Synthesis and Evaluation of New Pyrazoline Derivatives as Potential Anticancer Agents

Karabacak, Muhammed; Altıntop, Mehlika Dilek; Çiftçi, Halil; Koga, Ryoko; Otsuka, Masami; Fujita, Mikako; Özdemir, Ahmet

doi:10.3390/molecules201019066

Cited by 80 publications

(43 citation statements)

References 41 publications

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“…27,28) Cells were cultured in the presence of various concentrations of the tested compounds for 24 h. Cells were then stained with MTT solution and incubated for an additional 4 h at 37°C. The solution was removed and the formazan crystals were solubilized by adding 100 µL DMSO.…”

Section: Cytotoxicitymentioning

confidence: 99%

The First Pentacyclic Triterpenoid Gypsogenin Derivative Exhibiting Anti-ABL1 Kinase and Anti-chronic Myelogenous Leukemia Activities

Çiftçi

Öztürk

Ali

et al. 2018

Biological & Pharmaceutical Bulletin

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SummaryThe discovery of the chimeric tyrosine kinase breakpoint cluster region kinase-Abelson kinase (BCR-ABL)-targeted drug imatinib conceptually changed the treatment of chronic myelogenous leukemia (CML). However, some CML patients show drug resistance to imatinib. To address this issue, some artificial heterocyclic compounds have been identified as BCR-ABL inhibitors. Here we examined whether plant-derived pentacyclic triterpenoid gypsogenin and/or their derivatives show inhibitory activity against BCR-ABL. Among the three derivatives, benzyl 3-hydroxy-23-oxoolean-12-en-28-oate (1c) was found to be the most effective anticancer agent on the CML cell line K562, with an IC 50 value of 9.3 µM. In contrast, the IC 50 against normal peripheral blood mononuclear cells was 276.0 µM, showing better selectivity than imatinib. Compound 1c had in vitro inhibitory activity against Abelson kinase 1 (ABL1) (IC 50 =8.7 μM), the kinase component of BCR-ABL. In addition, compound 1c showed a different inhibitory profile against eight kinases compared with imatinib. The interaction between ATP binding site of ABL and 1c was examined by molecular docking study, and the binding mode was different from imatinib and newer generation inhibitors. Furthermore, 1c suppresses signaling downstream of BCR-ABL. This study suggests the possibility that plant extracts may be a source for CML treatment and offer a strategy to overcome drug resistance to known BCR-ABL inhibitors. KeywordsGypsogenin, Abelson tyrosine-protein kinase 1, chronic myelogenous leukemia Biological and Pharmaceutical Bulletin Advance PublicationCancer is a worldwide health problem, and despite intensive research efforts over the last several decades, an effective cure has not been identified. 1)However, the recent discovery of molecular targeted drugs against cancer at the end of the 20 th century has led to promising results. 1,2) Imatinib (Fig. 1), which targets the chimeric tyrosine kinase breakpoint cluster region kinase-Abelson kinase (BCR-ABL), [3][4][5][6] was discovered based on the findings that chronic myelogenous leukemia (CML) is caused by a chromosomal translocation that results in the constitutively expressed and active BCR-ABL. 7,8) While imatinib can be initially effective in treating CML, some patients have shown drug resistance to imatinib. [9][10][11] Several new generation drugs with a different binding mode to Abelson kinase (ABL) have thus been developed. 6,[12][13][14][15][16] These drugs are artificial heterocyclic compounds, however, if widely distributed natural products and/or their derivatives show the inhibitory activity against BCR-ABL, it would be more convenient to get.Pentacyclic triterpenoids, a category of natural compounds, can be extracted from a variety of plants and show various activities. 17,18) Some of these triterpenoids were reported to exhibit anti-tyrosine kinase activity. 19,20) Here we focused on a pentacyclic triterpenoid gypsogenin, 21,22) extracted from Gypsophila species, 23,24) which is widely distributed in the Eu...

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Section: Cytotoxicitymentioning

confidence: 99%

The First Pentacyclic Triterpenoid Gypsogenin Derivative Exhibiting Anti-ABL1 Kinase and Anti-chronic Myelogenous Leukemia Activities

Çiftçi

Öztürk

Ali

et al. 2018

Biological & Pharmaceutical Bulletin

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“…Carbon atom No. 5 in heterocyclic ring is deviated from the almost planar system of the other four atoms of the ring [6].…”

Section: Introductionmentioning

confidence: 92%

Synthesis and antimicrobial activity of some new pyrazoline derivatives bearing sulfanilamido moiety

2019

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In the present study, a series of new pyrazoline derivatives bearing sulfanilamido moiety were synthesized and obtained in good yields. The chemical structures of the compounds were elucidated by spectral data (FT-IR, MS, UV-VIS and NMR). The synthesized compounds 41-70 were screened for their antimicrobial activity and compared with controls. The in vitro antibacterial activity of compounds 41-45 and 48-57 was checked against two Gram positive microorganisms (S. aureus and S. mutans) and three Gram negative microorganisms (E. coli, K. pneumonia and P. aureginosa), their antifungal activity was checked against C. albicans. The preliminary results showed that these compounds had moderate activity against the tested organisms. Compounds 41, 48, 51 and 56 exhibited promising antimicrobial activity against S. aureus compared to standard drug Ampicilin. Final synthesized compounds 58-70 were tested against two Gram positive (S. aureus and B. subtilis) and two Gram negative (E. coli and P. aureginosa) microorganisms, their activity against C. albicans was also checked and they did not exhibit any antimicrobial activity.

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“…Several pyrazolines act as anticancer agents, and tumor inhibitors . Pyrazoline derivatives are important nitrogen containing compounds and have wide range of biological activity including anti‐inflammatory and analgesic activity, anticancer, antibacterial activities due to their pyrazole motif. These derivatives are also well established potential chemotherapeutic agents .…”

Section: Introductionmentioning

confidence: 99%

Deciphering Block Copolymers as Carriers of a Pyrazoline Derivative through Its Solvatochromic Behavior: A Spectroscopic and Theoretical Exploration

et al. 2018

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Many biologically active water‐insoluble drug molecules have limited clinical application because of strong hydrophobicity. Recently triblock copolymers have attracted enormous interest as potential drug carriers. For the purpose of delivering the 5‐(1‐(bromohexa‐1,3,5‐triyn‐1‐yl)‐3a,4,5,6,7,7a‐hexahydro‐1H‐4,7‐methanoindazol‐3‐yl)‐3‐methyl‐1‐phenyl‐1H‐pyrazole‐4‐carbonitrile (PYZ) molecule, triblock copolymers are used. In order to understand the delivery of this water‐insoluble probe through triblock copolymers (TBP), the solvent‐dependent fluorescence properties of this compound have been examined in different homogeneous solvents. Besides the experimental work, theoretical studies have also been conducted to explain actual orientation of atoms in PYZ through optimized structures to support the experimental findings. Moreover, the three TBP polymers P‐123 (PEO19PPO69PEO19), F‐127 (PEO100PPO65PEO100) and L‐64 (PEO13PPO30PEO13) have been treated here as potential carriers that encapsulate a pyrazoline derivative. The consequence of spatial captivity on the emission properties was systematically visualized by means of steady‐state and time‐resolved fluorescence spectroscopy. From DLS measurements the size variation with the polydispersity index of TBP in the presence and absence of PYZ in different triblock copolymers was also monitored. Furthermore these measurements have been supported by TEM imaging also.

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Synthesis and Evaluation of New Pyrazoline Derivatives as Potential Anticancer Agents

Cited by 80 publications

References 41 publications

The First Pentacyclic Triterpenoid Gypsogenin Derivative Exhibiting Anti-ABL1 Kinase and Anti-chronic Myelogenous Leukemia Activities

The First Pentacyclic Triterpenoid Gypsogenin Derivative Exhibiting Anti-ABL1 Kinase and Anti-chronic Myelogenous Leukemia Activities

Synthesis and antimicrobial activity of some new pyrazoline derivatives bearing sulfanilamido moiety

Deciphering Block Copolymers as Carriers of a Pyrazoline Derivative through Its Solvatochromic Behavior: A Spectroscopic and Theoretical Exploration

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