Discovery of Anti-TNBC Agents Targeting PTP1B: Total Synthesis, Structure–Activity Relationship, In Vitro and In Vivo Investigations of Jamunones

Abstract

Twenty-three natural jamunone analogues along with a series of jamunone-based derivatives were synthesized and evaluated for their inhibitory effects against breast cancer (BC) MDA-MB-231 and MCF-7 cells. The preliminary structure− activity relationship revealed that the length of aliphatic side chain and free phenolic hydroxyl group at the scaffold played a vital role in anti-BC activities and the methyl group on chromanone affected the selectivity of molecules against MDA-MB-231 and MCF-7 cells. Among them, jamunone M (JM) was screened as the most effective anti-triple-negative breast cancer (anti-TNBC) candidate with a high selectivity against BC cells over normal human cells. Mechanistic investigations indicated that JM could induce mitochondria-mediated apoptosis and cause G0/G1 phase arrest in BC cells. Furthermore, JM significantly restrained tumor growth in MDA-MB-231 xenograft mice without apparent toxicity. Interestingly, JM could downregulate phosphatidylinositide 3kinase (PI3K)/Akt pathway by suppressing protein-tyrosine phosphatase 1B (PTP1B) expression. These findings revealed the potential of JM as an appealing therapeutic drug candidate for TNBC.

Alzheimer’s Disease and Diabetes Mellitus in Comparison: The Therapeutic Efficacy of the Vanadium Compound

“…This was due to the inhibition of GSK3β by PTP1B inactivation [ 131 ]. These results are coincident with the observations that GSK3β was inhibited by jamunone M through PTB1B [ 132 ]. The evidences of the therapeutic effects of BEOV on different AD mice models is summarized in Table 1 .…”

Delivery of mRNA Encoding Interleukin-12 and a Stimulator of Interferon Genes Agonist Potentiates Antitumor Efficacy through Reversing T Cell Exhaustion

“…The synthesis of (9 Z ,12 Z )-octadeca-9,12-dien-1-ol (Compound b), (9 Z ,12 Z )-octadeca-9,12-dien-1-yl methanesulfonate (Compound c), (6 Z ,9 Z )-18-bromooctadeca-6,9-diene (Compound d), and (6 Z ,9 Z ,28 Z ,31 Z )-heptatriaconta-6,9,28,31-tetraen-19-ol (Compound e) followed the protocol as described previously. , …”

“…The corresponding results are illustrated in Figures S5−S15 The synthesis of (9Z,12Z)-octadeca-9,12-dien-1-ol (Compound b), (9Z,12Z)-octadeca-9,12-dien-1-yl methanesulfonate (Compound c), (6Z,9Z)-18-bromooctadeca-6,9-diene (Compound d), and (6Z,9Z,28Z,31Z)-heptatriaconta-6,9,28,31-tetraen-19-ol (Compound e) followed the protocol as described previously. 53,54 (6Z,9Z,28Z,31Z)-Heptatriaconta-6,9,28,31-tetraen-19-yl 3-Bromopropanoate (Compound f). Triethylamine (0.50 g, 4.92 mM) and Compound e (2.0 g, 3.78 mM) were dissolved in anhydrous THF (20 mL) and stirred at 0 °C for 30 min under nitrogen.…”

Copper(ii) complex enhanced chemodynamic therapy through GSH depletion and autophagy flow blockade

“…The increase in the ROS level can inhibit the electron transfer chain function, resulting in the change of mitochondrial membrane potential (ΔΨ m ) and apoptosis. 38,39 Therefore, the effect of C2 on ΔΨ m in T24 cells was measured using a JC-1 kit. As shown in Fig.…”