Synthesis and Biological Evaluation of BODIPY-PF-543

Shrestha, Jitendra; Hwang, Gil Tae; Lee, Tae‐Ho; Kim, Seon Woong; Oh, Yoon Sin; Kwon, Yongseok; Hong, Seung Woo; Kim, Sanghee; Moon, Hong Seop; Baek, Dong Jae; Park, Eun‐Young

doi:10.3390/molecules24234408

Cited by 8 publications

(10 citation statements)

References 25 publications

(28 reference statements)

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“…Compound 12 with a phenyl tail and compound 13 with an aliphatic tail were synthesized using compound 11 as a starting material by a click reaction and a known synthesis method [ 24 ]. Compounds 14 and 15 , into which an aldehyde was introduced, were synthesized through the reaction of compounds 12 and 13 with potassium carbonate (base), respectively.…”

Section: Resultsmentioning

confidence: 99%

Synthesis of PP2A-Activating PF-543 Derivatives and Investigation of Their Inhibitory Effects on Pancreatic Cancer Cells

Kim

et al. 2022

Molecules

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Sphingosine kinase (SK) is involved in the growth of cells, including cancer cells. However, which of its two isotypes—SK1 and SK2—is more favorable for cancer growth remains unclear. Although PF-543 strongly and selectively inhibits SK1, its anticancer effect is not high, and the underlying reason remains difficult to explain. We previously determined that the tail group of PF-543 is responsible for its low metabolic stability (MS). In this study, compounds containing aromatic or aliphatic tails in the triazole group were synthesized, and changes in the SK-inhibitory effect and anticancer activity of PF-543 were assessed using pancreatic cancer cells. The compounds with aliphatic tails showed high inhibitory effects on pancreatic cancer cells but slightly lower selectivity for SK1. A compound with an introduced aliphatic tail activated protein phosphatase 2A (PP2A), showing an effect similar to that of FTY720. Molecular docking analysis revealed that the PP2A-binding form of this newly synthesized compound was different from that noted in the case of FTY720. This compound also improved the MS of PF-543. These results indicate that the tail structure of PF-543 influences MS.

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Section: Resultsmentioning

confidence: 99%

Synthesis of PP2A-Activating PF-543 Derivatives and Investigation of Their Inhibitory Effects on Pancreatic Cancer Cells

Kim

et al. 2022

Molecules

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“…2.1.2. Chemical Synthesis (12)(13)(14)(15)(16) 4-(2-(Trityloxy)ethyl)phenol ( 12) ABC294640 (Opaganib, Apogee Biotech.) is a substance that exhibits anticancer activity by selectively inhibiting SK2 and is currently undergoing phase 2 clinical trials in various solid cancers (Figure 1) [8].…”

Section: Synthesis In Generalmentioning

confidence: 99%

“…High-resolution mass spectra were measured using an Agilent Technologies G6520A Q-TOF mass spectrometer (Santa Clara, CA, USA) using electrospray ionization (ESI). (12)(13)(14)(15)(16) 4-(2-(Trityloxy)ethyl)phenol (12) To a solution of 4-(2-hydroxyethyl)phenol (1 g, 0.007 mol) and 4-dimethylaminopyridine (DMAP) (88 mg, 0.72 mmol) in CH 2 Cl 2 /pyridine (1/2, 100 mL) was added trityl chloride (2 g, 0.007 mol) at rt. After the reaction, the mixture was stirred at room temperature for 1 d, and the mixture was extracted with EtOAc.…”

Section: Chemistry 211 Synthesis In Generalmentioning

confidence: 99%

Determining the Anticancer Activity of Sphingosine Kinase Inhibitors Containing Heteroatoms in Their Tail Structure

Shrestha

Kim

et al. 2022

Pharmaceutics

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Sphingosine kinase (SK) enzyme, a central player of sphingolipid rheostat, catalyzes the phosphorylation of sphingosine to the bioactive lipid mediator sphingosine 1 phosphate (S1P), which regulates cancer cell proliferation, migration, differentiation, and angiogenesis through its extracellular five G protein-coupled S1P receptors (S1PR1–5). Recently, several research studies on SK inhibitors have taken place in order use them for the development of novel anticancer-targeted therapy. In this study, we designed and synthesized analog derivatives of known SK1 inhibitors, namely RB005 and PF-543, by introducing heteroatoms at their tail structure, as well as investigated their anticancer activities and pharmacokinetic parameters in vitro. Compounds 1–20 of RB005 and PF-543 derivatives containing an aliphatic chain or a tail structure of benzenesulfonyl were synthesized. All compounds of set 1 (1–10) effectively reduced cell viability in both HT29 and HCT116 cells, whereas set 2 derivatives (11–20) showed poor anticancer effect. Compound 10, having the highest cytotoxic effect (48 h, HT29 IC50 = 6.223 µM, HCT116 IC50 = 8.694 µM), induced HT29 and HCT116 cell death in a concentration-dependent manner through the mitochondrial apoptotic pathway, which was demonstrated by increased annexin V-FITC level, and increased apoptotic marker cleaved caspase-3 and cleaved PARP. Compound 10 inhibited SK1 by 20%, and, thus, the S1P level decreased by 42%. Unlike the apoptosis efficacy, the SK1 inhibitory effect and selectivity of the PF-543 derivative were superior to that of the RB005 analog. As a result, compounds with an aliphatic chain tail exhibited stronger apoptotic effects. However, this ability was not proportional to the degree of SK inhibition. Compound 10 increased the protein phosphatase 2A (PP2A) activity (1.73 fold) similar to FTY720 (1.65 fold) and RB005 (1.59 fold), whereas compounds 11 and 13 had no effect on PP2A activation. Since the PP2A activity increased in compounds with an aliphatic chain tail, it can be suggested that PP2A activation has an important effect on anticancer and SK inhibitory activities.

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“…The studies showed that the cell viabilities were about 60% in the presence of BODIPY-PF-543 at 40 μM for 24 h. These results indicated that BODIPY-PF-543 has more cytotoxic effect than our compounds (BDPY-4 and BDPY-5). [33] 4 | CONCLUSION…”

Section: Cytotoxicity/phototoxicity Experimentsmentioning

confidence: 99%

Synthesis of water‐soluble BODIPY dyes and investigation of their DNA interaction properties and cytotoxicity/phototoxicity

Keleş

Barut

Yıldırım

et al. 2021

Applied Organom Chemis

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In this study, water‐soluble BODIPY dyes (BDPY‐4, BDPY‐5) bearing dimethylamino and diethylamino groups were synthesized for the first time. The DNA interaction and nuclease effect of two water‐soluble BODIPY dyes were examined using absorption, competitive binding experiments, and agarose gel electrophoresis. Then, cytotoxicity and phototoxicity of the compounds were determined against A549 cells by MTT cell viability assay. The ultraviolet–visible (UV–vis) spectra of BDPY‐4 and BDPY‐5 displayed hypochromism and absorption maxima shifted to the red region. In addition, Kb values of the compounds were calculated as 2.23 × 104 and 4.84 × 104 M−1, respectively. An high‐performance liquid chromatography (HPLC) instrument without a column was used to conduct competitive binding experiments for the first time. The approach prevented the decrease in the response due to dilution and enabled the analysis to be carried out in a short time. Upon increasing concentrations of the compounds, the emission intensity of EB‐DNA significantly decreased. These obtained results suggested that the compounds bound to CT‐DNA with intercalative mode. At the same time, the Stern–Volmer constants were determined as 1.80 × 106 and 1.79 × 106 M−1 for BDPY‐4 and BDPY‐5, respectively, which is coherent with intercalative binding mode. The compounds did not display noticeable photonuclease actions with light irradiation. BDPY‐4 and BDPY‐5 showed moderate phototoxic properties on light irradiation.

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Synthesis and Biological Evaluation of BODIPY-PF-543

Cited by 8 publications

References 25 publications

Synthesis of PP2A-Activating PF-543 Derivatives and Investigation of Their Inhibitory Effects on Pancreatic Cancer Cells

Synthesis of PP2A-Activating PF-543 Derivatives and Investigation of Their Inhibitory Effects on Pancreatic Cancer Cells

Determining the Anticancer Activity of Sphingosine Kinase Inhibitors Containing Heteroatoms in Their Tail Structure

Synthesis of water‐soluble BODIPY dyes and investigation of their DNA interaction properties and cytotoxicity/phototoxicity

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