A facile synthesis of diaryl pyrroles led to the discovery of potent colchicine site antimitotic agents

Romagnoli, Romeo; Oliva, Paola; Salvador, María Kimatrai; Manfredini, Stefano; Padroni, Chiara; Brancale, Andrea; Ferla, Salvatore; Hamel, Ernest; Ronca, Roberto; Maccarinelli, Federica; Rruga, Fatlum; Mariotto, Elena; Viola, Giampietro; Bortolozzi, Roberta

doi:10.1016/j.ejmech.2021.113229

Cited by 13 publications

(10 citation statements)

References 56 publications

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“…Prior studies have demonstrated that pyrrole formation necessitates the use of an acidic environment. 25,26 Herein, the DNA-linked starting material 1a was treated with 150 equiv of 2 in the presence of pH 5.5 phosphate buffer to determine the optimal reaction temperature and time. The reaction results obtained from the LCMS analysis were graphically visualized in Scheme 2B−D.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…The starting material applied for this chemistry is a covalently linked DNA duplex 1a with a free amine group, which is produced via amidation of headpiece with Fmoc-Gly-OH, followed by deprotection of the Fmoc group. Prior studies have demonstrated that pyrrole formation necessitates the use of an acidic environment. , Herein, the DNA-linked starting material 1a was treated with 150 equiv of 2 in the presence of pH 5.5 phosphate buffer to determine the optimal reaction temperature and time. The reaction results obtained from the LCMS analysis were graphically visualized in Scheme B–D.…”

Section: Results and Discussionmentioning

confidence: 99%

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A General Set of DNA-Compatible Reactions for Preparing DNA-Tagged Multisubstituted Pyrroles

Liu

Seydimemet

et al. 2021

Bioconjugate Chem.

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DNA-encoded library (DEL) technology provided a powerful screening platform for identifying potential bioactive small molecules with high affinity to biologically interesting targets. Essential to a successful DEL campaign are the drug-like small molecular moieties of DNA-encoded libraries with expanded chemical space. Our laboratory has been working on developing and producing novel DNA-encoded libraries that complement current reported DELs. Herein, we demonstrated a general set of DNA-compatible reactions that enable the preparation of pyrrole-based DNA-encoded libraries in which the DNA tags are linked to the N position of the pyrrole central core. Further diversification could be rapidly incorporated into the pyrrole scaffold by robust iodination and Suzuki coupling reactions.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Section: Results and Discussionmentioning

confidence: 99%

A General Set of DNA-Compatible Reactions for Preparing DNA-Tagged Multisubstituted Pyrroles

Liu

Seydimemet

et al. 2021

Bioconjugate Chem.

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“…This work was further extended and resulted in the generation of the JG03-14 analogs with potent anti-cancer activities [ 48 ]. Romagnoli R et al recently found that cis-restricted analogs of combretastatin A-4 (CA-4) that contained a pyrrole nucleus interposed between the two aryl rings, also exhibited potent anti-proliferative activities against several cancer cell lines due to their ability to inhibit tubulin polymerization, block the cell cycle in the metaphase and activate mitochondria-mediated apoptosis pathways [ 49 ]. Of note, all reports shown above highlighted that the tubulin-depolymerization activity of the pyrrole-based compounds was due to their binding to the colchicine-binding site of the tubulin.…”

Section: Discussionmentioning

confidence: 99%

The Design, Synthesis, and Biological Activities of Pyrrole-Based Carboxamides: The Novel Tubulin Inhibitors Targeting the Colchicine-Binding Site

et al. 2021

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Microtubule targeting agents (MTAs) that interfere with the dynamic state of the mitotic spindle are well-known and effective chemotherapeutic agents. These agents interrupt the microtubule network via polymerization or depolymerization, halting the cell cycle progression and leading to apoptosis. We report two novel pyrrole-based carboxamides (CAs) (CA-61 and -84) as the compounds exhibiting potent anti-cancer properties against a broad spectrum of epithelial cancer cell lines, including breast, lung, and prostate cancer. The anti-cancer activity of CAs is due to their ability to interfere with the microtubules network and inhibit tubulin polymerization. Molecular docking demonstrated an efficient binding between these ligands and the colchicine-binding site on the tubulin. CA-61 formed two hydrogen bond interactions with THR 179 (B) and THR 353 (B), whereas two hydrogen bonds with LYS 254 (B) and 1 with ASN 101 (A) were identified for CA-84. The binding energy for CA-84 and CA-61 was −9.910 kcal/mol and −9.390 kcal/mol. A tubulin polymerization assay revealed a strong inhibition of tubulin polymerization induced by CA-61 and -84. The immunofluorescence data revealed the disruption of the tubulin assembly in CA-treated cancer cells. As an outcome of the tubulin inhibition, these compounds halted the cell cycle progression in the G2/M phase, leading to the accumulation of the mitotic cells, and further induced apoptosis. Lastly, the in vivo study indicated that CAs significantly inhibited the HCC1806 breast cancer xenograft tumor growth in a nude mouse model. Collectively, we identified the novel CAs as potent MTAs, inhibiting tubulin polymerization via binding to the colchicine-binding site, disrupting the microtubule network, and exhibiting potent pro-apoptotic activities against the epithelial cancer cell lines both in vitro and in vivo.

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“…In addition, CA-4 has poor water solubility and is chemically unstable, with the active cis-isomer spontaneously converting to the thermodynamically favorable but less potent trans-isomer [16]. Numerous analogs of CA-4 have been tested to address these drawbacks [17][18][19][20]. The water-soluble phosphate prodrugs Zybrestat (2) and AVE-8082 (3) have shown promising results in pre-clinical and clinical studies, particularly in combination with other chemotherapeutic agents [21,22] against thyroid, non-small cell lung, and ovarian cancers [23][24][25].…”

Section: Introductionmentioning

confidence: 99%

“…1 H NMR (CDCl 3 , 400 MHz): δ 3.72 (s, 3H, NCH 3 ), 3.84 (s, 6H, OCH 3 ), 6.44 (t, 2H, J = 2.2 Hz, ArH), 6.64 (d, 2H, J = 2.2 Hz, ArH), 6.78 (d, 1H, J = 15.8, =CH), 7.14 (t, 1H, J = 7.8, ArH), 7.33-7.36 (m, 2H, ArH), 7.58 (d, 1H, J = 15.8, =CH). (E/Z)-3-Methyl-4-(3,4,5-Trimethoxystyryl)-2(3H)-Benzothiazolone(18) …”

mentioning

confidence: 99%

New Heterocyclic Combretastatin A-4 Analogs: Synthesis and Biological Activity of Styryl-2(3H)-benzothiazolones

et al. 2021

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Here, we describe the synthesis, characterization, and biological activities of a series of 26 new styryl-2(3H)-benzothiazolone analogs of combretastatin-A4 (CA-4). The cytotoxic activities of these compounds were tested in several cell lines (EA.hy926, A549, BEAS-2B, MDA-MB-231, HT-29, MCF-7, and MCF-10A), and the relations between structure and cytotoxicity are discussed. From the series, compound (Z)-3-methyl-6-(3,4,5-trimethoxystyryl)-2(3H)-benzothiazolone (26Z) exhibits the most potent cytotoxic activity (IC50 0.13 ± 0.01 µM) against EA.hy926 cells. 26Z not only inhibits vasculogenesis but also disrupts pre-existing vasculature. 26Z is a microtubule-modulating agent and inhibits a spectrum of angiogenic events in EA.hy926 cells by interfering with endothelial cell invasion, migration, and proliferation. 26Z also shows anti-proliferative activity in CA-4 resistant cells with the following IC50 values: HT-29 (0.008 ± 0.001 µM), MDA-MB-231 (1.35 ± 0.42 µM), and MCF-7 (2.42 ± 0.48 µM). Cell-cycle phase-specific experiments show that 26Z treatment results in G2/M arrest and mitotic spindle multipolarity, suggesting that drug-induced centrosome amplification could promote cell death. Some 26Z-treated adherent cells undergo aberrant cytokinesis, resulting in aneuploidy that perhaps contributes to drug-induced cell death. These data indicate that spindle multipolarity induction by 26Z has an exciting chemotherapeutic potential that merits further investigation.

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A facile synthesis of diaryl pyrroles led to the discovery of potent colchicine site antimitotic agents

Cited by 13 publications

References 56 publications

A General Set of DNA-Compatible Reactions for Preparing DNA-Tagged Multisubstituted Pyrroles

A General Set of DNA-Compatible Reactions for Preparing DNA-Tagged Multisubstituted Pyrroles

The Design, Synthesis, and Biological Activities of Pyrrole-Based Carboxamides: The Novel Tubulin Inhibitors Targeting the Colchicine-Binding Site

New Heterocyclic Combretastatin A-4 Analogs: Synthesis and Biological Activity of Styryl-2(3H)-benzothiazolones

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