Novel Zn(II)-complex with hybrid chalcone-thiosemicarbazone ligand: Synthesis, characterization, and inhibitory effect on HTLV-1-infected MT-2 leukemia cells

Estimates indicate >10 million individuals are living with human Adult T-cell lymphotropic virus type 1 (HTLV-1) worldwide [1]. The HTLV-1 is a highly oncogenic retrovirus causing in humans, adult T-cell leukemia/lymphoma (ATLL) [2] or inflammatory diseases, principally, HTLV-1-associated myelopathic/tropical spastic paraparesis (HAM/TSP) [3]. The epidemiological distribution of HTLV-1 involves endemic regions, such as Japan, South America, Africa, and Central Australia [1].

The ATLL is a T lymphocyte neoplasm with a heterogeneous clinical course that can manifest in four subtypes based on clinical characteristics: acute, lymphoma, chronic, and smoldering [4]. The risk of HTLV-1-infected individuals developing ATLL is 6–7% in men and 2–3% in women, usually after a long latency period. ATLL carriers have a poor prognosis for the evolution of the disease, with a life expectancy of 8 months for the acute form [5].

The treatment of patients depends on the ATLL subtype and for the most aggressive subtype the chemotherapy combination (CHOP cocktail, Fig. 1) is prescribed. However, the transformed cells are resistant to a large part of these agents [6]. Thus, the combination of zidovudine (AZT) and interferon-alpha (IFN-α) is also used in some cases with the acute forms of the disease [7]. Alternatively, ATLL patients can be submitted to allogeneic stem cell transplantation, which has shown great healing potential, but its use is limited [8]. Despite the great advances made in understanding the pathogenesis of HTLV-1, there is still a need to develop more effective therapies, and it is extremely important to investigate novel compounds with activity on HTLV-1-infected cells to increase the treatment strategies for ATLL.

In the past two decades, many organic compounds showed promising results in preclinical studies against HTLV-1 and ATLL [[9], [10], [11]]. The same is not true for metal-based compounds. Although transition metal complexes have demonstrated excellent antiviral [[12], [13], [14]] and anticancer activities [15], very few of them have been investigated on HTLV-1-infected cell lines. In fact, to the best of our knowledge, only two such reports were made in the past. In 2010, Pelosi and coworkers [16] assayed a nickel and a copper complex prepared with different thiosemicarbazone ligands against retroviruses. The complexes exhibited antiviral properties against human immunodeficiency virus (HIV), but not against HTLV-1 and HTLV-2. Not much later, Guimaraes-Correa and coworkers [17] demonstrated the activity of a biphosphinic cyclopalladated compound (C7a) toward HTLV-1-infected and uninfected leukemia cells. The C7a was effective in vitro, and significantly increased the survival of mice engrafted with the leukemia cell line RV-ATL.

Currently, our group has been interested in developing derivatives of natural compounds, such as chalcones. Chalcones are a relevant class of compounds in medicinal chemistry. They are widely distributed in vegetal species, and present diverse biological activities, such as antimicrobial [18], anticancer [19], antiparasitic [20], and antiviral [21,22]. Surprisingly, butein, a natural chalcone, reduced the viability of HTLV-1-infected T-cell lines in vitro. In mice containing ATLL tumors, butein proved to be effective, causing significant inhibition of tumor growth [23]. The broad therapeutic potential of the chalcones and another equally important class of molecules, the thiosemicarbazones, encouraged the design, synthesis, and biological investigation of chalcone-thiosemicarbazone (CT) hybrids. For instance, our group's recent work demonstrated the antileishmanial effects of the CT hybrids against Leishmania amazonensis [24]. In addition, our group reported the cytotoxic effects of the CT hybrids against the human hepatocarcinoma cell line HepG2 [25].

Metal complexes of CT [[26], [27], [28]] and azachalcone-thiosemicarbazone (ACT) [[29], [30], [31], [32]] hybrids were also reported. A series of 3-(4-X-phenyl)-1-pyridin-2-ylprop-2-en-1-one derived thiosemicarbazones were complexed with Cu(II) and evaluated against leukemia cells (HL-60 and Jurkat), human breast carcinoma (MDA-MB 231), and human colorectal carcinoma (HCT-116). Cytotoxicity against some of the cell lines significantly increased upon complexation, and the IC50 values of the ligands and complexes were found in the range of 0.020–5.49 μM [33]. Au(III) and Pd(II) complexes were also prepared with azachalcone-thiosemicarbazone as ligand. The Au(III) complex was highly cytotoxic against the cancer cell lines evaluated [31], while the Cu(II) complexes with the same ligand were cytotoxic on THP-1 leukemia and MCF-7 breast cancer cells. The complexes inhibited topoisomerase IB and exhibited increased cytotoxicity compared to the free ligand [32]. Finally, some Zn(II) and Ga(III) complexes prepared from azachalcone-thiosemicarbazone hybrids showed increased antibacterial activity against Staphylococcus aureus and Pseudomonas aeruginosa when compared with the free ligands [30].

Therefore, considering the good scenario of inorganic compounds to find novel treatments to a variety of diseases, including cancer, and the relatively small number of works in literature dealing with the screening of transition metal complexes against HTLV-1 infected cells (a poor prognosis of ATLL), the present work reports the synthesis and characterization of a novel Zn(II)-complex (CTCl-Zn, Fig. 2) with the ligand (Z)-2-((E)-3-(4-chlorophenyl)-1-phenylallylidene)hydrazine-1-carbothioamide (chalcone-thiosemicarbazone, CTCl, Fig. 2). The compounds were cell-based evaluated in terms of cytotoxicity against HTLV-1 infected leukemia cells (MT-2) and the experimental data were correlated with molecular docking calculations.

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