Novel sesquiterpene lactone analogues as potent anti‐breast cancer agents

Abstract

Triple-negative breast cancer (TNBC) is associated with high grade, metastatic phenotype, younger patient age, and poor prognosis. The discovery of an effective anti-TNBC agent has been a challenge in oncology. In this study, fifty-eight ester derivatives (DETDs) with a novel sesquiterpene dilactone skeleton were organically synthesized from a bioactive natural product deoxyelephantopin (DET). Among them, DETD-35 showed potent antiproliferative activities against a panel of breast cancer cell lines including TNBC cell line MDA-MB-231, without inhibiting normal mammary cells M10. DETD-35 exhibited a better effect than parental DET on inhibiting migration, invasion, and motility of MDA-MB-231 cells in a concentration-dependent manner. Comparative study of DETD-35, DET and chemotherapeutic drug paclitaxel (PTX) showed that PTX mainly caused a typical time-dependent G2/M cell-cycle arrest, while DETD-35 or DET treatment induced cell apoptosis. In vivo efficacy of DETD-35 was evaluated using a lung metastatic MDA-MB-231 xenograft mouse model. DETD-35 significantly suppressed metastatic pulmonary foci information along with the expression level of VEGF and COX-2 in SCID mice. DETD-35 also showed a synergistic antitumor effect with PTX in vitro and in vivo. This study suggests that the novel compound DETD-35 may have a potential to be further developed into a therapeutic or adjuvant agent for chemotherapy against metastatic TNBC.

Phytoagent Deoxyelephantopin and Its Derivative Inhibit Triple Negative Breast Cancer Cell Activity through ROS-Mediated Exosomal Activity and Protein Functions

“…The synthesis of DETD-35 followed the method described by Nakagawa-Goto et al (2016). The chemical purity of DET and DETD-35 were >99% as judged by NMR spectrometry.…”

A Novel Plant Sesquiterpene Lactone Derivative, DETD-35, Suppresses BRAFV600E Mutant Melanoma Growth and Overcomes Acquired Vemurafenib Resistance in Mice

“…DETD-3 was derived from DET by translactonization via the hydrolysis of DET followed by acidic treatment. DETD-5, −6, −13, −17, −19, −24, −31, −33, −35, −39, and −43 were further synthesized from DETD-3 (26). …”

Targeting pharmacophore with probe‐reactivity‐guided fractionation to precisely identify electrophilic sesquiterpenes and its activity of anti‐TNBC

“…which can be classified as electrophilic sesquiterpenes (ESs). Application of ES compounds to TNBC treatment shows promising prospects . These ESs may exercise their biological activities by reacting with an appropriately positioned nucleophilic residue available on targeted proteins or enzymes (usually, but not always, a cysteine thiol amino acid group) .…”

“…Moreover, thiol/disulphide homeostasis was reported to play a critical role in antioxidant defence and detoxification in the body . Thus, through Michel's reaction, ESs with specific electrophilic groups alkylate the enzymes or transcription factors, regulate key cellular signal pathways, and then produce anti‐TNBC activity . Targeted covalent modification has emerged as a validated approach to drug discovery with the recent US Food and Drug Administration (FDA) approvals of afatanib (2013), ibrutinib (2013), and osimertinib (2015) drugs that were designed to undergo an irreversible hetero‐Michael addition reaction with a unique cysteine residue of a specific protein …”

“…Application of ES compounds to TNBC treatment shows promising prospects. [7][8][9] These ESs may exercise their biological activities by reacting with an appropriately positioned nucleophilic residue available on targeted proteins or enzymes (usually, but not always, a cysteine thiol amino acid group). 6,7,[10][11][12] Thiol groups plays an important role in TNBC-related pathways and physiology.…”