Betulinic Acid and Brosimine B Hybrid Derivatives as Potential Agents against Female Cancers

Abstract

Background: Cancer is a multifactorial disease, representing one of the leading causes of death worldwide. On a global estimate, breast cancer is the most frequently occurring cancer in women and cervical cancer, the fourth most common. Both types of cancer remain the major cause of cancer-related mortality in developing countries. A strategy for rational drug design is hybridization, which aims to bring together in one molecule, two or more pharmacophores in order to reach several biological targets. Objective: The objective of this work was to develop new hybrids based on natural pharmacophores: Betulinic acid (1) and brosimine b (2), active in female cancer cell lines. Methods: The coupling reactions were carried out by Steglich esterification. Different compounds were designed for the complete and simplified structural hybridization of molecules. The anticancer activities of the compounds were evaluated in human cervical adenocarcinoma (HeLa), human cervical metastatic epidermoid carcinoma (ME-180), and human breast adenocarcinoma (MCF-7) cell lines. Results: Hybrid 3 presented higher potency (IC50 = 9.2 ± 0.5μM) and SI (43.5) selectively in MCF-7 cells (in relation to Vero cells) with its cytotoxic effect occurring via apoptosis. In addition, compound 6 showed activity in MCF-7 and HeLa cells with intermediate potency, but with high efficacy, acting via apoptosis as well. Conclusion: In this context, we showed that the combination of two complex structures generated the development of hybrids with differing inhibitory profiles and apoptotic modes of action, thus representing potential alternatives in female cancer treatment.

Enhanced Accumulation of Betulinic Acid in Transgenic Hairy Roots of Senna obtusifolia Growing in the Sprinkle Bioreactor and Evaluation of Their Biological Properties in Various Biological Models

“…Literature data shows that this compound has anti‐tumor properties against many neoplastic cells, such as equine melanoma [60] . human hepatoma (HepG2), [61] human breast cancer (MCF‐7) [62] or the colorectal [63] . Additionally, our research confirmed the influence of the extracts on the changes in the expression level of apoptosis‐related proteins, i. e., p53, and p53 upregulated modulator of apoptosis (PUMA), phorbol‐12‐myristate‐13‐acetate‐induced protein 1 (NOXA) and BCL2 Associated X, Apoptosis Regulator (BAX).…”

Oxidative Stress and Chronic Myeloid Leukemia: A Balance between ROS-Mediated Pro- and Anti-Apoptotic Effects of Tyrosine Kinase Inhibitors

“…Numerous plants, fruits, and vegetables contain betulinic acid (BA), a pentacyclic triterpene with a number of medicinal uses, including anti-inflammatory, antiviral, antibacterial, antimalarial, immunomodulatory, antidepressant, and anticancer properties [84][85][86]. Several tumor lines have reported the anticancer efficacy of BA [87,88]. Its main mode of action is the induction of cell death by many mechanisms, such as apoptosis, kinase protein regulation, autophagy, and suppression of DNA topoisomerases.…”

Betulinic Acid-Brosimine B Hybrid Compound Has a Synergistic Effect with Imatinib in Chronic Myeloid Leukemia Cell Line, Modulating Apoptosis and Autophagy

“…The triterpene-flavonoid hybrid compound was synthetized as described by Couto, et al [12] and shown in Figure 10. The synthesis is carried out from the natural product (betulinic acid), which is widely available and involves low-complexity steps.…”

“…Betulinic acid (BA) is a pentacyclic triterpene found in many plants, fruits and vegetables; this molecule has several therapeutic activities and is demonstrated to be antiinflammatory, antiviral, antibacterial, antimalarial, immunomodulatory, antidepressive and antitumor agent [8][9][10]. The antitumor activity of BA has been described in several tumor lines, such as melanoma, neuroblastoma, glioblastoma, colon, hepatocellular, lung, prostate, breast, ovary, cervical carcinoma and leukemia [11,12]. Its main mechanism of action is the induction of cell death by apoptosis, autophagy, modulation of kinase proteins and inhibition of DNA topoisomerases, among others [10,11].…”