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

• Published in: Anti-cancer agents in medicinal chemistry Vol. 20; no. 5; p. 622
• Main Authors: Garcês de Couto, Nádia M, Willig, Júlia B, Ruaro, Thaís C, de Oliveira, Diogo Losch, Buffon, Andréia, Pilger, Diogo A, Arruda, Mara S P, Miron, Diogo, Zimmer, Aline R, Gnoatto, Simone C B
• Format: Journal Article
• Language: English
• Published: Netherlands 01-01-2020
• Subjects: Antineoplastic Agents, Phytogenic - chemical synthesis; Antineoplastic Agents, Phytogenic - chemistry; Antineoplastic Agents, Phytogenic - pharmacology; Apoptosis - drug effects; Cell Proliferation - drug effects; Cell Survival - drug effects; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Female; Flavonoids - chemical synthesis; Flavonoids - chemistry; Flavonoids - pharmacology; HeLa Cells; Humans; Molecular Conformation; Moraceae - chemistry; Pentacyclic Triterpenes - chemical synthesis; Pentacyclic Triterpenes - chemistry; Pentacyclic Triterpenes - pharmacology; Plants, Medicinal - chemistry; Structure-Activity Relationship; Tumor Cells, Cultured; female cancer; triterpene; Hybrid compounds; anticancer activity; flavonoid; betulinic acid
• DOI: 10.2174/1871520620666200124111634
• EISSN: 1875-5992

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.
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.
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.
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.
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.