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      Synthesis, biological evaluation, and in silico studies of indole‐tethered pyrazoline derivatives as anticancer agents targeting topoisomerase IIα

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          Abstract

          We herein report a new series of indole‐tethered pyrazoline derivatives as potent anticancer agents. A total of 12 compounds were designed and synthesized by conventional as well as microwave‐irradiated synthesis methods. The latter method results in a significant reduction in the duration of reaction along with improved yields. All synthesized derivatives ( 7a−7l) were evaluated for their cytotoxic activity against A431, HeLa, and MDAMB‐231 cell lines. Compounds 7a and 7b were found most potent in the series and demonstrated an IC 50 value of 3.17 and 5.16 µM against the A431 cell line, respectively, compared to the standard drug doxorubicin. Compounds 7a and 7b significantly suppress colony formation, migration, and S phase cell cycle arrest of A431 cells. Furthermore, compound 7a regulated the expression of apoptotic proteins causing the downregulation of procaspase 3/9, antiapoptotic protein Bcl‐xL, and upregulation of proapoptotic protein Bax in a dose‐dependent manner. Topoisomerase enzyme inhibition assay confirmed that compounds 7a and 7b can significantly inhibit topoisomerase IIα. In vivo oral acute toxicity of compounds 7a and 7b revealed that both compounds are safe compared to doxorubicin; cardiomyopathy studies showed normal architecture of cardiomyocytes and myofibrils. In addition, molecular docking studies revealed the possible interaction of compounds 7a and 7b within the active binding site of the topoisomerase enzyme. The 100 ns molecular dynamic simulation of compounds 7a and 7b proved that both compounds validate all screening parameters.

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          Mitochondria-dependent ferroptosis plays a pivotal role in doxorubicin cardiotoxicity

          Doxorubicin (DOX), a chemotherapeutic agent, induces a cardiotoxicity referred to as doxorubicin-induced cardiomyopathy (DIC). This cardiotoxicity often limits chemotherapy for malignancies and is associated with poor prognosis. However, the molecular mechanism underlying this cardiotoxicity is yet to be fully elucidated. Here, we show that DOX downregulated glutathione peroxidase 4 (GPx4) and induced excessive lipid peroxidation through DOX-Fe 2+ complex in mitochondria, leading to mitochondria-dependent ferroptosis; we also show that mitochondria-dependent ferroptosis is a major cause of DOX cardiotoxicity. In DIC mice, the left ventricular ejection fraction was significantly impaired, and fibrosis and TUNEL + cells were induced at day 14. Additionally, GPx4, an endogenous regulator of ferroptosis, was downregulated, accompanied by the accumulation of lipid peroxides, especially in mitochondria. These cardiac impairments were ameliorated in GPx4 Tg mice and exacerbated in GPx4 heterodeletion mice. In cultured cardiomyocytes, GPx4 overexpression or iron chelation targeting Fe 2+ in mitochondria prevented DOX-induced ferroptosis, demonstrating that DOX triggered ferroptosis in mitochondria. Furthermore, concomitant inhibition of ferroptosis and apoptosis with ferrostatin-1 and zVAD-FMK fully prevented DOX-induced cardiomyocyte death. Our findings suggest that mitochondria-dependent ferroptosis plays a key role in progression of DIC and that ferroptosis is the major form of regulated cell death in DOX cardiotoxicity.
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            Indole: A privileged scaffold for the design of anti-cancer agents

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              Cardiotoxicity induced by tyrosine kinase inhibitors.

              Cardiotoxicity is a serious side effect of drugs used to treat cancer patients. Older chemotherapy drugs such as the anthracyclins and new targeted therapies, mainly trastuzumab, have been implicated in causing clinically significant cardiac dysfunction, which may be irreversible for many patients. The advent of a new category of drugs, the tyrosine kinase inhibitors has revolutionized the treatment of chronic myeloid leukemia, gastrointestinal stromal tumors and renal cancer, while their indications include a variety of other types of tumors. Assessment of the incidence and severity of cardiac toxicity caused by the tyrosine kinase inhibitors and discussion on the molecular mechanisms and mode of diagnosis based on recent clinical trials. Review of related literature. Cardiac toxicity can be caused by the tyrosine kinase inhibitors imatinib mesylate, dasatinib, nilotinib, sunitinib, sorafenib and lapatinib, while gefitinib and erlotinib have not been related to toxic effect on the heart. Although targeted therapies are considered less toxic and better tolerated by patients compared with classic chemotherapy drugs, certain complications can be very serious and as these agents have been in use for a limited period of time, the exact profile of side effects will be better defined in the years to come. Cardiac toxicity may range from asymptomatic subclinical abnormalities such as electrocardiographic changes and left ventricular ejection fraction decline to life threatening events like congestive heart failure and acute coronary syndromes. For patients with severe side effects, discontinuation of treatment is warranted. Careful cardiac monitoring and assessment by a cardiologist throughout the course of treatment with those TKIs that exert cardiac toxic effect is of primary importance.
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                Author and article information

                Contributors
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                Journal
                Drug Development Research
                Drug Development Research
                Wiley
                0272-4391
                1098-2299
                November 2022
                July 27 2022
                November 2022
                : 83
                : 7
                : 1555-1577
                Affiliations
                [1 ] Department of Pharmaceutical Chemistry, School of Pharmaceutical Education and Research Jamia Hamdard New Delhi India
                [2 ] Faculty of Life Science and Biotechnology South Asian University New Delhi India
                [3 ] Department of Pharmaceutical Chemistry, Manipal College of Pharmaceutical Sciences Manipal Academy of Higher Education Manipal Karnataka India
                [4 ] Department of Pharmacology, School of Pharmaceutical Education and Research Jamia Hamdard New Delhi India
                Article
                10.1002/ddr.21976
                35898169
                cd78e53f-29a6-460c-bb63-216c5258b7b2
                © 2022

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