Synthesis and evaluation of new antitumor 3-aminomethyl-4,11-dihydroxynaphtho[2,3-f]indole-5,10-diones

Shchekotikhin, Andrey E.; Glazunova, Valeria A.; Dezhenkova, Lyubov G.; Luzikov, Yu. N.; Buyanov, V. N.; Treshalina, H. M.; Lesnaya, N. A.; Романенко, В. И.; Kaluzhny, Dmitry N.; Balzarini, Jan; Agama, Keli; Pommier, ﻿Yves; Shtil, Alexander A.; Preobrazhenskaya, M. N.

doi:10.1016/j.ejmech.2014.09.021

Cited by 24 publications

(14 citation statements)

References 43 publications

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“…Полученное в ФГБНУ «Научно-исследовательский институт по изысканию новых антибиотиков им. Г. Ф. Гаузе» соединение антрафуран -синтетическое производное антрацендиона [5][6][7] -хорошо растворимо в биорелевантных средах. С учетом того, что антрациклины и близкие им по структуре антрацендионы -высокоактивные противоопухолевые препараты, широко применяемые для лечения злокачественных опухолей, на основе антрафурана был разработан препарат ЛХТА-2034, проявивший высокую противоопухолевую активность в отношении прогностически значимых перевиваемых опухолей мышей как при парентеральном (внутрибрюшинном), так и при пероральном введении [8,9].…”

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Experimental evaluation of toxic properties of LCTA-2034 by the oral routeof administration

Трещалин

Treshchalin

Голибродо

et al. 2018

Rossijskij bioterapevtičeskij žurnal

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Introduction.New antitumor multitarget drug LCTA-2034, obtained in Gause Institute of New Antibiotics, has demonstrated high activity against prognostically significant transplantable mice tumors by the oral application.Objective.To investigate the toxicological properties of LCTA-2034 by the oral route of administration on rats.Materials and methods.Toxicological study of LCTA-2034 was performed on 30 male Wistar rats. Drug substance dissolved in potable water. 2 % solution was administrated per os at the 1 and 5 therapeutic dose (15 × 20 mg/kg or 15 × 100 mg/kg with 24-h interval). During the study dynamics of body weight, hematological parameters, blood biochemical parameters, electrocardiography and urinalysis were performed for all animals. Five animals in each group were sacrificed 1 and 30 days post treatment. The internal organs were subjected to histological evaluation.Results.The results of the study demonstrate that the treatment with low dose of LCTA-2034 does not produce any changes in majority of examined clinical-laboratory parameters with the exception of urinalysis revealed hematuria on day 1 post treatment. Microscopic pathology observation showed structure abnormalities of varying severity in liver, kidneys, heart, stomach, jejunum, ileum, spleen and thymus. Administration of high dose of LCTA-2034 caused mortality of 2 rats in group. The rest of the rats were observed a body weight lag, decrease of total leukocyte and erythrocyte count, hemoglobin and hematocrit level, relative weight of the thymus. Erythrocytes and nitrates were found in urine both on day 1 and on day 30 post treatment. In groups treated with high dose of the drug in addition to the listed above organs damage of the structure of lymph nodes, pancreas, ileum and brain was detected. Conclusion. Revealed toxic properties of LCTA-2034 depended on dose. Multiple administration of 1 therapeutic dose of the drug produces transient toxic effects completely reversible within 30 days.

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Experimental evaluation of toxic properties of LCTA-2034 by the oral routeof administration

Трещалин

Treshchalin

Голибродо

et al. 2018

Rossijskij bioterapevtičeskij žurnal

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“…В результате целенаправленных исследований связи структура-активность, проведенных в ФГБНУ НИИНА, было показано, что антра [2,3-b] фуран-3-карбоксамиды являются перспективным классом соединений для дальнейшего поиска химиотерапевтических средств [16,17]. Соединение-лидер этого ряда антрафуран ЛХТА-2034 обладает способностью ингибировать активность нескольких внутриклеточных мишеней, важных для опухолевого роста, включая топоизомеразы I, II и протеинкиназы, и прояв ляет высокую противоопухолевую активность в экспериментах на животных [8]…”

Section: Discussionunclassified

Toxicological characteristic of novel antitumour multitargeted agent anthrafuran

Переверзева

Treschalin

Eremkin

et al. 2017

Rossijskij bioterapevtičeskij žurnal

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Introduction. One of the modern approaches to development of antitumor drugs is based on oriented search of specific tumor cells molecular targets inhibitors. The application of such therapeutic agents will improve selectivity of action and decrease side effects of antineoplastic therapy. Novel antitumor multitargeted drug anthrafuran (LCTA-2034), obtained in Gause Institute of new antibiotics, represents a derivative of anthra[2,3-b]furan-3-carboxamide. Compound exhibits pronounced antitumor activity in vivo. Objective. The objective of the present study was to investigate the toxicity of LCTA-2034. Materials and methods. Toxicological study was performed in male outbred rats. The drug was administrated intraperitoneally at the total doses of MTD and LD 50 (14 × 3 mg/kg or 14 × 4.5 mg/kg with 24-h interval). Dynamics of body weight, hematological parameters, blood biochemical parameters, electrocardiography and urinalysis were performed for all animals. 5 animals in each group were sacrificed 1 and 30 days post treatment. The mass coefficients of heart, kidneys, liver, spleen and thymus were calculated. The internal organs were subjected to histological evaluation. Results. The results of the study demonstrate that the intraperitoneal injections of LCTA-2034 don't produce any changes in examined clini cal-laboratory parameters. The treatment with LCTA-2034 in total dose of MTD had no effect on morphological structure of the internal organs of rats. The reversible structural damages in liver, kidneys and small intestine were found in group of rats, treated with high dose of the drug. Signs of cardiotoxicity were documented by microscopic pathology observation on day 30 post treatment in individual animals. Conclusion. Dose dependence and reversibility of toxic effects of LCTA-2034 allows us to recommend it to further advance.

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“…Changing the acridine core to anthracene‐9, 10‐dione gives an additional class of G4 stabilizers. The size of the backbone and the number of side arms on the backbone structure also affect the binding efficiency and selectivity of the G4 stabilizers to telomeric DNA . Different structures of anthrone derivatives ( 61 ) are shown in Figure .…”

Section: G‐quadruplex Stabilizermentioning

confidence: 99%

Therapeutic strategies for targeting telomerase in cancer

Chen

Tang

Shi

et al. 2019

Medicinal Research Reviews

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Telomere and telomerase play important roles in abnormal cell proliferation, metastasis, stem cell maintenance, and immortalization in various cancers. Therefore, designing of drugs targeting telomerase and telomere is of great significance. Over the past two decades, considerable knowledge regarding telomere and telomerase has been accumulated, which provides theoretical support for the design of therapeutic strategies such as telomere elongation. Therefore, the development of telomere‐based therapies such as nucleoside analogs, non‐nucleoside small molecules, antisense technology, ribozymes, and dominant negative human telomerase reverse transcriptase are being prioritized for eradicating a majority of tumors. While the benefits of telomere‐based therapies are obvious, there is a need to address the limitations of various therapeutic strategies to improve the possibility of clinical applications. In this study, current knowledge of telomere and telomerase is discussed, and therapeutic strategies based on recent research are reviewed.

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Synthesis and evaluation of new antitumor 3-aminomethyl-4,11-dihydroxynaphtho[2,3-f]indole-5,10-diones

Cited by 24 publications

References 43 publications

Experimental evaluation of toxic properties of LCTA-2034 by the oral routeof administration

Experimental evaluation of toxic properties of LCTA-2034 by the oral routeof administration

Toxicological characteristic of novel antitumour multitargeted agent anthrafuran

Therapeutic strategies for targeting telomerase in cancer

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