Behind the Mirror: Chirality Tunes the Reactivity and Cytotoxicity of Chloropiperidines as Potential Anticancer Agents

Carraro, Caterina; Francke, Alexander; Sosic, Alice; Kohl, Franziska; Helbing, Tim; Franco, Michele De; Fabris, Daniele; Göttlich, Richard; Gatto, Barbara

doi:10.1021/acsmedchemlett.8b00580

Cited by 14 publications

(49 citation statements)

References 27 publications

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“…As proof of principle of their mechanism of action, the representative aromatic derivative 2 demonstrated to damage cellular DNA to a higher extent compared to chlorambucil even at a much lower concentration. The tropism toward pancreatic cancer cells is exceptionally relevant considering the aggressiveness of this tumor type and recalls what observed with monofunctional 3‐chloropiperidines (M–CePs) against the same cell line [9] …”

Section: Discussionsupporting

confidence: 58%

“…Of note, all derivatives demonstrated a valuable cytotoxicity against the three human tumor cell lines, in most cases improved compared to the reference drug chlorambucil [9] . Interestingly, results suggest a separate analysis for HCT‐15 and 2008 compared to BxPC‐3 tumor cells: in fact, B−CePs behaved similarly against colorectal and ovarian cancer cells, exhibiting IC 50 values between 1 and 20 μ m , whereas the new set was one or two orders of magnitude more potent against the pancreatic cancer cells.…”

Section: Resultsmentioning

confidence: 95%

“…In line with our precedent studies on 3‐chloropiperidines, the new derivatives were initially evaluated for their ability to react with nucleic acids and induce DNA strand breaks [4,9] . The electrophoretic cleavage assay allows to visualize the compound‐mediated conversion of the supercoiled plasmid substrate (SC) into its retarded nicked and linearized forms (OC=open circular, L=linearized).…”

Section: Resultsmentioning

confidence: 99%

“…After analyzing the reactivity of compounds with water and with purified DNA, the biological value of compounds was assessed by the MTT assay on a panel of human cancer cell lines, namely colorectal adenocarcinoma HCT‐15, pancreatic adenocarcinoma BxPC‐3 and ovarian carcinoma 2008 cells. Table 1 reports the IC 50 values observed after 72 h of treatment with tested B−CePs along with previously determined IC 50 values of the reference nitrogen mustard chlorambucil (Chl) [9] . For its poor solubility and compatibly with the use of maximum 0.5 % DMSO in cell culture, compound 5 was not tested over 25 μ m .…”

Section: Resultsmentioning

confidence: 99%

“…MTT assay . The 72 h MTT assay was performed following previously reported materials and protocols [9,18] . Test compounds were dissolved in DMSO and added at defined concentrations to the cell growth medium to a final solvent concentration of 0.5 %, which had no detectable effect on cell killing.…”

Section: Methodsmentioning

confidence: 99%

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Aromatic Linkers Unleash the Antiproliferative Potential of 3‐Chloropiperidines Against Pancreatic Cancer Cells

et al. 2020

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In this study, we describe the synthesis and biological evaluation of a set of bis‐3‐chloropiperidines (B−CePs) containing rigid aromatic linker structures. A modification of the synthetic strategy also enabled the synthesis of a pilot tris‐3‐chloropiperidine (Tri‐CeP) bearing three reactive meta‐chloropiperidine moieties on the aromatic scaffold. A structure–reactivity relationship analysis of B−CePs suggests that the arrangement of the reactive units affects the DNA alkylating activity, while also revealing correlations between the electron density of the aromatic system and the reactivity with biologically relevant nucleophiles, both on isolated DNA and in cancer cells. Interestingly, all aromatic 3‐chloropiperidines exhibited a marked cytotoxicity and tropism for 2D and 3D cultures of pancreatic cancer cells. Therefore, the new aromatic 3‐chloropiperidines appear to be promising contenders for further development of mustard‐based anticancer agents aimed at pancreatic cancers.

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Section: Discussionsupporting

confidence: 58%

Section: Resultsmentioning

confidence: 95%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Aromatic Linkers Unleash the Antiproliferative Potential of 3‐Chloropiperidines Against Pancreatic Cancer Cells

et al. 2020

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Synthesis and Antiproliferative Activity of Cisplatin‐3–Chloropiperidine Conjugates

Georg,

Legin,

Hejl

et al. 2024

ChemBioChem

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We report the synthesis and characterization of two novel cisplatin‐ alkylating agents conjugates. Combining a platinum based cytostatic agent with a sterically demanding alkylating agent could potentially induce further DNA damage, block cell repair mechanisms and keep the substrate active against resistant tumor cell lines. The 3‐chloropiperidines utilized as ligands in this work are cyclic representatives of the N‐mustard family and were not able to coordinate platinum on their own. The introduction of a second coordination site, in form of a pyridine moiety, led to the isolation of the desired conjugates. They were characterized with HRMS, CHN‐analyses and XRD. We concluded this work by examining the cytotoxicity of the ligands and the obtained complexes with MTT assays in human cancer cell lines. While the ligands showed hardly any activity, the novel conjugates both displayed a high antiproliferative and cytotoxic potency in a panel of three cell lines. Moreover, both complexes were able to largely circumvent the acquired cisplatin resistance of A2780cisR ovarian cancer cells, both in the MTT assay and a flow‐cytometric apoptosis assay.

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Appended Aromatic Moieties in Flexible Bis‐3‐chloropiperidines Confer Tropism against Pancreatic Cancer Cells

et al. 2020

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Nitrogen mustards (NMs) are an old but still largely diffused class of anticancer drugs. However, spreading mechanisms of resistance undermine their efficacy and therapeutic applicability. To expand their antitumour value, we developed bis‐3‐chloropiperidines (B‐CePs), a new class of mustard‐based alkylating agent, and we recently reported the striking selectivity for BxPC‐3 pancreatic tumour cells of B‐CePs bearing aromatic moieties embedded in the linker. In this study, we demonstrate that such tropism is shared by bis‐3‐chloropiperidines bearing appended aromatic groups in flexible linkers, whereas esters substituted by aliphatic groups or by efficient DNA‐interacting groups are potent but nonselective cytotoxic agents. Besides, we describe how the critical balance between water stability and DNA reactivity can affect the properties of bis‐3‐chloropiperidines. Together, these findings support the exploitation of B‐CePs as potential antitumour clinical candidates.

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Behind the Mirror: Chirality Tunes the Reactivity and Cytotoxicity of Chloropiperidines as Potential Anticancer Agents

Cited by 14 publications

References 27 publications

Aromatic Linkers Unleash the Antiproliferative Potential of 3‐Chloropiperidines Against Pancreatic Cancer Cells

Aromatic Linkers Unleash the Antiproliferative Potential of 3‐Chloropiperidines Against Pancreatic Cancer Cells

Synthesis and Antiproliferative Activity of Cisplatin‐3–Chloropiperidine Conjugates

Appended Aromatic Moieties in Flexible Bis‐3‐chloropiperidines Confer Tropism against Pancreatic Cancer Cells

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