New anthra[2,3-b]furancarboxamides: A role of positioning of the carboxamide moiety in antitumor properties / Y. Volodina, L. Dezhenkova, A. Tikhomirov et al. // European Journal of Medicinal Chemistry. — 2019. — no. 165. — P. 31–45. Derivatives of the anthraquinone (anthracene-9,10-dione) such as doxorubicin, mitoxantrone and others have proved great clinical efficacy for decades. Currently the search in this exceptionally productive chemical class is aimed at optimization of antitumor properties including circumvention of drug resistance. Previously we have reported that heteroarene-fused anthraquinones fused to a 5-membered heterocyclic ring are advantageous in killing drug resistant tumor cells. Herein we present the synthesis and antitumor properties of a series of new anthra[2,3-b]furan-2-carboxamides. Vast majority of new derivatives were similarly cytotoxic to wild type tumor cell lines and their isogenic sublines with P-glycoprotein overexpression and/or p53 inactivation. Comparison of structurally close derivatives varying in their position relative to the furan moiety, that is, furan-3-carboxamide 1vs furan-2-carboxamides 5 and 6, revealed fundamental differences in the cytotoxicity profiles, formation of drug-DNA complexes, efficacy of topoisomerase 1 inhibition and mechanisms of tumor cell death. Together with previous SAR data on the role of individual substituents, these results provide evidence that regioisomerization of anthra[2,3-b]furancarboxamides generates the practically perspective derivatives whose properties may vary significantly. [ DOI ]
Tikhomirov A. S., Shtil A. A., Shchekotikhin A. E. Advances in the discovery of anthraquinone-based anticancer agents // Recent Patents on Anti-Cancer Drug Discovery. — 2018. — Vol. 13, no. 2. Background: The anthracene-9,10-dione (anthraquinone) derivatives represent an exceptionally valuable class in anticancer drug development. An outstanding antitumor potency of the anthracycline antibiotics attracted the attention of medicinal chemists since the discovery of these chemotypes. The prominent anthraquinone-based drugs doxorubicin, mitoxantrone as well as more recent epirubicin, idarubicin, and valrubicin are successfully used in chemotherapy of hematological malignancies and solid tumors. The anthraquinone core remains a promising scaffold for the search of new optimized drug candidates. Objective: In this study, we analyze the progress in discovery and development of antitumor anthracene- 9,10-diones based on patent and journal publications in 2008-2017. The main goal is to dissect novel chemotypes of anthraquinone derivatives; other important issues such as the success in bioconjugate chemistry of anthraquinone containing agents as well as the patents on new applications of anthracyclines are beyond the scope of this review. Conclusion: A number of newly discovered natural products, the perspective directions for chemical modifications to optimize the anticancer properties, and novel intracellular targets demonstrate that anthracene- 9,10-diones deserve further in-depth investigation as an important source of drug candidates. [ DOI ]
Aminomethylation of heliomycin: Preparation and anticancer characterization of the first series of semi-synthetic derivatives / G. Y. Nadysev, A. S. Tikhomirov, M.-H. Lin et al. // European Journal of Medicinal Chemistry. — 2018. — Vol. 143. — P. 1553–1562. Abstract A series of 4-aminomethyl derivatives of heliomycin 1 was prepared using the Mannich reaction. The modification significantly improved aqueous solubility of the initially poorly soluble antibiotic. Testing the antiproliferative efficacy revealed a potent activity of heliomycin as well as its new derivatives on a panel of mammalian tumor cells including drug resistant variants. In contrast to 1 the new derivatives 7a, 7l, 7p generated a high level of ROS associated with induction of apoptosis in T24 bladder cancer cells. Introduction of 4-aminomethyl moiety increased the affinity to DNA and the ability to inhibit topoisomerase 1 making 7p the most promising candidate for further preclinical evaluation. Thus, aminomethylation is the first-in-class successful transformation of the antibiotic 1 resulting in an improved water solubility of derivatives and promising properties in search of novel anticancer drug candidates. [ DOI ]
Design of an activity-based probe for human neutrophil elastase: Implementation of the lossen rearrangement to induce förster resonance energy transfers / S.-F. Anna-Christina, A. S. Tikhomirov, B. Annett et al. // Biochemistry. — 2018. — Vol. 57. — P. 742–752. Human neutrophil elastase is an important regulator of the immune response and plays a role in host defense mechanisms and further physiological processes. The uncontrolled activity of this serine protease may cause severe tissue alterations and impair inflammatory states. The design of an activity-based probe for human neutrophil elastase reported herein relies on a sulfonyloxyphthalimide moiety as a new type of warhead that is linker-connected to a coumarin fluorophore. The inhibitory potency of the activity-based probe was assessed against several serine and cysteine proteases, and the selectivity for human neutrophil elastase (Ki = 6.85 nM) was determined. The adequate fluorescent tag of the probe allowed for the in-gel fluorescence detection of human neutrophil elastase in the low nanomolar range. The coumarin moiety and the anthranilic acid function of the probe, produced in the course of a Lossen rearrangement, were part of two different Förster resonance energy transfers. [ DOI ]
Heterocyclic analogs of 5,12-naphthacenequinone 15*. synthesis of new anthra[2,3-b]thiophene-3(2)-carboxylic acids / D. V. Andreeva, Y. B. Sinkevich, A. S. Tikhomirov et al. // Chemistry of Heterocyclic Compounds. — 2018. — Vol. 54, no. 6. — P. 612–617. [ DOI ]
New antitumor anthra[2,3-b]furan-3-carboxamides: Synthesis and structure-activity relationship / A. S. Tikhomirov, L. Chia-Yang, Y. L. Volodina et al. // European Journal of Medicinal Chemistry. — 2018. — Vol. 148. — P. 128–139. Chemical modifications of the anthraquinone scaffold are aimed at optimization of this exceptionally productive class of antitumor drugs. In particular, our previously reported anthra[2,3-b]furan-3- carboxamides demonstrated a high cytotoxic potency in cell culture and in vivo. In this study, we expanded our series of anthra[2,3-b]furan-3-carboxamides by modifying the key functional groups and dissected the structure-activity relationship within this chemotype. The majority of new compounds inhibited the growth of mammalian tumor cell lines at submicromolar to low micromolar concentrations. We found that 4,11-hydroxy groups as well as the carbonyl moiety in the carboxamide fragment were critical for cytotoxicity whereas the substituent at the 2-position of anthra[2,3-b]furan was not. Importantly, the new derivatives were similarly potent against wild type cells and their variants resistant to doxorubicin due to P-glycoprotein (Pgp) expression or p53 inactivation. The most cytotoxic derivatives 6 and 9 attenuated plasmid DNA relaxation by topoisomerase 1. Finally, we demonstrated that 6 and 9 at 1 mM induced intracellular oxidative stress, accumulation in G2/M phase of the cell cycle, and apoptosis in gastric carcinoma cell lines regardless of their p53 status. These results further substantiate the potential of anthra[2,3-b]furan-3-carboxamides as antitumor drug candidates. [ DOI ]
Литвинова В. А., Тихомиров А. С. Методы синтеза эфиров индол-3-карбоновых кислот // Химия гетероциклических соединений. — 2018. — Т. 54, № 10. — С. 923–925. В микрообзоре рассмотрены недавние успехи в разработке методов циклизации индолов, приводящие к производным индол-3-карбоновой кислоты. Материал охватывает избранные работы, опубликованные начиная с 2013 г.
Современные тенденции органической химии в университетах России / А. И. Коновалов, И. С. Антипин, В. А. Бурилов и др. // Журнал органической химии. — 2018. — Т. 54, № 2. — С. 161–360.
Development and pharmaceutical evaluation of the anticancer anthrafuran/cavitron complex, a prototypic parenteral drug formulation / H. M. Treshalina, V. I. Romanenko, D. N. Kaluzhny et al. // European Journal of Pharmaceutical Sciences. — 2017. — Vol. 109. — P. 631–637. [ DOI ]
Heterocyclic analogs of 5,12-naphthacenequinone 14. synthesis of naphtho[2,3-f]indole-3-carboxylic acid derivatives / A. S. Tikhomirov, V. A. Litvinova, Y. N. Luzikov et al. // Chemistry of Heterocyclic Compounds. — 2017. — Vol. 53, no. 10. — P. 1072–1079. [ DOI ]
Rna g-quadruplexes in kirsten ras (kras) oncogene as targets for small molecules inhibiting translation / M. Giulia, C. Susanna, M. Jessica et al. // Journal of Medicinal Chemistry. — 2017. [ DOI ]
Новые производные антрафурана: химическая структура и механизмы цитотоксичности / Ю. Л. Володина, А. С. Тихомиров, Л. Г. Деженкова и др. // Российский биотерапевтический журнал. — 2017. — Т. 16. — С. 20–21.
Heterocyclic analogs of 5,12-naphtacenequinone 13*. synthesis of 4,11-diaminoanthra[2,3-b]furan-5,10-diones and sulfur-containing analogs / A. S. Tikhomirov, E. E. Bykov, Y. N. Luzikov et al. // Chemistry of Heterocyclic Compounds. — 2016. — Vol. 52, no. 10. — P. 797–802. [ DOI ]
ВЛИЯНИЕ ЗАМЕСТИТЕЛЕЙ В ПЕРИ-ПОЛОЖЕНИЯХ НА АНТИПРОЛИФЕРАТИВНЫЕ СВОЙСТВА АНТРАФУРАНКАРБОКСАМИДОВ / О. А. Омельчук, А. С. Тихомиров, Л. Г. Деженкова, А. Е. Щекотихин // Российский биотерапевтический журнал. — 2016. — Т. 15. — С. 81–81.
Омельчук О. А., Тихомиров А. С., Щекотихин А. Е. МЕТОДЫ АННЕЛИРОВАНИЯ ФУРАНОВОГО ЯДРА К АРЕНАМ // Успехи химии. — 2016. — Т. 85, № 8. — С. 817–835. Благодаря уникальным физико-химическим, химическим и биологическим свойствам бензо[ b ]фураны нашли применение в различных областях химии и технологии. Прежде всего следует отметить широкий спектр биологической активности природных и синтетических производных бензо[ b ]фурана, а также его конденсированных аналогов (нафтофуранов, антрафуранов и др.), который обусловливает значительный интерес ученых к использованию этих гетероциклов в качестве важных "строительных блоков" при создании лекарственных препаратов. В обзоре рассмотрены способы аннелирования фуранового ядра к аренам, разработанные преимущественно за последнее десятилетие. Проанализированы тенденции развития методов синтеза бензо[ b ]фуранов, ряд из которых показал высокую эффективность при получении полифункциональных производных. Библиография - 110 ссылок. [ DOI ]
Производные антрафуранкарбоксамидов с преимущественной цитотоксичностью для клеток миелоидного лейкоза / Л. Г. Деженкова, Ю. Л. Володина, А. С. Тихомиров и др. // Гематология и трансфузиология. — 2016. — Т. 61, № 1. — С. 111–111.
Тихомиров А. С., Деженкова Л. Г., Щекотихин А. Е. Цитотоксические свойства антрафуранкарбоксамидов, содержащих cf3-группу в положении 2 // Российский биотерапевтический журнал (Russian Journal of Biotherapy),. — 2016. — № 1. — С. 108–108.
Ring fusion strategy for synthesis and lead optimization of sulfur-substituted anthra[1,2-c][1,2,5]thiadiazole-6,11-dione derivatives as promising scaffold of antitumor agents / Y. R. Lee, T. C. Chen, C. C. Lee et al. // European Journal of Medicinal Chemistry. — 2015. — Vol. 102, no. 18. — P. 661–676. [ DOI ]
Synthesis and characterization of 4,11-diaminoanthra[2,3‑b]furan- 5,10-diones: Tumor cell apoptosis through tnox-modulated nad+/ nadh ratio and sirt1 / A. S. Tikhomirov, A. E. Shchekotikhin, L. Yi-Hui et al. // Journal of Medicinal Chemistry. — 2015. — Vol. 58. — P. 9522–9534. A series of new 4,11-diaminoanthra[2,3-b]furan-5,10-dione derivatives with different side chains were synthesized.Selected 2-unsubstituted derivatives 11−14 showed high antiproliferative potency on a panel of mammalian tumor cell lines including multidrug resistance variants. Compounds 11−14 utilized multiple mechanisms of cytotoxicity including inhibition of Top1/Top2-mediated DNA relaxation, reduced NAD+/NADH ratio through tNOX inhibition, suppression of a NAD+- dependent sirtuin 1 (SIRT1) deacetylase activity, and activation of caspase-mediated apoptosis. Here, for the first time, we report that tumor-associated NADH oxidase (tNOX) and SIRT1 are important cellular targets of antitumor anthracene-9,10-diones. [ DOI ]
Pd-catalyzed cross-coupling/heterocyclization domino reaction: facile access to anthra[2,3-b]furan-5,10-dione scaffold / A. S. Tikhomirov, A. E. Shchekotikhin, Y. N. Luzikov et al. // Tetrahedron. — 2014. — Vol. 70, no. 28. — P. 8062–8066. A new facile route to the synthesis of 4,11-dimethoxyanthra[2,3-b]furan-5,10-dione and its novel 2-substituted derivatives was proposed. The developed scheme was based on a Pd-catalyzed cross-coupling/heterocyclization domino reaction of 3-bromo-2-hydroxy-4,11-dimethoxyanthraquinone with terminal alkynes. [ DOI ]
ГЕТЕРОЦИКЛИЧЕСКИЕ АНАЛОГИ5,12-НАФТАЦЕНХИНОНА.12.СИНТЕЗ 2-ЗАМЕЩЕННЫХ ПРОИЗВОДНЫХ 4,11-ДИМЕТОКСИ-5,10-ДИОКСОАНТРА[2,3-b]ФУРАН-3-КАРБОНОВЫХ КИСЛОТ / А. С. Тихомиров, А. Е. Щекотихин, Ю. Н. Лузиков и др. // Химия гетероциклических соединений. — 2014. — С. 298–308. [ DOI ]
Тихомиров А. С., Щекотихин А. Е., Преображенская М. Н. Исследование влияния структуры боковой цепи антра[2,3-b]фуранкарбоксамидов на цитотоксические свойства // Российский биотерапевтический журнал. — 2014. — № 2. — С. 133–133.
Тихомиров А. С., Щекотихин А. Е., Преображенская М. Н. МЕТОДЫ СИНТЕЗА И МОДИФИКАЦИИ ЛИНЕЙНЫХ АНТРАФУРАНДИОНОВ (ОБЗОР) // Химия гетероциклических соединений. — 2014. — С. 193–208. [ DOI ]
Heterocyclic analogs of 5,12-naphthacene-quinone. 11. a new method for preparing 4,11-dimethoxyanthra[2,3-b]furan-5,10-dione / A. S. Tikhomirov, A. E. Shchekotikhin, Y. N. Luzikov et al. // Chemistry of Heterocyclic Compounds. — 2013. — Vol. 49. — P. 241–248. [ DOI ]
Исследование влияния заместителя в положении 2 на биологические свойства противоопухолевых антрафурандионов / А. С. Тихомиров, А. Е. Щекотихин, Л. Г. Деженкова, А. А. Штиль // Российский биотерапевтический журнал. — 2013. — № 2. — С. 83–83.
Heterocyclic analogs of 5,12-naphthacenequinone 10.* synthesis of furanoquinizarine and its new derivatives / A. S. Tikhomirov, A. E. Shchekotikhin, Y. N. Luzikov et al. // Chemistry of Heterocyclic Compounds. — 2012. — Vol. 47, no. 10. — P. 1206–1211. A new method was developed for synthesis of anthra[2,3-b]furan-5,10-dione derivatives. The key compound for annelation of the furan fragment to the anthraquinone chromophor is the previously unknown analog of salicylaldehyde, 1,4-dimethoxy-3-formyl-2-hydroxyanthraquinone, which we have synthesized by the Miller–Loudon–Schneider reaction. A chain of sequential transformations was used for its conversion into the target 4,11-dihydroxyanthra[2,3-b]furan-5,10-dione (furanoquinizarine): O-alkylation of the starting formylhydroxyanthraquinone with bromoacetic acid esters, cyclo-dehydration of the 3-formylanthraquinon-2-ylacetic acid esters in the presence of bases, hydrolysis of the obtained esters to 4,11-dimethoxy-5,10-dioxo-5,10-dihydroanthra[2,3-b]furan-2-carboxylic acid, its decarboxylation, and demethylation of the obtained 4,11-dimethoxyanthra[2,3-b]furan-5,10-dione. [ DOI ]
Тихомиров А. С., Щекотихин А. Е. Новый метод синтеза 4,11-диметоксиантра[2,3-b]фуран-5,10-диона // Успехи в химии и химической технологии. — 2012. — Т. 26, № 5. — С. 76–78.
Тихомиров А. С., Щекотихин А. Е. Разработка метода получения 4,11-диметокси-5,10-диоксо-антра[2,3-b]-фуран-2-карбоновой кислоты и синтез ее производных // Успехи в химии и химической технологии. — 2011. — Т. 25, № 4. — С. 17–20.
