Design and synthesis of DNA-intercalative naphthalimide-benzothiazole/cinnamide derivatives: cytotoxicity evaluation and topoisomerase-IIα inhibition

Rao, Nina; Nagesh, Narayana; Nayak, V. Lakshma; Sunkari, Satish; Tokala, Ramya; Kiranmai, Gaddam; Phanindranath, Regur; Shankaraiah, Nagula; Kamal, Ähmed

doi:10.1039/c8md00395e

Cited by 40 publications

(10 citation statements)

References 34 publications

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“…Unfortunately this combination was no better than standard treatment 36 . Sankara et al 37 , designed various naphthalimide benzothiazole/cinnamide analogues, all of which showed DNA intercalation, topoisomerase inhibition and low µM cytotoxicity using the MTT assay; however, none showed breast cancer selectivity in MCF-7 cells. Li et al 17 designed various naphthalimide-pyrazolyl derivatives that again showed DNA intercalation properties; the most potent of these showed a slight selectively towards MCF-7 cells (MTT assay 0.7 µM) compared with HeLa (3 µM) and A549 (5 µM) cells.…”

Section: Discussionmentioning

confidence: 99%

A novel naphthalimide that selectively targets breast cancer via the arylhydrocarbon receptor pathway

Gilbert

Iuliis

McCluskey

et al. 2020

Sci Rep

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We report that the naphthalimide analogue 2-(2-aminophenyl)-1H-benzo[de]isoquinoline-1,3(2H)dione (NAP-6) is a highly potent and selective breast cancer targeting molecule. These effects are mediated via the aryl hydrocarbon receptor (AHR) pathway and the subsequent induction of CYP1 metabolising monooxygenases in breast cancer cell line models. indeed the triple negative breast cancer cell line MDA-MB-468 with a GI 50 value of 100 nM is greater than 500-fold more sensitive to NAP-6 compared with other tumour derived cell models. Within 1 h exposure of these cells to NAP-6, CYP1A1 expression increases 25-fold, rising to 250-fold by 24 h. A smaller concurrent increase in CYP1A2 and CYP1B1 is also observed. Within 24 h these cells present with DNA damage as evident by enhanced H2AXγ expression, cell cycle checkpoint activation via increased CHK2 expression, S-phase cell cycle arrest and cell death. Specific small molecule inhibitors of the AHR and CYP1 family ameliorate these events. A positive luciferase reporter assay for NAP-6 induced XRE binding further confirms the role of the AHR in this phenomenon. Non-sensitive cell lines fail to show these biological effects. For the first time we identify 2-(2-aminophenyl)-1H-benzo[de]isoquinoline-1,3(2H)-dione as a new AHR ligand that selectively targets breast cancer. Breast cancer is the most common cancer in women and the incidence is on the rise. Despite advances in hormonal, immunological and targeted therapies, poor response and resistance mechanisms prevail, and metastatic disease is incurable 1. The aryl hydrocarbon receptor (AHR) pathway has been linked to the induction of breast cancer and to gene activation supporting the progression of this disease 2-9. The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor and a member of the basichelix-loop-helix-Per-ARNT-Sim (bHLH-PAS) family. The AHR regulates the transcription of several genes many of which are involved in xenobiotic metabolism. After ligand binding, the complex forms a heterodimer with the AHR nuclear transporter (ARNT), and translocates from the cytosol to the nucleus. The AHR-ARNT heterodimer then interacts with xenobiotic responsive elements (XREs) found on the promoter regions of several target genes. Such xenobiotic genes include the cytochrome P450 metabolising enzymes CYP1A1, CYP1A2 and CYP1B1 10-13. Although the AHR is renowned for its ability to metabolise and inactivate environmental toxins, this process can also produce DNA damaging carcinogens that initiate the formation of the cancer phenotype. The role of the AHR in breast cancer is even more sinister than this simple induction process. Indeed, enhanced expression of AHR is associated with malignant progression of the disease 14-16. Tumour-derived endogenous AHR ligands are known to constitutively activate AHR and drive the expression of CYP1 family members 15, 17. AHR activates genes involved in inflammation and breast tumour progression 9, 18. The AHR pathway crosstalks with the estrogen receptor pathway 2, 19, 20...

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Section: Discussionmentioning

confidence: 99%

A novel naphthalimide that selectively targets breast cancer via the arylhydrocarbon receptor pathway

Gilbert

Iuliis

McCluskey

et al. 2020

Sci Rep

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“…Compounds 25 and 26 are naphthalimide-benzothiazole derivatives reported by Rao et al [60] as potent topoisomerase-IIα inhibitors. The CDK2 enzyme is mainly responsible for DNA replication, cell division, and cell cycle progression.…”

Section: Topoisomerase Inhibitorsmentioning

confidence: 99%

Advances in 2‐substituted benzothiazole scaffold‐based chemotherapeutic agents

Haider

Rehman

Pathak

et al. 2021

Archiv der Pharmazie

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Targeted therapy plays a pivotal role in cancer therapeutics by countering the drawbacks of conventional treatment like adverse events and drug resistance. Over the last decade, heterocyclic derivatives have received considerable attention as cytotoxic agents by modulating various signaling pathways. Benzothiazole is an important heterocyclic scaffold that has been explored for its therapeutic potential.Benzothiazole-based derivatives have emerged as potent inhibitors of enzymes such as EGFR, VEGFR, PI3K, topoisomerases, and thymidylate kinases. Several researchers have designed, synthesized, and evaluated benzothiazole scaffold-based enzyme inhibitors. Of these, several inhibitors have entered various phases of clinical trials. This review describes the recent advances and developments of benzothiazole architecture-based derivatives as potent anticancer agents.

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“…Sankara Rao et al [87] have reported napthalimide-bearing benzothiazole derivatives as potent cytotoxic agents. The synthesized derivatives were screened against a selected panel of cancer Molecular docking studies revealed strong binding interactions within the ATP binding site of human DNA topoisomerase IIα (PDB ID:…”

Section: Phosphatidylinositol-3-kinases (Pi3k)/akt Inhibitorsmentioning

confidence: 99%

Benzothiazole‐based apoptosis inducers: A comprehensive overview and future prospective

Kamboj,

Mahore,

Husain

et al. 2024

Archiv der Pharmazie

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Cancer has become a major concern in healthcare globally, and over time, incidences and prevalence of cancer are increasing. To counter this, a lot of anticancer drugs are approved and are in clinical use, playing a pivotal role in its treatment. Due to drug resistance and adverse effects, a continuous demand for novel, potent, and safe candidates to treat cancer is always there. Over the last few decades, various heterocyclic ring‐based derivatives have been explored and reported in the literature. In this regard, benzothiazole scaffold‐based compound emerged as the versatile ring for developing novel and safe anticancer candidates. In this article, we have reported various benzothiazole heterocyclic ring‐based derivatives demonstrating potent antiproliferative activity by induction of apoptosis via an intrinsic pathway in a dose‐dependent manner. These compounds also displayed inhibition of different enzymes, for example, Aurora kinase, epidermal growth factor receptor, vascular endothelial growth factor receptor, phosphoinositide kinases, DNA topoisomerase, and tubulin polymerases. This study focused on a comprehensive overview of antiproliferative activity, structure–activity relationship, apoptosis induction activity, and enzyme inhibition by benzothiazole‐based compounds.

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Design and synthesis of DNA-intercalative naphthalimide-benzothiazole/cinnamide derivatives: cytotoxicity evaluation and topoisomerase-IIα inhibition

Abstract: A new series of different naphthalimide-benzothiazole/cinnamide derivatives were designed, synthesized and tested for their in vitro cytotoxicity on selected human cancer cell lines.

Cited by 40 publications

References 34 publications

A novel naphthalimide that selectively targets breast cancer via the arylhydrocarbon receptor pathway

A novel naphthalimide that selectively targets breast cancer via the arylhydrocarbon receptor pathway

Advances in 2‐substituted benzothiazole scaffold‐based chemotherapeutic agents

Benzothiazole‐based apoptosis inducers: A comprehensive overview and future prospective

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