Design, Synthesis, and Cancer Cell Growth Inhibitory Activity of Triphenylphosphonium Derivatives of the Triterpenoid Betulin

Abstract

A series of new triphenylphosphonium (TPP) derivatives of the triterpenoid betulin (1, 3-lup-20(29)-ene-3β,28-diol) have been synthesized and evaluated for cytotoxic effects against human breast cancer (MCF-7), prostate adenocarcinoma (PC-3), vinblastine-resistant human breast cancer (MCF-7/Vinb), and human skin fibroblast (HSF) cells. The TPP moiety was applied as a carrier group through the acyl linker at the 28- or 3- and 28-positions of betulin to promote cellular and mitochondrial accumulation of the resultant compounds. A structure-activity relationship study has revealed the essential role of the TPP group in the biological properties of the betulin derivatives produced. The present results showed that a conjugate of betulin with TPP (3) enhanced antiproliferative activity toward vinblastine-resistant MCF-7 cells, with an IC value as low as 0.045 μM.

Triphenylphosphonium Moiety Modulates Proteolytic Stability and Potentiates Neuroprotective Activity of Antioxidant Tetrapeptides in Vitro

“…PC-12 rat pheochromocytoma cell line (ATTC) and human skin fibroblasts (HSF) were used. HSF were isolated as detailed in ( Tsepaeva et al, 2017 ). The cells were cultured aseptically in α-MEM containing 10% fetal bovine serum (FBS), 2 mM L -glutamine, 100 U/mL penicillin and 100 μg/mL streptomycin at 37°C in humidified air atmosphere with 5% CO 2 .…”

“…The cytotoxicity of the oligopeptides was evaluated in the concentration range from 1 μM to 3.2 mM by means of the MTT proliferation assay in 96-well microplates as described in Tsepaeva et al (2017) . The cell viability was presented as a percentage of control cells grown without compounds (100% viability value).…”

“…Furthermore, conjugation of the TPP cations to various biomolecules, including vitamins, terpenes/terpenoids, polyphenols, antibiotics was also proved to be a promising strategy for generation of effective antimicrobial and anticancer compounds ( Pugachev et al, 2013 ; Strobykina et al, 2015 ; Tsepaeva et al, 2017 ; Zielonka et al, 2017 ). In spite of established importance of the TPP cations as a carrier and pharmacophoric groups, little is known about their effects on the properties of therapeutic peptides.…”

Natural Product Triterpenoids and Their Semi-Synthetic Derivatives with Potential Anticancer Activity

“…As one synthetic approach, the inhibitory effects of (+)-betulin (2) were greatly enhanced on the proliferation of vincristine-resistant MCF-7 human breast cancer cells by introduction of a triphenylphosphonium cation conjugate at the C-28 position to produce 4-oxobutyltriphylphosphonium bromide betulin (3) (▶ Fig. 1), which showed an IC 50 value of 45 nM that was much lower than the positive controls, doxorubicin (IC 50 0.3 µM) and vinblastine (IC 50 9.2 µM) [26]. Another potent cytotoxic agent produced is the chimera derivative, betulastatin 3 [30-N-(Dap-Dil-Val-Dov)-betulin] (4, ▶ Fig.…”

“…5), isolated from the leaves of Panax notoginseng (Birkill) F. H. Chen ex C. H. Chow (Araliaceae) showed cytotoxicity to-ward SW620 human colon cancer cells, with the IC 50 value being less than 5 µM. This sapogenin (26) induced LS174 and SW480 colon and A549 lung human cancer cell apoptosis by suppression of Wnt/β-catenin signaling [90], and it also inhibited t-HSC/Cl-6 murine hepatic stellate cell activation by inducing apoptosis and elevating the level of cellular glutathione, indicating that it exerts an antifibrosis effect on activated t-HSC/Cl-6 cells [91].…”