Design, Synthesis and Evaluation of New Bioactive Oxadiazole Derivatives as Anticancer Agents Targeting Bcl-2

A series of 2-(1H-indol-3-yl)-5-substituted-1,3,4-oxadiazoles, 4a–m, were designed, synthesized and tested in vitro as potential pro-apoptotic Bcl-2 inhibitory anticancer agents based on our previously reported hit compounds. Synthesis of the target 1,3,4-oxadiazoles was readily accomplished through a cyclization reaction of indole carboxylic acid hydrazide 2 with substituted carboxylic acid derivatives 3a–m in the presence of phosphorus oxychloride. New compounds 4a–m showed a range of IC50 values concentrated in the low micromolar range selectively in Bcl-2 positive human cancer cell lines. The most potent candidate 4-trifluoromethyl substituted analogue 4j showed selective IC50 values of 0.52–0.88 μM against Bcl-2 expressing cell lines with no inhibitory effects in the Bcl-2 negative cell line. Moreover, 4j showed binding that was two-fold more potent than the positive control gossypol in the Bcl-2 ELISA binding affinity assay. Molecular modeling studies helped to further rationalize anti-apoptotic Bcl-2 binding and identified compound 4j as a candidate with drug-like properties for further investigation as a selective Bcl-2 inhibitory anticancer agent.

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Design, Synthesis and Characterization of Novel Amine Derivatives of 5-[5-(Chloromethyl)-1, 3, 4-Oxadiazol-2-yl]- 2-(4-Fluorophenyl)-Pyridine as a New Class of Anticancer Agents

Dhaka University Journal of Pharmaceutical Sciences ◽

10.3329/dujps.v16i1.33377 ◽

2017 ◽

Vol 16 (1) ◽

pp. 11-19 ◽

Cited By ~ 1

Author(s):

Adimule Vinayak ◽

Medapa Sudha ◽

Kumar S Lalita

Keyword(s):

Cell Lines ◽

Anticancer Agents ◽

Human Cancer ◽

Secondary Amines ◽

Design Synthesis ◽

Human Cancer Cell Lines ◽

Ic50 Values ◽

High Cytotoxicity ◽

Hepg2 Cell Lines

A linear strategy was adopted in synthesizing the novel amine derivatives 7(a-h) of 5-[5- (chloromethyl)-1, 3, 4-oxadiazol-2-yl]-2-(4-fluorophenyl)-pyridine (6) and screened these compounds for in vitro anticancer activity against three human cancer cell lines (HeLa,Caco-2 and HepG2). The synthesised novel compounds were characterized by 1H NMR, MS and 13C NMR spectroscopic evidences. Microwave irradiation of compound (5) in presence of chloroacetyl chloride and phosphoryl oxychloride yielded the dehydrated cyclized key intermediate 5-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]-2-(4-fluorophenyl)-pyridine which upon treatment with various primary or secondary amines (a-h) resulted into the corresponding amine derivatives. The IC50 values of the final compounds were compared with that of 5-fluorouracil (5-FU) taken as the standard. Compounds 7a and 7d were found to be highly cytotoxic against HepG2 cell lines with IC50 values of 2.6 ?M (IC50 = 34.0 ± 0.5 ?M) and 5.8 ?M (IC50 = 112 ± 1.4 ?M) respectively. The compound (7f) alone was found to have high cytotoxicity against Caco-2 cell lines with IC50 value of 2.3 ?M (IC50 = 87 ± 2.6 ?M).Dhaka Univ. J. Pharm. Sci. 16(1): 11-19, 2017 (June)

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Six New neo-Clerodane Diterpenoids from Aerial Parts of Scutellaria barbata and Their Cytotoxic Activities

Planta Medica ◽

10.1055/a-0638-8255 ◽

2018 ◽

Vol 84 (17) ◽

pp. 1292-1299 ◽

Cited By ~ 9

Author(s):

Guo-Chun Yang ◽

Jia-Hui Hu ◽

Bing-Long Li ◽

Huan Liu ◽

Jia-Yue Wang ◽

...

Keyword(s):

Cell Lines ◽

Human Cancer ◽

In Vitro Cytotoxicity ◽

Cytotoxic Activities ◽

Scutellaria Barbata ◽

Human Cancer Cell Lines ◽

Aerial Parts ◽

Ic50 Values ◽

Clerodane Diterpenoids

AbstractSix new neo-clerodane diterpenoids (1–6), scutebatas X – Z, A1-C1, along with twelve known ones (7–18) were obtained via the phytochemical investigation of the aerial parts of Scutellaria barbata. Their structures were established by detailed spectroscopic analysis. The absolute configurations of 1 and 2, as the representative members of this type, were identified based on a circular dichroic exciton chirality method. Moreover, in vitro cytotoxicity of compounds 1–6 were evaluated against three human cancer cell lines (SGC-7901, MCF-7, and A-549) using the MTT method. Compound 6 showed cytotoxic activities against all the three cell lines with IC50 values of 17.9, 29.9, and 35.7 µM, respectively.

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Structurally Simple Phenanthridine Analogues Based on Nitidine and Their Antitumor Activities

Molecules ◽

10.3390/molecules24030437 ◽

2019 ◽

Vol 24 (3) ◽

pp. 437

Author(s):

Shu-Qin Qin ◽

Lian-Chun Li ◽

Jing-Ru Song ◽

Hai-Yun Li ◽

Dian-Peng Li

Keyword(s):

Anticancer Agents ◽

Human Cancer ◽

A549 Cells ◽

Anticancer Activities ◽

Human Cancer Cell Lines ◽

Ic50 Value ◽

Ic50 Values ◽

Diphenyl Tetrazolium Bromide ◽

Conjugated Compounds

A series of novel structurally simple analogues based on nitidine was designed and synthesized in search of potent anticancer agents. The antitumor activity against human cancer cell lines (HepG2, A549, NCI-H460, and CNE1) was performed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay in vitro. The results showed that some of them had good anticancer activities, especially derivatives with a [(dimethylamino)ethyl]amino side chain in the C-6 position. Planar conjugated compounds 15a, 15b, and 15c, with IC50 values of 1.20 μM, 1.87 μM, and 1.19 μM against CNE1 cells, respectively, were more active than nitidine chloride. Compound 15b and compound 15c with IC50 values of 1.19 μM and 1.37 μM against HepG2 cells and A549 cells demonstrated superior activities to nitidine. Besides, compound 5e which had a phenanthridinone core displayed extraordinary cytotoxicity against all test cells, particularly against CNE1 cells with the IC50 value of 1.13 μM.

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Design, Synthesis, and Molecular Docking Study of Novel Heterocycles Incorporating 1,3,4-Thiadiazole Moiety as Potential Antimicrobial and Anticancer Agents

Molecules ◽

10.3390/molecules24061066 ◽

2019 ◽

Vol 24 (6) ◽

pp. 1066 ◽

Cited By ~ 10

Author(s):

Mohamed El-Naggar ◽

Hanan A. Sallam ◽

Safaa S. Shaban ◽

Salwa S. Abdel-Wahab ◽

Abd El-Galil E. Amr ◽

...

Keyword(s):

Molecular Docking ◽

Cell Lines ◽

Anticancer Agents ◽

Human Cancer ◽

Docking Study ◽

Molecular Docking Study ◽

Reference Drug ◽

Human Cancer Cell Lines ◽

Dhfr Inhibitors

A new series of 5-(3,5-dinitrophenyl)-1,3,4-thiadiazole derivatives were prepared and evaluated for their in vitro antimicrobial, antitumor, and DHFR inhibition activity. Compounds 9, 10, 13, and 16 showed strong and broad-spectrum antimicrobial activity comparable to Amoxicillin and Fluconazole as positive antibiotic and antifungal controls, respectively. Compounds 6, 14, and 15 exhibited antitumor activity against four human cancer cell lines, CCRF-CEM leukemia, HCT-15 colon, PC-3 prostate, and UACC-257 melanoma cell lines using Doxorubicin as a reference drug. Compounds 10, 13, 14, and 15 proved to be the most active DHFR inhibitors with an IC50 range of 0.04 ± 0.82–1.00 ± 0.85 µM, in comparison with Methotrexate (IC50 = 0.14 ± 1.38 µM). The highly potent DHFR inhibitors shared a similar molecular docking mode and made a critical hydrogen bond and arene‒arene interactions via Ser59 and Phe31 amino acid residues, respectively.

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Synthesis of Novel Benzamide- piperazine-sulfonamide Hybrids as Potential Anticancer Agents

Croatica Chemica Acta ◽

10.5562/cca3535 ◽

2019 ◽

Vol 92 (3) ◽

pp. 393-402

Author(s):

B. Ramalingeswara Rao ◽

Mohana Rao Katiki ◽

Dileep Kommula ◽

SaiShyam Narayanan ◽

Ruby John Anto ◽

...

Keyword(s):

Anticancer Agents ◽

Human Cancer ◽

In Vitro Cytotoxicity ◽

Sensitive Cell Line ◽

Human Cancer Cell Lines ◽

Ic50 Values ◽

Different Origins ◽

New Compounds ◽

A549 Lung

The synthesis of a series of substituted hippuric acid (2-benzamidoacetic acid) derivatives containing arylsulfonylpiperazine nucleus (3a–j, 4a–j) is described. The compounds were synthesized by coupling hippuric/4-fluorohippuric acid with various arylsulfonylpiperazines using N-(3-dimethylaminopropyl)-N-ethylcarbodiimide (EDCI). The structures of all the new compounds were confirmed by IR, NMR and MS spectral data. All the synthesized compounds have been evaluated for their in vitro cytotoxicity towards five human cancer cell lines of different origins viz. HeLa (Cervical), A549 (Lung), A375 (Skin), MD-AMB-231(Breast) and T98G (brain) and their IC50 values were determined. Among the compounds tested, 3b, 3d, 3g, 4c and 4e displayed significant cytotoxic activity (IC50 = 24.2–38.2 µM). T98G was the most sensitive cell line towards the compounds studied followed by HeLa, A375, A549 and MD-AMB-231.

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Design, Synthesis and Biological Evaluation of a Novel Series of Thiadiazole-Based Anticancer Agents as Potent Angiogenesis Inhibitors

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520621666201231143535 ◽

2020 ◽

Vol 21 ◽

Author(s):

Burcugül Altuğ-Tasa ◽

Betül Kaya-Çavuşoğlu ◽

Ayşe T. Koparal ◽

Gülhan Turan ◽

Ali S. Koparal ◽

...

Keyword(s):

Cell Line ◽

Cell Lines ◽

Anticancer Agents ◽

Human Cancer ◽

Biological Evaluation ◽

Tube Formation ◽

In Vivo Studies ◽

Human Cancer Cell Lines ◽

Ic50 Values

Background: Thiadiazole has attracted a great deal of interest as a versatile heterocycle for the discovery and development of potent anticancer agents. Thiadiazole derivatives exert potent antitumor activity against a variety of human cancer cell lines through various mechanisms. Objective: The goal of this work was to design and synthesize thiadiazole-based anticancer agents with anti-angiogenic activity. Methods: N-aryl-2-[(5-(aryl)amino-1,3,4-thiadiazol-2-yl)thio]acetamides (4a-r) were synthesized via the reaction of 5-(aryl)amino-1,3,4- thiadiazole-2(3H)-thiones with N-(aryl)-2-chloroacetamides in the presence of potassium carbonate. The compounds were investigated for their cytotoxic effects on three cancer (A549, HepG2, SH-SY5Y), two normal (HUVEC and 3T3-L1) cell lines using MTT and WST1 assays. In order to examine whether the compounds have anti-angiogenic effects or not, HUVEC were cultured on matrigel matrix to create a vascular-like tube formation. Results: Compounds 4d, 4m and 4n were more effective on A549 human lung adenocarcinoma cells than cisplatin. The IC50 values of compounds 4d, 4m and 4n for A549 cell line were found to be 7.82±0.4, 12.5±0.22, 10.1±0.52 µM, respectively when compared with cisplatin (IC50= 20±0.51 µM), whilst their IC50 values for HUVEC cell line were determined as 138.7±0.84, 78±0.44, 177.6±0.2 µM, respectively after 48 h treatment. The concentrations (10-20-50 µM) of compounds 4d, 4e, 4l, 4m, 4n, 4q and 4r were found to inhibit vascular like tube formation. Conclusion: According to their anticancer and anti-angiogenic effects, compounds 4d, 4m and 4n may be potential anticancer agents for further in vivo studies.

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Two New Cytotoxic Steroidal Alkaloids from Sarcococca Hookeriana

Molecules ◽

10.3390/molecules24010011 ◽

2018 ◽

Vol 24 (1) ◽

pp. 11 ◽

Cited By ~ 1

Author(s):

Shaojie Huo ◽

Jichun Wu ◽

Xicheng He ◽

Lutai Pan ◽

Jiang Du

Keyword(s):

Cell Lines ◽

Human Cancer ◽

Cytotoxic Activities ◽

Steroidal Alkaloids ◽

X Ray ◽

Human Cancer Cell Lines ◽

X Ray Crystallography ◽

Ic50 Values ◽

Mcf 7

Two new steroidal alkaloids, named hookerianine A (1) and hookerianine B (2) were isolated from the stems and roots of Sarcococca hookeriana Baill., along with two known compounds, sarcorucinine G (3) and epipachysamine D (4). On the basis of spectroscopic methods and by comparison with literature data, their structures were determined. As well as X-ray crystallography was performed to confirm compound 4. To identify novel antitumor inhibitors, all compounds were performed a CCK-8 assay against five human cancer cell lines SW480, SMMC-7721, PC3, MCF-7 and K562 in vitro. Compound 2 exhibited moderate cytotoxic activities to all cell lines with IC50 values in the range of 5.97–19.44 μM. Compound 3 was the most effective one against SW480 and K562 cell lines with IC50 values of 5.77 and 6.29 μM, respectively.

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Molecular Structure, In Vitro Anticancer Study and Molecular Docking of New Phosphate Derivatives of Betulin

Molecules ◽

10.3390/molecules26030737 ◽

2021 ◽

Vol 26 (3) ◽

pp. 737

Author(s):

Elwira Chrobak ◽

Maria Jastrzębska ◽

Ewa Bębenek ◽

Monika Kadela-Tomanek ◽

Krzysztof Marciniec ◽

...

Keyword(s):

Molecular Structure ◽

Cell Lines ◽

Human Cancer ◽

Amelanotic Melanoma ◽

Human Cancer Cell Lines ◽

Ic50 Values ◽

C 32 ◽

New Compounds ◽

Derivatives Of

A series of 30-diethylphosphate derivatives of betulin were synthesized and evaluated for their in vitro cytotoxic activity against human cancer cell lines, such as amelanotic melanoma (C-32), glioblastoma (SNB-19), and two lines of breast cancer (T47D, MDA-MB-231). The molecular structure and activities of the new compounds were also compared with their 29-phosphonate analogs. Compounds 7a and 7b showed the highest activity against C-32 and SNB-19 cell lines. The IC50 values for 7a were 2.15 and 0.91 μM, and, for 7b, they were 0.76 and 0.8 μM for the C-32 and SNB-19 lines, respectively. The most potent compounds, 7a and 7b, were tested for their effects on markers of apoptosis, such as H3, TP53, BAX, and BCL-2. For the whole series of phosphate derivatives, a lipophilicity study was performed, and the ADME parameters were calculated. The most active products were docked to the active site of the EGFR protein. The relative binding affinity of selected phosphate betulin derivatives toward EGFR was compared with standard erlotinib on the basis of ChemScore and KDEEP score. Positively, all derivatives docked inside the cavity and showed significant interactions. Moreover, a molecular dynamics study also reveals that ligands 7a,b form stable complexes and the plateau phase started after 7 ns.

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Synthesis and Antiproliferative Evaluation of Novel Longifolene-Derived Tetralone Derivatives Bearing 1,2,4-Triazole Moiety

Molecules ◽

10.3390/molecules25040986 ◽

2020 ◽

Vol 25 (4) ◽

pp. 986

Author(s):

Xia-Ping Zhu ◽

Gui-Shan Lin ◽

Wen-Gui Duan ◽

Qing-Min Li ◽

Fang-Yao Li ◽

...

Keyword(s):

Cell Lines ◽

Cancer Cell ◽

Human Cancer ◽

Cancer Cell Lines ◽

Positive Control ◽

In Vitro Cytotoxicity ◽

Human Cancer Cell Lines ◽

Ft Ir ◽

Almost All

Seventeen novel 2-(5-amino-1-(substituted sulfonyl)-1H-1,2,4-triazol-3-ylthio)-6- isopropyl-4,4-dimethyl-3,4-dihydronaphthalen-1(2H)-one compounds were synthesized from the abundant and naturally renewable longifolene and their structures were confirmed by FT-IR, NMR, and ESI-MS. The in vitro cytotoxicity of the synthesized compounds was evaluated by standard MTT assay against five human cancer cell lines, i.e., T-24, MCF-7, HepG2, A549, and HT-29. As a result, compounds 6d, 6g, and 6h exhibited better and more broad-spectrum anticancer activity against almost all the tested cancer cell lines than that of the positive control, 5-FU. Some intriguing structure–activity relationships were found and are discussed herein by theoretical calculation.

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New Bioactive Fused Triazolothiadiazoles as Bcl-2-Targeted Anticancer Agents

International Journal of Molecular Sciences ◽

10.3390/ijms222212272 ◽

2021 ◽

Vol 22 (22) ◽

pp. 12272

Author(s):

Rania Hamdy ◽

Arwyn T. Jones ◽

Mohamed El-Sadek ◽

Alshaimaa M. Hamoda ◽

Sarra B. Shakartalla ◽

...

Keyword(s):

Binding Affinity ◽

Cell Lines ◽

Anticancer Agents ◽

Inhibitory Activity ◽

Human Cancer ◽

Drug Candidate ◽

Human Cancer Cell Lines ◽

Growth Inhibitory ◽

Growth Inhibitory Activity ◽

Ic50 Values

A series of 3-(6-substituted phenyl-[1,2,4]-triazolo[3,4-b]-[1,3,4]-thiadiazol-3-yl)-1H-indoles (5a–l) were designed, synthesized and evaluated for anti-apoptotic Bcl-2-inhibitory activity. Synthesis of the target compounds was readily accomplished through a reaction of acyl hydrazide (1) with carbon disulfide in the presence of alcoholic potassium hydroxide to afford the corresponding intermediate potassium thiocarbamate salt (2), which underwent cyclization reaction in the presence of excess hydrazine hydrate to the corresponding triazole thiol (3). Further cyclisation reaction with substituted benzoyl chloride derivatives in the presence of phosphorous oxychloride afforded the final 6-phenyl-indol-3-yl [1,2,4]-triazolo[3,4-b]-[1,3,4]-thiadiazole compounds (5a–l). The novel series showed selective sub-micromolar IC50 growth-inhibitory activity against Bcl-2-expressing human cancer cell lines. The most potent 6-(2,4-dimethoxyphenyl) substituted analogue (5k) showed selective IC50 values of 0.31–0.7 µM against Bcl-2-expressing cell lines without inhibiting the Bcl-2-negative cell line (Jurkat). ELISA binding affinity assay (interruption of Bcl-2-Bim interaction) showed potent binding affinity for (5k) with an IC50 value of 0.32 µM. Moreover, it fulfils drug likeness criteria as a promising drug candidate.

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