Synthesis of novel indole derivatives as promising DNA-binding agents and evaluation of antitumor and antitopoisomerase I activities

Lafayette, Elizabeth Almeida; Almeida, Sinara Mônica Vitalino de; Santos, Roana Carolina Bezerra dos; Oliveira, Jamerson Ferreira de; Amorim, Cézar Augusto da Cruz; Silva, Rosali Maria Ferreira da; Pitta, Maíra Galdino da Rocha; Pitta, Ivan da Rocha; Moura, Ricardo Olímpio de; Júnior, Luiz Bezerra de Carvalho; Rêgo, Moacyr Jesus Barreto de Melo; Lima, Maria do Carmo Alves de

doi:10.1016/j.ejmech.2017.05.012

Cited by 37 publications

(8 citation statements)

References 60 publications

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“…Indole, carbazole and their derivatives are colorless solid crystalline substances that do not dissolve in water. Under standard conditions, the melting point of indole is 52°C, of carbazole, it is 247-248°C, and their boiling points are 253°C and 354-355°C, respectively 2,3 fragment serves as a ligand for many receptors and has the property of reverse coupling to enzymes, in particular, to DNA topoisomerase I [19], and the indole element is responsible for the interaction with DNA [20,21].…”

Section: Results and Discussion General Characteristics Of Indolocarbazole Group Compoundsmentioning

confidence: 99%

Antitumor Drugs Based on Indolocarbazol Derivatives

Kolpaksidi

Дмитриева²,

Ярош

et al. 2021

Farm. farmakol. (Pâtigorsk)

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The aim of the work is to generalize the literature data on indolocarbazole derivatives with an antitumor activity.Materials and methods. The objects of the study were the preparations based on indolocarbazole derivatives with the antitumor activity. To search for materials on the problem under study, the following search and information as well as library databases were used: ebibrary, PubMed, CyberLeninka, ResearchGate, the State Register of Medicines, clinical trials registries clinline.ru and clinicaltrials.gov. The search for the following words / phrases was performed: indolocarbazoles, indolocarbazole derivatives, staurosporine, rebeccamycin, staurosporine derivatives. The search was conducted from January 11 until March 1, 2021. The compounds with a biological activity which were undergoing or had undergone preclinical and clinical trials, were taken into account. All the materials from 1977 to January 1, 2021, were taken into account.Results. The materials obtained indicate that indolocarbazole derivatives are promising compounds for the creation of anticancer medicinal preparations due to their properties and peculiarities of the action mechanism. These drugs have a selective action due to the targeted interaction with specific molecular targets: kinases (especially protein kinase C and its isozymes), DNA and DNA topoisomerase. To date, many compounds from the class of indolocarbazoles have been synthesized and investigated. They have shown a high antitumor activity in the treatment of systemic and solid tumors. However, despite this, only one MP based on a staurosporine derivative, registered by the TN of Rydapt® (in the USA and EU countries) and Miticaid® (in the Russian Federation), is approved for use in the clinical practice.Conclusion. Thus, the basic data from scientific publications on promising anticancer medicinal preparations based on compounds from the class of indolocarbazoles, have been summarized. The information is provided, in particular, on their molecular structure, the origin, classification, the main representatives of the class, which are at various stages of the research and are approved for use in the clinic.

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Section: Results and Discussion General Characteristics Of Indolocarbazole Group Compoundsmentioning

confidence: 99%

Antitumor Drugs Based on Indolocarbazol Derivatives

Kolpaksidi

Дмитриева²,

Ярош

et al. 2021

Farm. farmakol. (Pâtigorsk)

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“…Thus, a hypochromic effect in the absence of any red/blue shift, as seen with the propellane derivatives 5c, 5d and 5f, suggests the possibility of a non-intercalative binding mechanism (e.g. groove binding), rather than intercalation [39][40][41].…”

Section: Uv-vis Spectroscopymentioning

confidence: 91%

Design, synthesis, and DNA interaction studies of furo-imidazo[3.3.3]propellane derivatives: Potential anticancer agents

Hassan

Aly

Mohamed

et al. 2019

Bioorganic Chemistry

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A large number of natural products containing the propellane scaffold have been reported to exhibit cytotoxicity against several cancers; however, their mechanism of action is still unknown. Anticancer drugs targeting DNA are mainly composed of small planar molecule/s that can interact with the DNA helix, causing DNA malfunction and cell death. The aim of this study was to design and synthesize propellane derivatives that can act as DNA intercalators and/or groove binders. The unique structure of the propellane derivatives and their ability to display planar ligands with numerous possible geometries, renders them potential starting points to design new drugs targeting DNA in cancer cells. New substituted furo-imidazo[3.3.3]propellanes were synthesized via the reaction of substituted alkenylidene-hydrazinecarbothioamides with 2-(1,3-dioxo-2,3dihydro-1H-2-ylidene) propanedinitrile in tetrahydrofuran at room temperature. The structures of the products were confirmed by a combination of elemental analysis, NMR, ESI-MS, IR and single crystal X-ray analysis. Interestingly, 5c, 5d and 5f showed an ability to interact with Calf Thymus DNA (CT-DNA). Their DNA-binding mode was investigated using a combination of absorption spectroscopy, DNA melting, viscosity, CD spectroscopy measurements, as well as competitive binding studies with several dyes. Their cytotoxicity was evaluated against the NCI-60 panel of cancer cell lines. 5c, 5d and 5f exhibited similar anti-proliferative activity against the A549 non-small cell lung cancer (NSCLC) cell line. Further mechanistic studies revealed their ability to induce DNA damage in the A549 cell line, as well as apoptosis, evidenced by elevated *

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“…Drugs from the class of indolocarbazoles have attracted the attention of researchers by their ability to interact with several intracellular targets and the ability to induce different cell death paths. Among the representatives of this class, there are the compounds that cause damage to DNA structure by means of intercalation, and that are inhibitors of topoisomerases controlling the processes of DNA replication, transcription and repair, as well as inhibitors of kinases, in particular, CDK-1 kinase and protein kinase C involved in transmission of intracellular proliferative signals (Civenni et al 2016;Lafayette et al 2017;Zenkov et al 2020).…”

Section: Introductionmentioning

confidence: 99%

Antiproliferative activity of a new derivative from the class of N-glycoside of indolo[2,3-a]pyrrolo[3,4-c]carbazoles

Киселева¹,

Borisova²,

Smirnova³

et al. 2022

RRP

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Introduction: The creation of highly effective original anticancer drugs remains an urgent direction of scientific research in tumor therapy. One of the promising groups in this regard is indolocarbazoles and their derivatives, which are capable of initiating various pathways of tumor cell death. The aim of the study was to evaluate an antiproliferative activity of a new, Russian derivative of N-glycoside substituted indolocarbazole 6-amino-12-(α-L-arabinopyranosyl)indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7-dione (LCS-1208) on models of transplantable tumors of mice and on human tumors in Balb/c nude mice. Materials and methods: Indolocarbazole sensitivity to LCS-1208 was assessed on transplantable tumors of mice – lymphatic leukemia L-1210, cervical carcinoma (CC-5), and colon adenocarcinoma (CAC) by five-fold intraperitoneal administration (ip) of the LCS-1208 substance in single doses of 50, 75, 100 mg/kg. Investigation into the effectiveness of the LCS-1208 lyo dosage form was performed on subcutaneous xenografts of human colon cancer SW620 by an intravenous administration (iv). The antitumor effect was evaluated by the tumor growth inhibition (TGI) and an increase in life span (ILS) of the treated animals as compared with the control ones. Evaluation of specific antitumor activity on xenografts was performed according to the tumor/control (T/C%) criterion (maximum criterion T/C≤42%). Results and discussion: According to the results of the study, the most sensitive to the action of the LCS-1208 substance in the case of an ip administration of a total dose of 375 mg/kg were CAC with TGI=97–62%, p≤0.001 up to 16 days after the treatment, and ILS=36% (criteria for TGI≥70% and ILS≥25%). On xenografts of a human colon cancer SW620, the effectiveness of the LCS-1208 lyo drug dosage form within the range of total doses from 50 to 150 mg/kg in case of iv to Balb/c nude mice was set at T/C = 35–2% (criterion T/C<42%). Conclusion: The presented results suggest possible effectiveness of LCS-1208 in treatment of colon malignant tumors of humans.

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Synthesis of novel indole derivatives as promising DNA-binding agents and evaluation of antitumor and antitopoisomerase I activities

Cited by 37 publications

References 60 publications

Antitumor Drugs Based on Indolocarbazol Derivatives

Antitumor Drugs Based on Indolocarbazol Derivatives

Design, synthesis, and DNA interaction studies of furo-imidazo[3.3.3]propellane derivatives: Potential anticancer agents

Antiproliferative activity of a new derivative from the class of N-glycoside of indolo[2,3-a]pyrrolo[3,4-c]carbazoles

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