boc-terminated aromatic oligoamide, is non-toxic towards non-malignant cells, unlike all cisplatin (CDDP), carboplatin (CARB) and oxaplatin (OXA), which all demonstrate high cytotoxicity
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