N-glycosidesindolo[2,3,-a]pyrrolo[3,4,-c]carbazole derivatives  chemical structure influence on antitumor activity

Киселева, М. П.; Покровский, В. С.; Борисова, Л. М.; Голубева, И. С.; Эктова, Л. В.

doi:10.17650/1726-9784-2019-18-2-32-39

Cited by 4 publications

(7 citation statements)

References 13 publications

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“…The first indolocarbazoles were found out in streptomycetes and subsequently isolated from numerous representatives of flora and fauna. To date, this class of compounds has also been supplemented by a wide variety of synthetic compounds [18] 1 .…”

Section: Results and Discussion General Characteristics Of Indolocarbazole Group Compoundsmentioning

confidence: 99%

“…Indolocarbazoles are a class of heterocyclic compounds that include a planar ring consisting of indole and carbazole elements (Fig. 1, 2) [18]. Indole, carbazole and their derivatives are colorless solid crystalline substances that do not dissolve in water.…”

Section: Results and Discussion General Characteristics Of Indolocarbazole Group Compoundsmentioning

confidence: 99%

“…In this case, 5 isomers of the polycyclic sys- (4) and indolo[3,2-b]carbazole (5) (Fig. 3) [18] -are meant.…”

Section: Results and Discussion General Characteristics Of Indolocarbazole Group Compoundsmentioning

confidence: 99%

“…The indole moieties are linked through 1 or 2 bonds to the carbohydrate moiety. At the same time, this subclass also includes a small group of compounds that do not include an additional pyrrole ring in their composition [18].…”

Section: Results and Discussion General Characteristics Of Indolocarbazole Group Compoundsmentioning

confidence: 99%

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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%

Section: Results and Discussion General Characteristics Of Indolocarbazole Group Compoundsmentioning

confidence: 99%

“…In this case, 5 isomers of the polycyclic sys- (4) and indolo[3,2-b]carbazole (5) (Fig. 3) [18] -are meant.…”

Section: Results and Discussion General Characteristics Of Indolocarbazole Group Compoundsmentioning

confidence: 99%

Section: Results and Discussion General Characteristics Of Indolocarbazole Group Compoundsmentioning

confidence: 99%

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Antitumor Drugs Based on Indolocarbazol Derivatives

Kolpaksidi

Дмитриева²,

Ярош

et al. 2021

Farm. farmakol. (Pâtigorsk)

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“…На противоопухолевый эффект, спектр противоопухолевого действия и биодоступность N-гликозидов индолокарбазолов оказывают влияние как заместители в агликоне (ароматический, при малеимидном атоме азота), так и природа углеводного остатка [7][8][9][10].…”

Section: Introductionunclassified

Antitumor Activity of Some Derivatives of Indolo[2,3-A]carbazoles N-Glycosides With Xylose Carbohydrate Residue

Голубева

Яворская

Эктова

et al. 2020

Rossijskij bioterapevtičeskij žurnal

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Introduction. The search for new antineoplastic agents in a series of indolo[2,3-a]-carbazole derivatives is an urgent and promising direction, since compounds with antitumor activity have been found in this class. In the chemical fusion laboratory, N.N. Blokhin National Medical Research Center оf the Ministry of Health of Russia has developed an original and effective method for the synthesis of glycosides of indolo[2,3-a]-pyrrolo[3,4-c]carbazoles, which makes it possible to synthesize derivatives of N-glycosides of indolo[2,3-a]carbazoles with different substituents in the heterocyclic parts including at the maleimide nitrogen atom and with different carbohydrate residues.The purpose of the study – the primary assessment of the antitumor activity of new derivatives of indolocarbazoles with a carbohydrate residue xylose in models of tumor growth mice.Materials and methods. The compounds studied at transplanted tumors of mice: the Lewis epidermoid carcinoma (LLC), colon cancer ACATOL, cervical cancer RSHM-5, breast adenocarcinoma CA-755. Studies were performed on immunocompetent mice: males and females of BDF1 hybrids (C57Bl/6 × DBA/2), females CBA/Lac and Balb/c. Compound solutions were prepared ex tempore and administered to the mice intraperitoneally at a dose of 60 mg/kg daily for five days. The antitumor effect was evaluated as to of tumor growth inhibition and increase of life span of the treated animals as compared with the control ones.Results. Eight compounds studied, containing D-xylose as a carbohydrate component and various substituents at the maleimide nitrogen atom, showed different degrees of antitumor activity. Two derivatives have been identified: N-[5,7-dioxo-12-(β-D-xylopyranosyl)-indole[2,3-a]pyrrolo[3,4-c]carbazol-6-il]benzamide (compound 4) and N-[5,7-dioxo-12-(β-D-xylopyranosyl)-5,7,12,13-tetrahydro-6H-indole[2,3-a]pyrrolo[3,4-c]carbazole-6-il]pyridin-2-carboxamide (compound 8), which showed high antitumor activity on 4 solid tumors of mice with a duration of effect of 12 days or more. The most pronounced antitumor effect was obtained in compounds 4 and 8 in RSHM-5 and Ca-755, tumor growth inhibition was amounted, respectively: in RSHM-5 – 68–82 % and 80–72 %; for Ca-755 – 57–62 % and 86–68 % (p <0.05).Conclusion. For further research, we chose the compound (N-[5,7-dioxo-12-(β-D-xilopiranosil)-5,7,12,13-tetrahydro-6H-indole[2,3-a] pyrrolo[3,4-c]carbazol-6-il]pyridin-2-carboxamide).

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Optimization of algorithms for in vivo preclinical screening of compounds with an alleged antitumor effect

Dodokhova,

Voronova,

Alkhusein-Kulyaginova

et al. 2023

Russian Journal of Oncology

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BACKGROUND: Despite a large number of publications on preclinical studies of compounds with a suspected antitumor effect on in silico and in vitro models, in vivo studies are the most informative. The experimental part of the work on laboratory animals has its own peculiarities in the field of preclinical research: a large number of animals and analog compounds in the series, two- and three-phase staging, and, consequently, high cost and labor-intensive execution. AIMS: Optimization of algorithms for screening preclinical in vivo studies of compounds with a suspected antitumor effect. MATERIALS AND METHODS: To form the algorithm in the preclinical study, primary data obtained using standard pharmacological (determination of the toxicity class index with a single intragastric injection, on tumor models - determination of antitumor and antimetastatic activity by the index of inhibition of metastasis, inhibition of tumor growth by weight, average life expectancy of animals) and morphological methods (autopsy, preparation of micropreparations with hematoxylin and eosin staining, as well as immunohistochemical study using monoclonal antibodies) with the selection of leading compounds for indepth study with a description of the mechanism of pharmacological activity. RESULTS: Based on a series of comparative experimental series, the following algorithm of preclinical in vivo study for newly synthesized compounds with an alleged antitumor effect has been tested. Stage 1. Determination of the toxicity class with a single intragastric administration to Wistar rats according to the OECD 420 protocol and selection of candidates for antitumor drugs according to the principle of the greatest safety of use. Stage 2. Determination of the presence/absence of pharmacological activity of the tested compounds. Compounds of toxicity classes IV and V according to the Globally Harmonized System of Hazard Classification and Labeling of Chemical Products (GHS) in a wide range of doses (doses are selected depending on the toxicity class) are examined for pharmacological activity before the natural death of tumor-bearing animals with the identification of leader substances, in-depth study of which is appropriate. The selection of promising substances and total doses for administration at the next stage is determined by the life expectancy of tumor-bearing animals. Stage 3. Determination of indicators of antitumor and antimetastatic activity of leader substances with a fixed euthanasia period for all tumor-bearing animals and determination of possible mechanisms for the implementation of the therapeutic effect using immunohistochemical analysis. Stage 4. To study the effect of the tested compounds on the growth rates of the primary tumor node and metastatic foci at different stages of the development of the tumor process, when administered in different modes, as part of combined and monochemotherapy with mandatory clarification of the mechanisms for the implementation of antitumor and antimetastatic activity using biochemical and immunohistochemical techniques. Stage 5. The study of the most promising compounds according to the guidelines for preclinical safety studies for the purpose of clinical trials and registration of medicines (The document was approved by the decision of the Board of the Eurasian Economic Commission of November 26, 2019 N 202): Toxicity studies with repeated (multiple) administration of the drug, preclinical studies conducted in order to justify the conduct of exploratory clinical studies, studies of local tolerability of the drug, studies of genotoxicity of the drug, carcinogenicity of the drug, etc. CONCLUSIONS: The step-by-step exclusion of the tested compounds described by us from the line of substances similar in structure will increase the efficiency of selecting promising candidates for antitumor drugs and reduce the cost of conducting preclinical studies of compounds with an alleged antitumor effect.

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N-glycosidesindolo[2,3,-a]pyrrolo[3,4,-c]carbazole derivatives chemical structure influence on antitumor activity

Cited by 4 publications

References 13 publications

Antitumor Drugs Based on Indolocarbazol Derivatives

Antitumor Drugs Based on Indolocarbazol Derivatives

Antitumor Activity of Some Derivatives of Indolo[2,3-A]carbazoles N-Glycosides With Xylose Carbohydrate Residue

Optimization of algorithms for in vivo preclinical screening of compounds with an alleged antitumor effect

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