Введение. Проведен синтез конъюгата, состоящего из метотрексата и бифункционального хелатирующего агента. Подобное соединение отличается свойством таргетности по отношению к очагам аутоиммунных артритов. Цель работы – синтезировать комплекс, содержащий радионуклид лютеций-177, для терапии аутоиммунных артритов. Методика. После проведения синтеза радиохимическую чистоту полученного препарата определяли методом тонкослойной хроматографии. В исследованиях in vivo в качестве тест-системы были задействованы аутбредные крысы, самцы в количестве 12 особей. Перед началом исследования животные были распределены на контрольную группу и исследуемую по биораспределению. Исследование биораспределения радиоконъюгата производилось общепринятым способом прямой радиометрии. Оценка производилась путем прямого сравнения распределения радиофармацевтического препарата в крови и органах животных. С учетом периода полураспада радионуклида 177Lu исследования в контрольных точках при изучении фармакокинетики и биораспределения тестируемых препаратов оценивалось не менее 3 особей животных. Результаты. Радиохимическая чистота синтезированного препарата составила не менее 95%. Исследования биораспределения показали тенденции к накоплению препарата в ткани почек, сердца, легких, в остальных оцениваемых органах и тканях накопление препарата имело умеренный и транзиторный характер. Терапевтический радиофармацевтический препарат продемонстрировал удовлетворительный уровень эффективности в отношении целевой нозологии: отмечалось клинически значимое улучшение и частичное восстановление функций пораженной конечности. Заключение. Результаты исследования могут быть внедрены в практику научной работы по разработке лекарственных средств и средств медицинского применения и являются основанием для проведения расширенного углубленного исследования и оптимизации механизмов таргетного действия исследуемых в данной работе радиофармацевтических лекарственных препаратов. Background. A conjugate consisting of methotrexate and a bifunctional chelating agent was synthesized. This compound is distinguished by its ability to target foci of autoimmune arthritis. Aim. To synthesize a radionuclide 177Lu-based complex for the treatment of autoimmune arthritis. Methods. After synthesis, the radiochemical purity of the complex was determined by thin layer chromatography. In the in vivo study, 12 outbred male rats were used as a test system. Prior to the biodistribution study, the animals were divided into a control group and a study group. The radioconjugate biodistribution was assessed with the generally accepted method of direct radiometry by direct comparison of radiopharmaceutical distribution in blood and organs. Taking into account the 177Lu half-life, at least three animals were assessed at measurement points when studying the radiopharmaceutical pharmacokinetics and biodistribution. Results. The radiochemical purity of the 177Lu-based complex was no less than 95%. Biodistribution studies showed a tendency towards radioactivity accumulation in the kidneys, heart, and lungs. In the remaining assessed organs and tissues, the radioactivity accumulation was moderate and transient. The therapeutic radiopharmaceutical demonstrated a satisfactory effectiveness in relation to the target nosology, autoimmune arthritis, evident as clinically significant improvement and partial restoration of the functions of the affected limb. Conclusion. The results of the study can be implemented in the practice for the development of drugs and medical devices and justify conducting an expanded study and optimizing the mechanisms for targeted action of the radiopharmaceuticals, such as studied in the present work.

Histone deacetylase 6 (HDAC6) is a promising drug target for the treatment of human diseases such as cancer, neurodegenerative diseases (in particular, Alzheimer's disease), and multiple sclerosis. Considerable attention is paid to the development of selective non-toxic HDAC6 inhibitors. To this end, we successfully form a set of 3854 compounds and proposed adequate regression QSAR models for HDAC6 inhibitors. The models have been developed using the PubChem, Klekota-Roth, 2D atom pair fingerprints, and RDkit descriptors and the gradient boosting, support vector machines, neural network, and k-nearest neighbours methods. The models are integrated into the developed HT_PREDICT application, which is freely available at https://htpredict.streamlit.app/. In vitro studies have confirmed the predictive ability of the proposed QSAR models integrated into the HT_PREDICT web application. In addition, the virtual screening performed with the HT_PREDICT web application allowed us to propose two promising inhibitors for further investigations.

Thz-Phe-D-Trp-Lys-Thr-DOTA, a conjugate of the DOTA chelator and the Thz-Phe-D-Trp-Lys-Thr pentapeptide, was labeled with 152Eu and 161Tb radionuclides, where 161Tb has decay characteristics suitable for its use in cancer therapy. For the [152Eu]Eu-Thz-Phe-D-Trp-Lys-Thr-DOTA complex, the biodistribution in nude mice bearing IMR-32 tumors was evaluated for the first time. It was shown that the complexes of the conjugate demonstrate accumulation in the tumor at the level of DOTA-TATE, another peptide conjugate widely used in nuclear medicine for the diagnosis and therapy of neuroendocrine tumors, which allows Thz-Phe-D-Trp-Lys-Thr-DOTA to be considered as a potential biological vector for radiopharmaceuticals.

The HDAC6 (histone deacetylase 6) enzyme plays a key role in many biological processes, including cell division, apoptosis, and immune response. To date, HDAC6 inhibitors are being developed as effective drugs for the treatment of various diseases. In this work, adequate QSAR models of HDAC6 inhibitors are proposed. They are integrated into the developed application HDAC6 Detector, which is freely available at . The web application HDAC6 Detector can be used to perform virtual screening of HDAC6 inhibitors by dividing the compounds into active and inactive ones relative to the reference vorinostat compound (IC50 = 10.4 nM). The web application implements a structural interpretation of the developed QSAR models. In addition, the application can evaluate the compliance of a compound with Lipinski's rule. The developed models are used for virtual screening of a series of 12 new hydroxamic acids, namely, the derivatives of 3-hydroxyquinazoline-4(3H)-ones and 2-aryl-2,3-dihydroquinazoline-4(1H)-ones. In vitro evaluation of the inhibitory activity of this series of compounds against HDAC6 allowed us to confirm the results of virtual screening and to select promising compounds V-6 and V-11, the IC50 of which is 0.99 and 0.81 nM, respectively.

New precursors with various linkers for the construction of targeted radiopharmaceuticals based on a pharmacophore fragment of the hormone somatostatin, tetrapeptide H-Phe-d-Trp-Lys-Thr-OH, were synthesized. The tetrapeptide was additionally modified by adding 1,3-thiazolidinecarboxylic acid (Thz) and l-proline (Pro) to improve the cytotoxic properties. Synthesis routes were developed and conjugates of peptides with chelators were obtained.

New derivatives of 5-bromo-3-(4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)cyclopent-2-enone in combination with different derivatives of aromatic aldehydes have been proposed as potential Tubulin/Tdp1 inhibitors. Precursors for cyclopentadienothiazole condensation were obtained by described in literature methods with yields of 55- 86% and were characterized by 1H NMR spectra.

Histone deacetylase inhibitors represent the most important class of drugs for the treatment of human cancer and other diseases due to their influence on cell growth, differentiation, and apoptosis. Among the well-known eighteen histone deacetylases, histone deacetylase 6 (HDAC6), which is involved in oncogenesis, cell survival, and cancer cell metastasis, is of great importance. Using the CDK and alvaDesc molecular descriptors and the Random Forest and EXtreme Gradient Boosting methods, we propose a number of adequate QSAR classification models, which are integrated into a consensus model and are freely available on the OCHEM web platform (https://ochem.eu). The consensus QSAR model is used for virtual screening of a series of seven new compounds, the derivatives of N-((hydroxyamino)-oxoalkyl)-2-(quinazoline-4-ilamino)benzamides, the synthesis schemes of which are also presented in this work. In vitro evaluation of the inhibitory activity (IC50) of this series of compounds against HDAC6 allowed us to confirm the results of virtual screening and to reveal promising compounds V-2 and V-4, IC50 of which is 3.25 nM and 0.04 nM, respectively. The subsequent in silico evaluation of the main ADMET properties of active compounds V-2 and V-4 allowed us to find that they have acceptable pharmacokinetic parameters and level of acute toxicity.

ИССЛЕДОВАНИЕ ПРОИЗВОДНЫХ ГИДРОКСАМОВЫХ КИСЛОТ В КАЧЕСТВЕ ГИБРИДНЫХ HDAC/VEGFR-2 ИНГИБИТОРОВ

Somatostatin analogues play an important role in the therapy of neuroendocrine tumors by binding to somatostatin receptors on the surface of cancer cells. In this work, we analyze the receptor‐binding affinity and in vitro stability of a novel ultra‐short somatostatin analogue Thz‐Phe‐D‐Trp‐Lys‐Thr‐DOTA (DOTA‐P4). This conjugate is successfully radiolabeled with 44Sc, 90Y, 152Eu, and 207Bi, characterized and validated by thin layer and high‐performance liquid chromatography. The optimum conditions for M‐DOTA‐P4 labeling are found. In vitro stability studies are performed in saline, in the presence of serum proteins, and with biologically relevant metal cations. All complexes demonstrate no cation release in vitro within 4–24 h. The conformations of DOTA‐conjugates are studied by circular dichroism spectroscopy. The circular dichroism spectra of DOTA‐P4 conjugates show a negative peak at 225 nm, which may correspond to the required β‐sheet conformation. The binding to somatostatin receptors of types 2 and 5 is performed with the IMR‐32 cells at 4°C, with non‐specific binding representing 26% of the total binding. A two‐line approximation of the Scatchard plot results in the apparent dissociation constants of 0.10 and 2.25 nM. It is shown that the chelator position with respect to the amino acid sequence significantly affects the labeling conditions with cations of different ionic radii. For the first time, the binding of a linear type ultra‐short peptide conjugate with DOTA to somatostatin receptors is demonstrated. The obtained results are promising for experiments with DOTA‐P4 in vivo in mice with inoculated tumors.

As potential HDAC inhibitors, new derivatives of 1,2-dihydroquinazolin-4-one in combination with alkyl hydroxamic acid have been proposed. The latter were obtained by the interaction of an alkyl hydroxyamide derivative of anthranilamide with various aldehydes by boiling in ethanol with yields of 73-99% and were characterized by H-1-NMR and ESI-MS spectra..ytotoxic properties of target compounds were also studied by the MTT test on cell lines of human tumors (MCF-7, A549, PC-3, and HCT-116). Based on the SAR results, the resulting products can potentially be used as a new candidate drug for a promising anti-cancer strategy.

New 2-cyclohexenone derivatives were synthesized via the Michael reaction in the presence of potassium carbonate. These derivatives containing the acetyl substituent in position 6 are of special interest due to the ability to form boron chelate complexes, 1,3-dioxaborines, possessing luminescence properties. The dependence of the position of the absorption and luminescence absorption band maxima on the donor properties of the substituents was found.

Vasculogenic mimicry, the formation of vascular channels lined with tumor cells of a highly malignant phenotype, is currently considered as an additional system of blood supply of the tumor. Experimental studies in vivo have repeatedly demonstrated that vascular channels form in the areas of a tumor with a low density of blood vessels. It is supposed that the formation of a network of these channels inside the tumor maintains homeostasis and prevents early necrosis within it. In this work, bifunctional compounds based on a combination of quinazoline and hydroxamic acid in one molecule were examined for the ability to inhibit the migration of tumor cells and vasculogenic mimicry.

Synthesis pathways were developed and new hydroxamic acids were obtained as potential inhibitors of HDAC/VEGFR2, including tetracycles containing quinazolinone fragment as a "cap". Further biological testing of the obtained compounds will give an opportunity to estimate the real prospects of the chosen research direction.

Ингибиторы гистондеацетилаз (HDACi) рассматриваются в качестве перспективного класса препаратов для лечения рака из-за их влияния на рост клеток, дифференцировку и апоптоз. Ангиогенез играет важную роль в росте солидных опухолей и развитии метастазов. Фактор роста эндотелия сосудов (VEGF) является ключевым ангиогенным агентом, который секретируется злокачественными опухолями, что индуцирует пролиферацию и миграцию эндотелиальных клеток сосудов. В настоящее время наиболее перспективной стратегией в борьбе с онкологическими заболеваниями является создание гибридных лекарств, одновременно действующих на несколько физиологических мишеней. Значительный интерес с точки зрения создания бифункциональных противоопухолевых средств представляют соединения, содержащие одновременно N-фенил-4-аминохиназолин и гидроксамовую кислоту, так как данные фрагменты по отдельности присутствуют в уже успешно применяемых противоопухолевых лекарственных средствах. В этой связи в ходе литературного анализа была сформирована выборка из 42 соединений, содержащих указанные молекулярные фрагменты и обладающих экспериментальными данными по ингибированию HDAC, VEGFR-2 и росту клеток рака легкого человека MCF-7. С использованием симплексных дескрипторов и метода опорных векторов (Support Vector Machine, SVM) для указанной выборки, предварительно разделенной на обучающий и тестовый наборы, были построены удовлетворительные (R2test = 0.64–0.87) модели количественной связи «структура–активность» (Quantitative Structure- Activity Relationship, QSAR). Для полученных QSAR-моделей была проведена структурная интерпретация. Было оценено согласованное влияние различных молекулярных фрагментов на увеличение противоопухолевой активности исследуемых соединений. Среди заместителей N-фенильного фрагмента можно выделить положительный вклад брома в пара-положении для всех трех видов активности. По результатам интерпретации был проведен рациональный молекулярный дизайн и предложены перспективные соединения. Для сравнительного QSAR-исследования использованы физико-химические дескрипторы, рассчитываемые программой HYBOT, метод случайного леса (Random Forest, RF), а также онлайн-версия экспертной системы OCHEM (https://ochem.eu). При моделировании OCHEM были выбраны PyDescriptor-дескрипторы и метод экстремального градиентного бустинга. Кроме того, полученные с помощью экспертной системы OCHEM модели были использованы для виртуального скрининга 300 соединений с целью отбора перспективных VEGFR-2/HDAC-ингибиторов для последующего синтеза и испытаний.

Reaction of alkyl chlorides and N-benzylimidazole was conducted by refluxing them in dioxane. The synthesized product was characterized using 1H-NMR. The reaction yielded white solid quaternary ammonium salts (QAS) in 31-82%. QAS have been widely researched its activity as antimicrobial and antibacterial. The substitution of the functional groups on the QAS structure affects its biological activity. Antimicrobial activity of QAS was assayed by the method of serial twofold dilutions in a liquid nutrient medium. According to the results, QAS could potentially be developed as a new drug candidate for the treatment of microbial infections.

Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is a promising therapeutic target in cancer therapy. Combination chemotherapy using Tdp1 inhibitors as a component can potentially improve therapeutic response to many chemotherapeutic regimes. A new set of usnic acid derivatives with hydrazonothiazole pharmacophore moieties were synthesized and evaluated as Tdp1 inhibitors. Most of these compounds were found to be potent inhibitors with IC50 values in the low nanomolar range. The activity of the compounds was verified by binding experiments and supported by molecular modeling. The ability of the most effective inhibitors, used at non-toxic concentrations, to sensitize tumors to the anticancer drug topotecan was also demonstrated. The order of administration of the inhibitor and topotecan on their synergistic effect was studied, suggesting that prior or simultaneous introduction of the inhibitor with topotecan is the most effective.

It is shown for the first time that the Wurtz reaction can be realized by the action of an organic substance (triphenylphosphine) on an alkyl halide (perfluoroalkyl iodide) without the use of metals. It was found that when trying to prepare the bis(3,3'-aminophenyl)(fluoroalkyl)phosphine oxide by four-step synthesis, in the first stage of the reaction of perfluoro-l-iodohexane with triphenylphosphine does not proceed towards the formation of an intermediate quaternary phosphonium salt. Instead, the carbon chain of perfluoroalkyl iodide dimerizes to form perfluorododecane - Wurtz reaction product. We have proposed a new pathway for homocoupling of perfluoroalkylhalides into even-numbered perfluoroalkanes. (C) 2018 Elsevier Ltd. All rights reserved.