BR-102024017300-A2 - Platinum-based conjugate, with potential antitumor action and reduced side effects.

BR102024017300A2BR 102024017300 A2BR102024017300 A2BR 102024017300A2BR-102024017300-A2

Abstract

The present invention consists of a novel antineoplastic conjugate containing a platinum(II) complex with the ligand 3,6-Dithia-1,8-octanediol, and biocompatibilized in a levan matrix (bacterial exopolysaccharide). The synthesized platinum(II) complex and the antineoplastic conjugate showed potential antitumor activities and reduced side effects, with this reduction being more significant with the conjugate. The percentage of tumor inhibition of the present invention proved satisfactory, as confirmed by animal experimentation in an animal model with sarcoma 180, male Swiss albino mice (Mus musculus). A significant decrease in the side effects commonly presented by this class of platinum-based antineoplastic compounds was observed, which was expressed by the absence of deaths, no involvement of the liver, spleen, kidneys and lungs, evaluated macroscopically; and gain in body mass, in the groups subjected to treatment with the synthesized compound. Tumor inhibition assays (in vivo) showed that a dosage of the complex and conjugate, measured in mg Kg-1, resulted in tumor inhibition percentages of approximately 78.5% and 90.0%, respectively.

Inventors

MONICA FREIRE BELIAN
WAGNER EDUARDO DA SILVA
LEONARDO SEVERIANO DE ALBUQUERQUE
Teresinha Goncalves Da Silva
Andre Galembeck

Assignees

UNIVERSIDADE FEDERAL RURAL DE PERNAMBUCO
UNIVERSIDADE FEDERAL DE PERNAMBUCO

Dates

Publication Date: 20260310
Application Date: 20240823

Claims (4)

1. PLATINUM-BASED CONJUGATE WITH POTENTIAL ANTITUMOR ACTION AND REDUCED SIDE EFFECTS, characterized by being a platinum complex with the ligand 3,6-Dithia-1,8-octanediol, conjugated to a polymeric matrix of bacterial homopolysaccharide (levan), the complex having the following structure: (i) platinum ion in the 2+ oxidation state (divalent cation), (ii) the ligand 3,6-Dithia-1,8-octanediol, which binds in a bidentate manner to the platinic acid center through sulfur atoms and (iii) two chloride ions, Figure 1 present in the drawings of the descriptive report.
2. PLATINUM-BASED CONJUGATE WITH POTENTIAL ANTITUMOR ACTION AND REDUCED SIDE EFFECTS, as claimed in claim 1, characterized by preferably being presented in the form of a conjugate with a saccharide polymeric matrix.
3. PLATINUM-BASED CONJUGATE, WITH POTENTIAL ANTITUMOR ACTION AND REDUCED SIDE EFFECTS, according to claims 1 and 2, characterized by its antineoplastic activity upon intraperitoneal administration in a range of 1 to 200.0 mg Kg-1, inclusive.
4. PLATINUM-BASED CONJUGATE, WITH POTENTIAL ANTITUMOR ACTION AND REDUCED SIDE EFFECTS, according to claims 1, 2 and 3, characterized by its water solubility, allowing for oral, intraperitoneal and intravenous administration.

Description

Field of invention [001] The present invention relates to a conjugate composed of a polysaccharide matrix (levan) and a platinum complex PtDitia, potentially active against malignant neoplasms, and therefore should be applied as a cancer therapy. The percentages of tumor inhibition were satisfactory for the free complex and the conjugate, 78.5% and 90%, respectively; confirmed by animal experimentation in an animal model with sarcoma 180, male Swiss albino mice (Mus musculus). At specific dosages used, in a range of 0.1 to 200.0 mg Kg-1, the compounds showed antitumor activity at the end of a 7 (seven) day treatment. The invention presents itself as a technological innovation for solving toxicological problems related to the class of platinum antineoplastic compounds. Thus, the present invention constitutes a potential oncological tool, which may assist in the clinical treatment of malignant tumors, and should be applied to chemotherapy regimens, also recommended by oncology. The invention represents a therapeutic innovation for oncological chemotherapy, and should contribute significantly, through the use of synergistic vehicles and platinum complexes, to the treatment of tumors. Fundamentals of the invention [002] Antineoplastic or antiblastic chemotherapeutic agents are divided into different classes according to their potential pharmacological action. Among these classes, the non-cell cycle specific (NCCS) stand out, which include platinum complexes, whose action is independent of the cell cycle phase, acting at any stage in which the target cell is found. [003] Since the discovery of the antitumor action of cisplatin (CDDP), platinum complexes have been studied as potential pharmacological agents. Various side effects are usually attributed to the diverse platinum-based complexes, resulting in a search for new toxicological solutions (antineoplastic prototypes with low side effects). [004] The clinical use of platinum-based drugs is widespread, given that this class of compounds has a broad range of action against the most diverse types of tumors, such as CDDP. The most commonly used platinum compounds available on the market are CDDP, carboplatin (CBDCA), oxaliplatin, and nedaplatin. [005] The mechanism of action of platinum complexes, including cisplatin, for example, consists of restricting the degrees of freedom of nuclear DNA (nDNA) through coordinative bonds, by forming Pt-nDNA complexes (platinum bonds to nitrogenous bases of nDNA), which causes intra- and interstrand lesions in the nDNA, thus preventing the replication process. In this way, biochemical signaling occurs, the recognition of which compromises the cell cycle and may trigger apoptosis (ALDERDEN, Rebecca A., HALL, MD, HAMBLEY, TW. The Discovery and Development of Cisplatin. Journal of Chemical Education, v. 83 n. 5, p. 728-734, 2006). For the commercially available platinum-based drugs mentioned above, it is possible to verify several inherent side effects (Table 1), as well as a variation in their action against tumors. Table 1 - Toxicological profile of some platinum-based drugs available on the market. [006] The low average survival rate for the various types of chemotherapy regimens, combined with the side effects presented in Table 1, has been driving the search for new technological prototypes capable of solving the toxicological problems of this class of compounds, and may contribute to a better quality of life for cancer patients. [007] One of the main limitations presented by the most varied types of chemotherapeutic agents, regardless of whether they belong to the platinum compound class, consists of their side effects, which represents a great risk for any chemotherapy regimen prescribed by doctors. The suggestion of the appropriate therapeutic dose, even when administering a combination of drugs (cocktail) capable of promoting the reduction of tumor mass, is not free from its side effects, which means a great difficulty in adapting the most varied doses to the most varied patient profiles (body mass, patient condition, and evolutionary picture and severity of the tumor). The proper adjustment of chemotherapy dosage and regimen is not always favorable for the recovery of cancer patients, which is reflected in the low average survival rates, representing a number of deaths caused by the administration of the drugs themselves or the suggested compositions (DILRUBA, S.; KALAYDA, G. V. Platinum-based drugs: past, present and future. Cancer Chemotherapy and Pharmacology, v. 77, n. 6, p.1103-1124, 2016); (MONNERET, C. Platinum anticancer drugs. From serendipity to rational design. Annales Pharmaceutiques Françaises, v. 69, n. 6, p.286-295, 2011). [008] In addition to this last fact, we can also mention the emergence of the phenomenon of multidrug resistance (MDR), which consists of the emergence of tumor cell lines resistant to the most varied types of chemotherapeutic agents, even if there is no structural correlation or correl