Wyniki wyszukiwania - BazTech

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Natural products as potential inhibitors of FLT3 for acute myeloid leukemia: HTVS, docking, and molecular dynamic simulation

Salah Salsabeel, Sami Najat, Ali Sarah, Khalid Teemah-Alrahman, Alnajjar Radwan

Scientiae Radices

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2023

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Vol. 2, Iss. 4

325--346

EN

Cancer is one the most common health issues worldwide, with cancer-related mortality of 9.5 million in 2018, with an expectation to become 29.5 by 2040. Among others, acute myeloid leukemia (AML) is common among older people. FLT3 mutations are one of the most common genetic aberrations found in Acute Myeloid Leukemia and are associated with poor prognosis. Herein, we attempt to identify natural compounds as potential candidates to treat AML by targeting the FLT3 kinase domain using in silico approaches. The COCONUT database, which contains 407,270 natural compounds, was HTVS against the FLT3 kinase domain active site, and promising compounds were subject to molecular docking. Finally, frontier compounds were validated further using molecular dynamic simulation. In total, ten compounds were identified with docking scores higher than Quizartinib (-11.606 kcal/mol), with the best three compounds showing a docking score of -18.052, -15.772, and -16.767 kcal, respectively, and compound 2 showing excellent stability in molecular dynamic simulation.

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Wybrane związki kompleksowe miedzi(I) jako potencjalne czynniki przeciwnowotworowe

Płotek M., Dudek K., Kyzioł A.

Chemik

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2013

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Vol. 67, nr 12

1181--1190

PL

Choroby nowotworowe są drugą co do częstości występowania przyczyną zgonów na świecie. Jednym z metali przejściowych, którego związki kompleksowe są intensywnie badane pod kątem zastosowania w terapii antynowotworowej jest miedź. W artykule, na wybranych przykładach, omówiono aktywność i mechanizmy cytotoksycznego działania kompleksów miedzi(I).

EN

Cancer is the second most frequent cause of death in the world. One of the transition metal, whose complexes are extensively tested for antitumor application is copper. This article presents selected examples of cytotoxic activity and mode of action of copper(I) complexes.

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Kompleksy rutenu w terapii antynowotworowej

Richert M., Budzisz E.

Wiadomości Chemiczne

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2010

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[Z] 64, 5-6

357-387

EN

Chemotherapy is a major cancer treatment besides surgery and ratiotherapy. One of the most popular chemotherapeutic drugs that are currently in use are platinum compounds. Despite the success of cisplatin and other platinum-based anticancer compounds in cancer therapy [1, 2] there is still a need for new improved drugs with lower toxicity against healthy cells, better activity against tumor, less side effects, and without problems with drug resistance in primary and metastatic cancers [3, 4]. One of the most promising metals in the cancer treatment is ruthenium [6, 21,22]. Ruthenium complexes appear generally less toxic than platinum-based complexes and show activity in cisplatin-resistant cells or in cells where cisplatin is inactive. In spite of development of promising ruthenium(II) compounds, in particular organometallics [50, 51], only ruthenium(III) complexes like (H2Im)[trans-Ru(DMSO)Cl4(HIm)], (NAMI-A) [62] (Ryc. 7a) and (HInd)[Ru(III)Cl4(Ind)2], (KP1019) [23] (Ryc. 7b) gain the phase II of clinical trials. The complex NAMI-A showed marked efficacy against metastases whereas KP1019 was highly active against a colorectal tumor cells both in vivo and in vitro. Moreover the second compound is completely devoid of side effects and drug induced lethality at therapeutically relevant doses. Its therapeutic index is better than that of (HIm)[Ru(III)Cl4(Im)2]. The complex (HInd)[Ru(III)Cl4(Ind)2] has been shown to be efficiently taken up into the cells probably via interaction with transferrin. It induces apoptosis, but the cellular mechanisms of the apoptosis induction are still largely unknown [30]. Non-cross-resistance in cisplatin-resistant cancer cells and reduced toxicity, which is in part due to the ability of ruthenium complexes to mimic the binding of iron to molecules of biological significance, exploiting the mechanisms that the body has evolved for non-toxic transport of iron, is a particularly attractive feature of ruthenium complexes [16]. In addition, some chemical properties, such as rate of ligand exchange, range of accessible oxidation states, and ability of ruthenium to mimic iron in binding to certain biological molecules make these compounds well suited for medicinal applications as an alternative to platinum antitumor drugs in the treatment of cancer cells resistant to cisplatin and its analogues justifying further development of this novel and interesting group of metal complexes [30].

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Kierunki poszukiwania preparatów przeciwnowotworowych

Mikiciuk-Olasik E., Błaszczak-Świątkiewicz K.

Wiadomości Chemiczne

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2000

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[Z] 54, 9-10

705-724

EN

Cancer chemotherapy over twenty years has been under extremely intensive investigation. Failure in the treatment of neoplasms is due to characteristic fe-atures of cancer cells. Their structure delays and decreases the efficacy of drugs administered orally or intravenously. Therefore, greater emphasis is placed on the development of new molecular studies. The development of particular molecular diagnostic methods is based on new advances in immunology, genetics and nuclear medicine. Nuclear medicine concentrates on the diagnostics and treatment of various diseases, including neoplasms treated by means of radiopharmaceuticals. The isotope most commonly used as a source of g radiation for radiopharma-ceuticals is technetium (99mTc). The complexes of this radiotracer (e.g. 99mTc-HM-PAO, 99mTc-CB-PAO, 99mTc-ECD) are widely used for brain imaging. These compounds indicate areas of normal blood supply in the brain, but do not enter hypoxic tumour cells. The differences in oxygenation level between normal and cancer cells is key strategy used not only in the diagnostics, but also in the treatment of neoplasms. Some compounds [quinone antibiotics,nitroimidazoles, tirapazamine] are known as hypoxia selective agents activated in low oxygen concentrations. Another strategy used in anticancer therapy aims at the inhibition of angiogenesis in the tumour; other methods limit the growth of tumour - these include use of inhibitory enzymes such as telomerase inhibitors (phosphorothioate oligonucleotides, cisplatin) and polyamine metabolism inhibitors (DFMO, MGBG). Valuable antineoplastic drugs originate from natural sources. Currently, the derivatives of acronycine and spongiostatin are being investigated. Natural compounds with a documented anticancer activity include, for example, taxol , etopozide and tenipozide. New directions in the research of new compounds for use in the diagnostics and treatment of neoplastic diseases are closely related to the development of molecular studies, which offer explanation of complex patophysiology of tumours on molecular level. Also. medical chemistry plays an important role in modern investigation methods, such as molecular modelling.

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Związki metali jako potencjalne środki wspomagające promienioterapię

Kudak-Jaworowska Janina

Wiadomości Chemiczne

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1999

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[Z] 53, 5-6

349-377

EN

This review describes some current approaches in using metal compounds to modulate the response of tumors and normal tissues to cell killing byionizing radiation. It is known that many tumors contain necrotic, oxygen-defficient areas which show diminished radiation sensitivity. Normal tissues contain mostly oxic cells; so antihypoxia therapies should be relatively tumor-specific. The biochemical role of oxygen is in fixing , or making permanent, the damage done to the critical DNA target. Radiation can damage DNA either by direct interaction or indirectly by ionizing created in nearby water molecules. The resulting DNA state depends on a competition between oxygen for damage fixation and reducing species, such as hydrated electron or thiol compounds (-SH), for chemical restitution. (...) Metal complexes would appear to represent ideal candidates for studies of their potential sensitizing properties, but only few such studies have been carried out. Metal complexes which exhibit greater radiosensitizing properties in hypoxia may be divided into three classes: (1) cisplatin and related Pt complexes; (2) metal (mainly Pt, Ru, Rh) complexes of nitroaromatic radiosensitizeres; (3) complexes of early transition metal series which may act by electron affinity or thiol depletion.(...)

6

Poszukiwanie nowych leków na bazie cisplatyny

Wysokiński R.

Wiadomości Chemiczne

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1998

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[Z] 52, 7-8

531-544

EN

Cancer therapy is one most the challenging tasks for medicine at the end of this century. The subject of discussion in this paper is cisplatin which about thirty years ago has awaked a hope for an effective treatment of cancer. The following problems have been reviewed : the effect of various substituents on the biological activity of the compounds : cis-PtAm2X2 (where Am is ammine or amine and X is an anionic group), the mechanism of action of cisplatin and the structures of its coordination compounds with DNA. The side effects of cisplatin therapy, in particular its nefrotoxicity and the attempts to establish the structure-activity relationship have been discussed. The second and third generation of platinum-based drugs are presented, including the cisplatin drugs which are joint with some biologically active compounds. They act as the vectors delivering the drug directly to the cancerous cells, hereby decreasing toxicity of these drugs.

7

Ekstaza i udręka, czyli o chemii taksolu

Kacprzak K.

Wiadomości Chemiczne

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1998

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[Z] 52, 11-12

843--870

EN

Taxol (1), highly functionalised complex diterpenoid originally derived from the bark of Pacific yew, has received in recent decade wide attention of scientists in all fields of life sciences and chemistry, after the discovery of its strong and unique anticancer properties. Fast and spectracular career of this molecule is a subject of the present review. The Jarge scale of research on taxol is the consequence of public and commercial response to successful treatment of various cancer diseases and impossibility of solving basic technological and intellectual problems such as: production, drug formulation, structure-activity relationship elucidation. The discussion is divided into following sections: 1. Activity and pharmacological phenomena of taxol. 2. Production of taxol by biotechnological and chemical methods, including synthesis of taxol side chain. 3. Structure-activity relationship (SAR) of taxoids. After Horwitz reported in 1979 a strongly antimitotic activity of taxol, interest in developing the pharmacology and biochemistry of this class of natural products increased. Taxol molecule promotes anticancer activity by enhancing polymerization of tubulin and stabilization of microtubules. This process has the effect of inhibiting the normal dynamic reorganization of the cytoskeleton (with consists of microtubules) that is necessary for interphase and cell division in mitosis. Taxol and taxotere are successfully used for the treatment of a variety of cancers, in particular ovarian and breast cancer. The biggest problem hindering wider application of this drug is its limited availability from natural sources. One kg of Taxus brevifolia bark yields only 100-170 mg of taxol, after long and complicated extraction procedure. Since the yew is slow growing species this method of obtaining the drug is controvertible and unprofitable. An alternative source of taxol is semisynthesis, where natural precursor of taxol 10-deacetylbaccatin (10-DAB) can be extracted from regenerable twigs of popular yew Taxus baccata and after coupling with synthetically prepared side chain can be converted to taxol or taxotere. Taxol has also been prepared by a number of total syntheses but none of these is expected to enter the phase of commercial production. Biotechnological approaches to production by tissue culture or fungi cultivation have been reprted. Studies in the area of taxoids structure-activity relationships have first demonstrated two basic principles. The so-called 'southern' substituents, such as C-2 benzoate and the side chain, are crucial for the activity. 'Northern' substituents at C-7, C-9 and C-10 can be changed without drastic effect on the activity. The role of the substituents at C-1, the oxetane ring and diterpenoid core modifications are less well understood. There are many reports of significant activity of highly transformed taxoids, including those with: modified ABC core, open C-ring structure and aromatic C-ring. These results indicate the possibility of obtaining a synthetic, structurally simplified variant of taxol.