Bis-3-chloropiperidines containing bridging lysine linkers: Influence of side chain structure on DNA alkylating activity

Zuravka, Ivonne; Roesmann, Rolf; Sosic, Alice; Göttlich, Richard; Gatto, Barbara

doi:10.1016/j.bmc.2015.01.050

Cited by 13 publications

(38 citation statements)

References 14 publications

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“…MS studies . The formation of B−CePs reactive species upon incubation at 37 °C in water was followed in time by ESI‐MS as reported previously [4a] . A 80 μ m solution of test compounds was prepared in MilliQ water from 1 m m DMSO stocks and incubated at 37 °C for 3 h. Small samples were taken after 0, 20, 40, 60 and 180 min, diluted 1 : 10 with methanol, and analyzed by ESI‐MS.…”

Section: Methodsmentioning

confidence: 99%

“…The ability of compounds to cleave the supercoiled plasmid pBR322 (Inspiralis Ltd) was investigated at the electrophoretic cleavage assay. The assay was performed following previously reported materials and protocols [4a,b] . B−CePs dilutions were freshly prepared from a 10 m m DMSO stock in Milli‐Q water, resulting in a 0.5 % DMSO concentration in the final reaction volume.…”

Section: Methodsmentioning

confidence: 99%

“…Thanks to their marked electrophilicity, these compounds efficiently react with nucleobases, forming mono‐ and bi‐functional adducts preferentially with the N7 of guanines [5] . These base lesions rearrange into apurinic sites leading to DNA cleavage, [5] with in vitro potencies modulated by the chemistry of the linker connecting the two 3‐chloropiperidine reactive centers [4a,b] . Along with potent derivatives characterized by aliphatic linkers, our previous studies examined the activity toward DNA of one B−CeP bearing a para ‐xylene linker (compound 3 , Figure 1c) [4b] …”

Section: Introductionmentioning

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: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

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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“…Experiments were performed by exploiting previously reported materials and protocols at the specified incubation time. 8−10…”

Section: Experimental Sectionmentioning

confidence: 99%

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

Carraro

Francke

Sosic

et al. 2019

ACS Med. Chem. Lett.

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The pressing demand for sustainable antitumor drugs prompted us to investigate 3-chloropiperidines as potential mustard-based anticancer agents. In this study, an explorative set of variously decorated monofunctional 3-chloropiperidines (M-CePs) was efficiently synthesized through a fast and affordable route providing high yields of pure racemates and enantiomers. Consistently with their reactivity, M-CePs were demonstrated to alkylate DNA in vitro . On a panel of carcinoma cell lines, M-CePs exhibited low nanomolar cytotoxicity indexes, which showed their remarkable activity against pancreatic cancer cells and in all cases performed strikingly better than the chlorambucil control. Very interestingly, stereochemistry modulated the activity of M-CePs in unexpected ways, pointing to additional molecular mechanisms of action beyond the direct damage of genomic DNA. This encouraging combination of efficacy and sustainability suggests they are valid candidates for anticancer agent development.

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“…Following this line of evidence, we investigate here whether aromatic moieties appended to the flexible aliphatic side chain of 3 could reproduce the cytotoxicity and pancreatic tumour tropism evidenced for rigid aromatic B‐CePs [1f] . To do that, we expanded our library of compounds bearing lysine linkers variously derivatized on the carboxyl group, [1b,c] and completed the evaluation of their cytotoxicity and reactivity toward the biologically relevant nucleophiles.…”

Section: Introductionmentioning

confidence: 99%

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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Bis-3-chloropiperidines containing bridging lysine linkers: Influence of side chain structure on DNA alkylating activity

Cited by 13 publications

References 14 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

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

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

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