The Antileukemic Potential of New Derivatives of 5-Fluoro-1H-Indole-2,3-Dione-3-Thiosemicarbazone on in Vitro Cell Lines

Abstract 1H-Indole-2,3-dione (isatin) is an endogenous compound identified in many organisms, possesses a wide range of biological activities. Biological properties of isatin include a range of actions in brain and offer protection against certain types of infections. This molecule has a versatile moiety that displays diverse biological activities, including anticancer activity. The discovery of numerous biologically active 3-substituted 2-indolinones led in the past decade to extensive synthesis of related compounds and as a result, anticancer agents were developed. In particular, among the 5-substituted analogs tested in the growth inhibitions against several human cancer cell lines, 5-halide, methoxy and trifluoromethoxy groups containing 3-substituted 2-indolinones show high antiproliferative effects. For this purpose, we first synthesized twelve 5-fluoro-1H-indole-2,3-dione-3-thiosemicarbazones that antituberculosis activities were shown previously by our teamwork and we researched anticancer drug potential in this study. The cytotoxic effects of twelve thiosemicarbazone derivatives were investigated by MTT assay in chronic myeloid leukemia cell lines (K562, HL60), B-lymphoma cell lines (P3HR1) and in vincristine resistant forms. The IC50 values (IC50 is a concentration that kills 50% of cells) were calculated from dose-response curve according to cytotoxicity index. The effectiveness of thiosemicarbazone derivatives were evaluated by comparing IC50 values in leukemic cell lines. All of the compounds were found cytotoxic in B-lymphoma cell lines (P3HR1, P3HR1Vin) in range 0.95–2.41 μM. However, the allyl derivative of thiosemicarbazones has cytotoxic activity in all the cancer cell lines (K562, K562Vin, HL-60, P3HR1, P3HR1Vin) that were tested. As a result, 5-fluoro-1H-indole-2,3-dione-3-thiosemicarbazones derivates might have chemotherapeutic drug potential in B-lymphoma patients. The allyl derivative of thiosemicarbazones has benefit both B-lymphoma and chronic myeloid leukemia patients in a large spectrum.

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Naphthoquinone-based hydrazone hybrids: synthesis and potent activity against cancer cell lines

Medicinal Chemistry ◽

10.2174/1573406416666200817164308 ◽

2020 ◽

Vol 16 ◽

Author(s):

Délis Galvão Guimarães ◽

Arlan de Assis Gonsalves ◽

Larissa Araújo Rolim ◽

Edigênia Cavalcante Araújo ◽

Victória Laysna dos Anjos Santos ◽

...

Keyword(s):

Anticancer Activity ◽

Cell Lines ◽

Cancer Cell ◽

Biological Activities ◽

Supporting Electrolyte ◽

Cancer Cell Lines ◽

Molecular Structures ◽

Cytotoxic Activities ◽

Electrochemical Studies ◽

Ic50 Values

Background: Natural naphthoquinones have shown diversified biological activities including antibacterial, antifungal, antimalarial, and cytotoxic activities. However, they are also compounds with acute cytotoxicity, immunotoxicity, carcinogenesis, and cardio- and hepatotoxicity, then the modification at their redox center is an interesting strategy to overcome such harmful activity. Objective: In this study, four novel semisynthetic hydrazones, derived from the isomers α- and β-lapachones (α and β, respectively) and coupled with the drugs hydralazine (HDZ) and isoniazid (ACIL), were prepared, evaluated by electrochemical methods and assayed for anticancer activity. Method: The semisynthetic hydrazones were obtained and had their molecular structures established by NMR, IR, and MS. Anticancer activity was evaluated by cell viability determined by reduction of 3-(4,5-dimethyl-2-thiazol)-2,5-diphenyl-2H-tetrazolium bromide (MTT). The electrochemical studies, mainly cyclic voltammetry, were performed, in aprotic and protic media. Result: The study showed that the compounds 2, 3, and 4 were active against at least one of the cancer cell lines evaluated, being compounds 3 and 4 the most cytotoxic. Toward HL-60 cells, compound 3 was 20x more active than β-lapachone, and 3x more cytotoxic than doxorubicin. Furthermore, 3 showed an SI value of 39.62 for HL-60 cells. Compound 4 was active against all cancer cells tested, with IC50 values in the range 2.90–12.40 μM. Electrochemical studies revealed a profile typical of self-protonation and reductive cleavage, dependent on the supporting electrolyte. Conclusion: These results therefore indicate that compounds 3 and 4 are strong candidates as prototypes of new antineoplastic drugs.

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The Pro-Metastasis Tyrosine Phosphatase, PRL-3 (PTP4A3), Is a Novel Target of BCR-ABL Signaling Involved in Human Chronic Myeloid Leukemia

Blood ◽

10.1182/blood.v118.21.2741.2741 ◽

2011 ◽

Vol 118 (21) ◽

pp. 2741-2741

Author(s):

Jianbiao Zhou ◽

Lip-Lee Cheong ◽

Sylvia Mahara ◽

Shaw-Cheng Liu ◽

Phyllis SY Chong ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Cell Lines ◽

Cancer Cell ◽

Myeloid Leukemia ◽

Tyrosine Phosphatase ◽

Cancer Cell Lines ◽

Self Renewal ◽

Downstream Target ◽

Transformed Cell Lines

Abstract Abstract 2741 Chronic myeloid leukemia (CML) is the best and most successful disease model for tyrosine kinase inhibitor (TKI). The mechanism of BCR-ABL leading transformation and signaling transduction networks have been intensively characterized over decades. However, resistance to TKIs remains a challenge in management of patients with CML. A better understanding BCR-ABL signaling network will lead to a better therapy. Here we report the discovery of a novel downstream target of BCR-ABL signalling, PRL-3 (PTP4A3), an oncogenic tyrosine phosphatase. Analysis of CML cancer cell lines and CML patient samples reveals the upregulation of PRL-3. A search of Gene Expression Atlas (http://www.ebi.ac.uk/gxa/gene/ENSG00000184489) identified the expression level of PRL-3 was highest in CML among 950 human cancer cell lines crossing 32 different types of cancers (Dataset code: E-MTAB-37), suggesting a potential role of PRL-3 in CML pathogenesis. Inhibition of BCR-ABL signalling either by Imatinib or by RNAi silencing BRC-ABL in CML cell line K562, KCL-22 and primary patient samples reduces PRL-3, in parallel with suppression of signal transducer and activator of transcription (STAT) pathway activities and increased cleavage of PARP, a hallmark of apoptosis. In contrast, the amount of PRL-3 protein remains constant or even increased in response to Imatinib treatment in drug resistant cells expressing BaF3-P210 T315I. Finally, analysis with specific shRNA demonstrated K562-shPRL-3 (shP) cells proliferated as much as 2-time lesser than K562-shControl (shC) at day 8 (p < 0.001). Colony-forming efficiency is an indicator of self-renewal capacity of leukemic cell. K562-shP cells also showed significantly impaired colony generating capacity by 3-fold compared to K562-shC (p < 0.001). These results indicate a critical role for PRL-3 in CML cell expansion and self-renewal. In summary, the present study demonstrates that PRL-3 is remarkably upregulated in human CML cell lines, BCR-ABL transformed cell lines and primary CML patient samples. Our results highlight that PRL-3 is a novel downstream target of BCR-ABL pathway, which is crucial for BRC-ABL-mediated cell survival and self-renewal. These data support a functionally important role of PRL-3 in CML biology downstream of BCR-ABL and maybe a viable therapeutic target in BCR-ABL positive cells even in those with Imatinib resistant mutations. Disclosures: Off Label Use: Imatinib will be used as a tool to dissect BCR-ABL signaling.

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Biological Activities of Flavonoids from the Wood Extract of Artocarpus heterophyllus L. (Jackfruit)

The Natural Products Journal ◽

10.2174/2210315508666181018103353 ◽

2020 ◽

Vol 10 (3) ◽

pp. 216-225

Author(s):

Hiroyuki Akazawa ◽

Takuro Shinozaki ◽

Motohiko Ukiya ◽

Toshihiro Akihisa ◽

Manosroi Jiradej ◽

...

Keyword(s):

Cell Lines ◽

Cancer Cell ◽

Human Cancer ◽

Biological Activities ◽

Cancer Cell Lines ◽

Human Cancer Cell ◽

Artocarpus Heterophyllus ◽

Human Cancer Cell Lines ◽

Ic50 Values ◽

Wood Extract

Background: Artocarpus heterophyllus L. (Jackfruit) has been used traditionally as treatment for inflammation and cancer. The aim of this study was to isolate compounds from A. heterophyllus wood extract and evaluate their biological activities such as anti-tumor promoting effect on Epstein-Barr virus early antigen induction, melanogenesis inhibitory activity on the B16 mouse melanoma 4A5 cell line and cytotoxic activity against three human cancer cell lines (HL60, A549, SK-BR-3). Methods: A. heterophyllus wood was extracted with n-hexane and methanol. The ethyl acetate soluble- fraction separated from the methanol extract was separated and purified with column chromatography to isolate compounds. The structures of isolated compounds were elucidated with spectroscopic methods. These compounds were evaluated for their biological activities. Results: Thirteen known compounds including four prenylflavonoids were isolated from the wood extracts. Nine flavonoids (2, 3, 5-11) exhibited potent anti-tumor promoting activity with IC50 values of 259-296 molar ratio / 32 pmol TPA. Two flavonoids, Norartocarpetin (6) at concentration of 30 μM and cyanomaclurin (11) at the concentration of 100 μM showed melanin content value of 47.6 % and 80.1 %, respectively. Two prenylflavonoids, cudraflavone B (2) and artocarpin (5), showed cytotoxicity against the human cancer cell lines tested. Cudraflavone B (2) showed cytotoxicity against all three human cancer cell lines whereas artocarpin (5) only exhibited cytotoxicity against two out three cell lines testes. The IC50 values were comparable to or better than cisplatin. Conclusion: From the view point of structure activity relationships of the flavonoids isolated, side chains such as prenyl and 3-methyl-1-butenyl moiety were key for their potent biological activities.

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Phenothiazines Modified with the Pyridine Ring as Promising Anticancer Agents

Life ◽

10.3390/life11030206 ◽

2021 ◽

Vol 11 (3) ◽

pp. 206

Author(s):

Beata Morak-Młodawska ◽

Małgorzata Jeleń ◽

Krystian Pluta

Keyword(s):

Nitrogen Atom ◽

Cell Lines ◽

Cancer Cell ◽

Mechanism Of Action ◽

Anticancer Agents ◽

Pyridine Ring ◽

Current Knowledge ◽

Biological Activities ◽

Cancer Cell Lines ◽

Ic50 Values

Azaphenothiazines are the largest and most perspective group of modified phenothiazines, and they exhibit variety of biological activities. The review sums up the current knowledge on the anticancer activity of isomeric pyridobenzothiazines and dipyridothiazines, which are modified azaphenothiazines with one and two pyridine rings, respectively, against 10 types of cancer cell lines. Some 10-substituted dipyridothiazines and even 10-unsubstituted parent compounds, such as 10H-1,9-diazaphenothiazine and 10H-3,6-diazaphenothiazine, exhibited very potent action with the IC50 values less than 1 µg/mL and 1 µM against selected cancer cell lines. The strength of the anticancer action depends both on the tricyclic ring scaffolds and the substituents at the thiazine nitrogen atom. The review discusses the kind of the substituents, nature of tricyclic ring scaffolds with the location of the azine nitrogen atoms, the types of the cancer cell lines, and the mechanism of action.

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Synthesis, Characterization andIn VitroAnticancer Activity of C-5 Curcumin Analogues with Potential to Inhibit TNF-α-Induced NF-κB Activation

BioMed Research International ◽

10.1155/2014/524161 ◽

2014 ◽

Vol 2014 ◽

pp. 1-10 ◽

Cited By ~ 24

Author(s):

Amit Anthwal ◽

Bandana K. Thakur ◽

M. S. M. Rawat ◽

D. S. Rawat ◽

Amit K. Tyagi ◽

...

Keyword(s):

Colon Cancer ◽

Chronic Myeloid Leukemia ◽

Cell Lines ◽

Cancer Cell ◽

Myeloid Leukemia ◽

Hct116 Cell ◽

Cancer Cell Lines ◽

Curcumin Analogues ◽

Tnf Α ◽

New Compounds

In a search of new compounds active against cancer, synthesis of a series of C-5 curcumin analogues was carried out. The new compounds demonstrated good cytotoxicity against chronic myeloid leukemia (KBM5) and colon cancer (HCT116) cell lines. Further, these compounds were found to have better potential to inhibit TNF-α-induced NF-κB activation in comparison to curcumin, which show their potential to act as anti-inflammatory agents. Some compounds were found to show higher cytotoxicity against cancer cell lines in comparison to curcumin used as standard.

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Microwave-assisted Synthesis of Polymethoxychalcone Mannich Bases and Their Antiproliferative Activity

Letters in Organic Chemistry ◽

10.2174/1570178615666180627110223 ◽

2019 ◽

Vol 16 (2) ◽

pp. 117-121 ◽

Cited By ~ 1

Author(s):

Peipei Han ◽

Wenhua Zhou ◽

Mingxia Chen ◽

Qiuan Wang

Keyword(s):

Cell Lines ◽

Cancer Cell ◽

Antiproliferative Activity ◽

Mannich Base ◽

Cancer Cell Lines ◽

Secondary Amines ◽

Conventional Heating ◽

Microwave Assisted ◽

Ic50 Values ◽

Antiproliferative Activities

A series of eight polymethoxychalcone Mannich base derivatives 2a-2h was synthesized via the microwave-assisted Mannich reaction of natural product 2'-hydroxy-3,4,4',5,6'-pentamethoxychalcone (1) with various secondary amines and formaldehyde. Compared to conventional heating method (80°C), the microwave-assisted method (700W, 65°C) is efficient with short reaction time (0.5-1 h) and good yields (74-88%). The antiproliferative activities of eight Mannich base derivatives were evaluated in vitro on a panel of three human cancer cell lines (Hela, HCC1954 and SK-OV-3) by CCK-8 assay. The results showed that all of the Mannich base derivatives exhibited potential antiproliferative activities on tested cancer cell lines with the IC50 values of 9.13-48.51 µM. Some active compounds exhibited more activity as compared to positive control cis-Platin. Among them, compound 2b revealed to have the strongest antiproliferative activity against all the three cancer cell lines with IC50 values ranging from 9.13 to 11.24 µM.

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Design, Synthesis and Biological Evaluation: 5-amino-1H-pyrazole-1- carbonyl derivatives as FGFR Inhibitors

Letters in Drug Design & Discovery ◽

10.2174/1570180817999200608140628 ◽

2020 ◽

Vol 17 (11) ◽

pp. 1330-1341

Author(s):

Yan Zhang ◽

Niefang Yu

Keyword(s):

Cancer Cells ◽

Cell Lines ◽

Cancer Cell ◽

Cancer Cell Lines ◽

Biological Evaluation ◽

Human Gastric Cancer ◽

Design Synthesis ◽

Carbonyl Derivatives ◽

Ic50 Values ◽

Inhibitory Activities

Background: Fibroblast growth factors (FGFs) and their high affinity receptors (FGFRs) play a major role in cell proliferation, differentiation, migration, and apoptosis. Aberrant FGFR signaling pathway might accelerate development in a broad panel of malignant solid tumors. However, the full application of most existing small molecule FGFR inhibitors has become a challenge due to the potential target mutation. Hence, it has attracted a great deal of attention from both academic and industrial fields for hunting for novel FGFR inhibitors with potent inhibitory activities and high selectivity. Objective: Novel 5-amino-1H-pyrazole-1-carbonyl derivatives were designed, synthesized, and evaluated as FGFR inhibitors. Methods: A series of 5-amino-1H-pyrazole-1-carbonyl derivatives were established by a condensation of the suitable formyl acetonitrile derivatives with either hydrazine or hydrazide derivatives in the presence of anhydrous ethanol or toluene. The inhibitory activities of the target compounds were screened against the FGFRs and two representative cancer cell lines. Tests were carried out to observe the inhibition of 8e against FGFR phosphorylation and downstream signal phosphorylation in human gastric cancer cell lines (SNU-16). The molecular docking of all the compounds were performed using Molecular Operating Environment in order to evaluate their binding abilities with the corresponding protein kinase. Results: A series of 5-amino-1H-pyrazole-1-carbonyl derivatives have been designed and synthesized, screened for their inhibitory activities against FGFRs and cancer cell lines. Most of the target compounds showed moderate to good anti-proliferate activities against the tested enzymes and cell lines. The most promising compounds 8e suppressed FGFR1-3 with IC50 values of 56.4, 35.2, 95.5 nM, and potently inhibited the SNU-16 and MCF-7 cancer cells with IC50 values of 0.71 1.26 μM, respectively. And 8e inhibited the growth of cancer cells containing FGFR activated by multiple mechanisms. In addition, the binding interactions were quite similar in the molecular models between generated compounds and Debio-1347 with the FGFR1. Conclusion: According to the experimental findings, 5-amino-1H-pyrazole-1-carbonyl might serve as a promising template of an FGFR inhibitor.

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Use of Half-Generation PAMAM Dendrimers (G0.5–G3.5) with Carboxylate End-Groups to Improve the DACHPtCl2 and 5-FU Efficacy as Anticancer Drugs

Molecules ◽

10.3390/molecules26102924 ◽

2021 ◽

Vol 26 (10) ◽

pp. 2924

Author(s):

Cláudia Camacho ◽

Helena Tomás ◽

João Rodrigues

Keyword(s):

Cancer Cells ◽

Cell Lines ◽

Cancer Cell ◽

Anticancer Drug ◽

Water Solubility ◽

Cancer Cell Lines ◽

Pamam Dendrimers ◽

Binding Assays ◽

End Groups ◽

Ic50 Values

The DACHPtCl2 compound (trans-(R,R)-1,2-diaminocyclohexanedichloroplatinum(II)) is a potent anticancer drug with a broad spectrum of activity and is less toxic than oxaliplatin (trans-l-diaminocyclohexane oxalate platinum II), with which it shares the active metal fragment DACHPt. Nevertheless, due to poor water solubility, its use as a chemotherapeutic drug is limited. Here, DACHPtCl2 was conjugated, in a bidentate form, with half-generation PAMAM dendrimers (G0.5–G3.5) with carboxylate end-groups, and the resulting conjugates were evaluated against various types of cancer cell lines. In this way, we aimed at increasing the solubility and availability at the target site of DACHPt while potentially reducing the adverse side effects. DNA binding assays showed a hyperchromic effect compatible with DNA helix’s disruption upon the interaction of the metallodendrimers and/or the released active metallic fragments with DNA. Furthermore, the prepared DACHPt metallodendrimers presented cytotoxicity in a wide set of cancer cell lines used (the relative potency regarding oxaliplatin was in general high) and were not hemotoxic. Importantly, their selectivity for A2780 and CACO-2 cancer cells with respect to non-cancer cells was particularly high. Subsequently, the anticancer drug 5-FU was loaded in a selected metallodendrimer (the G2.5COO(DACHPt)16) to investigate a possible synergistic effect between the two drugs carried by the same dendrimer scaffold and tested for cytotoxicity in A2780cisR and CACO-2 cancer cell lines. This combination resulted in IC50 values much lower than the IC50 for 5-FU but higher than those found for the metallodendrimers without 5-FU. It seems, thus, that the metallic fragment-induced cytotoxicity dominates over the cytotoxicity of 5-FU in the set of considered cell lines.

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Synthesis and Biological Activities of Cyclodepsipeptides of Aurilide Family from Marine Origin

Marine Drugs ◽

10.3390/md19020055 ◽

2021 ◽

Vol 19 (2) ◽

pp. 55

Author(s):

Synthia Michon ◽

Florine Cavelier ◽

Xavier J. Salom-Roig

Keyword(s):

Cell Lines ◽

Cancer Cell ◽

Biological Activities ◽

Natural Compounds ◽

Cancer Cell Lines ◽

Hydroxy Ester ◽

Marine Cyanobacteria ◽

Synthetic Analogues ◽

Marine Origin ◽

Total Syntheses

Aurilides are a class of depsipeptides occurring mainly in marine cyanobacteria. Members of the aurilide family have shown to exhibit strong cytotoxicity against various cancer cell lines. These compounds bear a pentapeptide, a polyketide, and an α-hydroxy ester subunit in their structure. A large number of remarkable studies on aurilides have emerged since 1996. This comprehensive account summarizes the biological activities and total syntheses of natural compounds of the aurilide family as well as their synthetic analogues.

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Design, Synthesis, and Antitumor Activity of Olmutinib Derivatives Containing Acrylamide Moiety

Molecules ◽

10.3390/molecules26103041 ◽

2021 ◽

Vol 26 (10) ◽

pp. 3041

Author(s):

Xiaohan Hu ◽

Sheng Tang ◽

Feiyi Yang ◽

Pengwu Zheng ◽

Shan Xu ◽

...

Keyword(s):

Antitumor Activity ◽

Cell Lines ◽

Cancer Cell ◽

Antitumor Agents ◽

Cancer Cell Lines ◽

Design Synthesis ◽

Structure Activity ◽

Excellent Activity ◽

Ic50 Values ◽

Mcf 7

Two series of olmutinib derivatives containing an acrylamide moiety were designed and synthesized, and their IC50 values against cancer cell lines (A549, H1975, NCI-H460, LO2, and MCF-7) were evaluated. Most of the compounds exhibited moderate cytotoxic activity against the five cancer cell lines. The most promising compound, H10, showed not only excellent activity against EGFR kinase but also positive biological activity against PI3K kinase. The structure–activity relationship (SAR) suggested that the introduction of dimethylamine scaffolds with smaller spatial structures was more favorable for antitumor activity. Additionally, the substitution of different acrylamide side chains had different effects on the activity of compounds. Generally, compounds H7 and H10 were confirmed as promising antitumor agents.

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