Design, synthesis and evaluation of thiohydantoin derivatives as potent topoisomerase I (Top1) inhibitors with anticancer activity

Majumdar, Papiya; Bathula, Chandramohan; Basu, Suparna Mercy; Das, Subhendu; Agarwal, Rahul; Hati, Santanu; Singh, Ashutosh; Sen, Subhabrata; Das, Benu Brata

doi:10.1016/j.ejmech.2015.08.032

Cited by 70 publications

(61 citation statements)

References 36 publications

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“…Camptothecin, the first small molecule targeting Top I for the treatment of advanced digestive carcinoma in clinical2331, which stabilizes the DNA cleavable complex to block the transient breaking and rejoining of DNA173233 and has been used as the Top I poison for the treatment of many digestive solid tumors widely34, was served as the positive control. As shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The molecular docking simulations between Top I and hippeastrine was carried out using the Genetic Algorithm of AutoDock 4.2 software52. Briefly, the 3D structure of hippeastrine was established with MOE Molecule Builder tool, and then its energy minimization was executed by the MMFF94× force field.…”

Section: Methodsmentioning

confidence: 99%

“…As a result, the structural and functional studies on Top I have provided a reliable platform for the development of Top I inhibitors, which block the DNA synthesis and malignant cell proliferation during many pivotal cellular processes such as transcriptions, replication, chromosome condensation, and are considered as important antineoplastic chemotherapeutic agents with the mechanism of DNA interaction1920. In clinic, Top I inhibitors have been successfully applied for the treatment of colorectal, lung and ovarian cancers nowadays21, such as camptothecin (CPT) families, particularly the two CPT derivatives topotecan (TPT) and irinotecan (IFL), the only two Top I inhibitors approved by the FDA for the treatments of ovarian, colorectal and lung cancer, have displayed significant anticancer effects192223.…”

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confidence: 99%

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Antiproliferative activities of Amaryllidaceae alkaloids from Lycoris radiata targeting DNA topoisomerase I

Chen

Tian

et al. 2016

Sci Rep

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Crude Amaryllidaceae alkaloids (AAs) extracted from Lycoris radiata are reported to exhibit significant anti-cancer activity. However, the specific alkaloids responsible for the pharmacodynamic activity and their targets still remain elusive. In this context, we strived to combine affinity ultrafiltration with topoisomerase I (Top I) as a target enzyme aiming to fish out specific bioactive AAs from Lycoris radiata. 11 AAs from Lycoris radiata were thus screened out, among which hippeastrine (peak 5) with the highest Enrichment factor (EF) against Top I exhibited good dose-dependent inhibition with IC50 at 7.25 ± 0.20 μg/mL comparable to camptothecin (positive control) at 6.72 ± 0.23 μg/mL. The molecular docking simulation further indicated the inhibitory mechanism between Top I and hippeastrine. The in vitro antiproliferation assays finally revealed that hippeastrine strongly inhibited the proliferation of HT-29 and Hep G2 cells in an intuitive dose-dependent manner with the IC50 values at 3.98 ± 0.29 μg/mL and 11.85 ± 0.20 μg/mL, respectively, and also induced significant cellular morphological changes, which further validated our screening method and the potent antineoplastic effects. Collectively, these results suggested that hippeastrine could be a very promising anticancer candidate for the therapy of cancer in the near future.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Antiproliferative activities of Amaryllidaceae alkaloids from Lycoris radiata targeting DNA topoisomerase I

Chen

Tian

et al. 2016

Sci Rep

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“…18 Thiohydantoin ( 7 ) derivatives have been identified as antimicrobials 19 and antitumor 20 agents with topoisomerase I inhibitory activities. 21 Rhodanine ( 8 ) derivatives are well known beta-lactamase inhibitors. 22,23 Analogues of thiazolidinedione ( 9 ) are peroxisome proliferator-activated receptor (PPAR) agonists and have been used as antidiabetic drugs.…”

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Isatin derivatives with activity against apoptosis-resistant cancer cells

Evdokimov

Magedov

McBrayer

et al. 2016

Bioorganic & Medicinal Chemistry Letters

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In a search of small molecules active against apoptosis-resistant cancer cells, a series of isatin-based heterocyclic compounds were synthesized and found to inhibit proliferation of cancer cell lines resistant to apoptosis. The synthesis of these compounds involved a condensation of commercially available, active methylene heterocycles with isatin proceeding in moderate to excellent yields. The heterocyclic scaffolds prepared in the current investigation appear to be a useful starting point for the development of agents to fight cancers with apoptosis resistance, and thus, associated with dismal prognoses.

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“…Topoisomerases (Topo) are universal nuclear enzymes that modulate DNA supercoiling during DNA replication, transcription, and chromatin assembly by forming a reversible covalent Topo‐DNA complex (Figure ) . Topo I and Topo II are two types of DNA topoisomerases, which cleave single or double DNA strands leading to transient DNA single‐strand breaks or double‐strand breaks, respectively . The mechanism of Topo inhibitors is to stabilize the DNA‐enzyme cleavable complex through intercalation between DNA base pairs.…”

Section: Introductionmentioning

confidence: 99%

Comparative in vitro Studies of the Topoisomerase I Inhibition and Anticancer Activities of Metallated N‐Confused Porphyrins and Metallated Porphyrins

et al. 2020

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Using the original approach, a series of metallated N‐confused porphyrins and metallated porphyrins have been synthesized and characterized. For all the synthesized porphyrins, in vitro studies of cytotoxic activity against K562, U937, HL‐60, Jurkat, A549 and HeLa cancer cell lines, the ability to induce apoptosis and effects on the cell cycle as well as the kinetics of proliferative activity of porphyrins and their respective metallated complexes in real time have been developed. The inhibitory activity of metallated porphyrins against human topoisomerase I and the possible mechanism of inhibition have been carried out by modelling using molecular docking.

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Design, synthesis and evaluation of thiohydantoin derivatives as potent topoisomerase I (Top1) inhibitors with anticancer activity

Cited by 70 publications

References 36 publications

Antiproliferative activities of Amaryllidaceae alkaloids from Lycoris radiata targeting DNA topoisomerase I

Antiproliferative activities of Amaryllidaceae alkaloids from Lycoris radiata targeting DNA topoisomerase I

Isatin derivatives with activity against apoptosis-resistant cancer cells

Comparative in vitro Studies of the Topoisomerase I Inhibition and Anticancer Activities of Metallated N‐Confused Porphyrins and Metallated Porphyrins

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