Mechanisms of the Cytotoxic Action of Novel Cyclic Hydroxamic Acids
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chanisms of the Cytotoxic Action of Novel Cyclic Hydroxamic Acids M. E. Neganovaa, *, Yu. R. Aleksandrovaa, S. A. Pukhova, S. G. Klochkova, and V. N. Osipovb aInstitute
of Physiologically Active Compounds of the Russian Academy of Sciences (IPAC RAS), Severnii pr. 1, Chernogolovka, Moscow region, 142432 Russia b N.N. Blokhin National Medical Research Center of Oncology (Blokhin NMRC of Oncology), Kashirskoe sh. 23, Moscow, 115478 Russia *e-mail: [email protected] Received April 22, 2020; revised July 7, 2020; accepted July 10, 2020
Abstract—Cyclic hydroxamic acids (CHAs) based on quinazoline-4(3H)-one and dihydroquinazoline4(1H)-one have been synthesized. The antioxidant and iron-chelating properties of these compounds, their effect on the activity of the histone deacetylase enzyme, and their cytotoxic effect on cells of various tumor lines have been investigated. Among the synthesized CHAs two compounds-hits exhibiting the multipharmacological type of the antineoplastic activity have been identified. Their cytotoxic effect on cells of human lung carcinoma A549 and breast adenocarcinoma MCF-7 is obviously associated with their ability to modulate the level of reactive oxygen species (ROS) and to chelate Fe(II) ions, as well as to inhibit the metalloenzymes, histone deacetylases (HDACs), involved in the epigenetic regulation of tumor genesis. Thus, the synthesized CHAs may be considered as a promising basis for creating potential oncolytics. Keywords: hydroxamic acids, lipid peroxidation, chelation, HDAC inhibitors, cytotoxicity DOI: 10.1134/S1990750820040095
INTRODUCTION Cancer is a serious clinical problem affecting millions of patients [1]. According to the prognosis made by the World Health Organization, by 2030 15 million people in the world will die from cancer annually [2]. This is associated with the fact that numerous studies in this area have not culminated by unequivocally positive results, and the arsenal of methods applicable for cancer treatment is still rather limited. The complexity of the adequate chemotherapeutic treatment is determined by a wide variety of pathogenesis and etiology of tumors, their development and symptoms. In this context, rational creation of multitarget antitumor substances has recently become a promising approach in the search for highly effective low-toxic oncolytics. Using this approach it will possible to develop a new generation drugs that simultaneously act on several crucial links of the pathological process, thus preventing the development of oncological diseases. The processes associated with oxidative stress [3], imbalance of biometals and changes in the level of metalloenzymes, particularly histone deacetylases [4], are considered as important links in the development of oncopathologies; it is suggested that the simultaneous action of novel pharmacological agents on them will trigger elimination of transformed cells.
Hydroxamic acids are one of the promising classes of antitumor compounds that can perform all the above outlined functions; their most important targ
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