Synthesis and Cytotoxicity of Thieno[2,3-b]Pyridine Derivatives Toward Sensitive and Multidrug-Resistant Leukemia Cells

A new series of substituted ethyl 7-cyclopropyl-2-(2-aryloxo)-3-nitro-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxylates 3a–e were prepared by utilizing ethyl 2-chloro-7-cyclopropyl-3-nitro-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxylate (1) and replacing of the 2-chlorine with anions obtained from phenol (2a), salicylaldehyde derivatives 2b–d or thiophenol (2e), leading to the respective ethyl 7-cyclopropyl-2-(2-aryloxo)-3-nitro-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxylates 3a–e. The new compounds were evaluated for their in vitro cytotoxicity towards sensitive CCRF-CEM and multidrug-resistant CEM/ADR5000 leukemia cells. The screening revealed that compounds 3a, 3b, and 3e inhibited the growth of both cell lines. Compound 3b, with a phenol moiety, exhibited the highest growth inhibitory activity against CEM/ADR5000 and CCRF-CEM cells with IC50 values 4.486 ± 0.286 and 2.580 ± 0.550 μM, respectively. Collectively, the presented results demonstrate that the synthesized thieno[2,3-b]pyridines warrant further exploration for potential use as anti-cancer agents.

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Arsenic induces apoptosis of multidrug-resistant human myeloid leukemia cells that express Bcr-Abl or overexpress MDR, MRP, Bcl-2, or Bcl-xL

Blood ◽

10.1182/blood.v95.3.1014.003k04_1014_1022 ◽

2000 ◽

Vol 95 (3) ◽

pp. 1014-1022 ◽

Cited By ~ 162

Author(s):

Charles Perkins ◽

Caryn N. Kim ◽

Guofu Fang ◽

Kapil N. Bhalla

Keyword(s):

Myeloid Leukemia ◽

Blast Crisis ◽

K562 Cells ◽

Cell Types ◽

Multidrug Resistant ◽

Leukemia Cells ◽

Protein Levels ◽

Growth Inhibitory ◽

Induced Apoptosis

We investigated the in vitro growth inhibitory and apoptotic effects of clinically achievable concentrations of As2O3 (0.5 to 2.0 μmol/L) against human myeloid leukemia cells known to be resistant to a number of apoptotic stimuli. These included chronic myelocytic leukemia (CML) blast crisis K562 and HL-60/Bcr-Abl cells, which contain p210 and p185 Bcr-Abl, respectively, and HL-60 cell types that overexpress Bcl-2 (HL-60/Bcl-2), Bcl-xL(HL-60/Bcl-xL), MDR (HL-60/VCR), or MRP (HL-60/AR) protein. The growth-inhibitory IC50 values for As2O3 treatment for 7 days against all these cell types ranged from 0.8 to 1.5 μmol/L. Exposure to 2 μmol/L As2O3 for 7 days induced apoptosis of all cell types, including HL-60/Bcr-Abl and K562 cells. This was associated with the cytosolic accumulation of cyt c and preapoptotic mitochondrial events, such as the loss of inner membrane potential (▵Ψm) and the increase in reactive oxygen species (ROS). Treatment with As2O3 (2 μmol/L) generated the activities of caspases, which produced the cleavage of the BH3 domain containing proapoptotic Bid protein and poly (ADP-ribose) polymerase. Significantly, As2O3-induced apoptosis of HL-60/Bcr-Abl and K562 cells was associated with a decline in Bcr-Abl protein levels, without any significant alterations in the levels of Bcl-xL, Bax, Apaf-1, Fas, and FasL. Although As2O3 treatment caused a marked increase in the expression of the myeloid differentiation marker CD11b, it did not affect Hb levels in HL-60/Bcr-Abl, K562, or HL-60/neo cells. However, in these cells, As2O3 potently induced hyper-acetylation of the histones H3 and H4. These findings characterize As2O3 as a growth inhibiting and apoptosis-inducing agent against a variety of myeloid leukemia cells resistant to multiple apoptotic stimuli.

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Radiation-induced PEGylated Ethambutol Has Low Antimycobacterial Activity in Vitro

Biointerface Research in Applied Chemistry ◽

10.33263/briac112.88848894 ◽

2020 ◽

Vol 11 (2) ◽

pp. 8884-8894

Keyword(s):

Antimycobacterial Activity ◽

Multidrug Resistant ◽

Biological Evaluation ◽

Rapid Screening ◽

Promising Tool ◽

Growth Inhibitory ◽

Growth Inhibitory Activity ◽

Radiation Induced ◽

Airborne Disease

Tuberculosis is an airborne disease caused by Mycobacterium tuberculosis and remains one of the leading causes of death worldwide. The rise in multidrug-resistant strains has prompted the search for novel strategies to produce tuberculostatic agents. This research is aimed at developing a derivative of ethambutol by gamma radiation-induced polymerization with polyethylene glycol (PEG). The synthesis was verified by Raman spectroscopy and UV–Vis spectrometry. The results show that PEG can be chemically bonded to ethambutol by amine and alcohol groups. In in vitro biological evaluation, PEGylated and neat ethambutol showed similar cell viabilities, while the modified drug lowered bacterial growth inhibitory activity. A mechanism for the polymerization is proposed. The particle size increased for PEGylated drugs concerning the starting polyether. Despite the low antimycobacterial activity in vitro, the product seems to be a promising tool for the rapid screening of hydrolase activity.

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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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Synthesis, spectral, molecular modeling, biological and antitumor studies of new nifuroxazide complexes

Materials Express ◽

10.1166/mex.2021.2023 ◽

2021 ◽

Vol 11 (7) ◽

pp. 1071-1083

Author(s):

Eid H. Alosaimi ◽

Walaa H. El-Shwiniy ◽

Saad M. Alshahrani ◽

Ayman A. O. Younes ◽

Mostafa Y. Nassar ◽

...

Keyword(s):

Bacterial Species ◽

Thermal Analyses ◽

Molar Conductance ◽

Cancer Drug ◽

Growth Inhibitory ◽

Growth Inhibitory Activity ◽

Anti Cancer ◽

Hct 116 ◽

Mcf 7

Series of Zr(IV), Ce(IV) and U(VI) complexes were synthesized with nifuroxazide ligand. Design and formulae of the complexes suggested in the light of analytical, spectral, magnetic and thermal analyses (1HNMR, IR, UV-Vis). The calculated values of molar conductance mean that, all isolated complexes were electrolytes. The data revealed the complexes formation and suggested that nifuroxazide binds as a bidentate at NO sites with metal ions. The kinetic parameters evaluated using Coats Redfern (CR) and Horowitz-Metzeger (HM) methods. The thermodynamic data reflect the thermal stability for all complexes. The calculated bond length and force constant values for UO2 bond are 1.741 Å and 459.409 Nm−1. The research investigations were related to quantum chemical calculations conducted at the theory level of DFT/B3LYP/LANL2DZ. The nifuroxazide, inorganic salts and their metal complexes were assayed against different bacterial species as well as the in vitro growth inhibitory activity against human breast carcinoma (MCF-7) and HCT-116 cell lines. Zr(IV) complex was found to have the highest activity against all the tested organisms and a powerful anti-cancer drug.

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Spiculisporic Acid E, a New Spiculisporic Acid Derivative and Ergosterol Derivatives from the Marine-Sponge Associated Fungus Talaromyces trachyspermus (KUFA 0021)

Natural Product Communications ◽

10.1177/1934578x1400900822 ◽

2014 ◽

Vol 9 (8) ◽

pp. 1934578X1400900 ◽

Cited By ~ 3

Author(s):

Decha Kumla ◽

Tida Dethoup ◽

Suradet Buttachon ◽

Narong Singburaudom ◽

Artur M.S. Silva ◽

...

Keyword(s):

Acid Derivative ◽

Marine Sponge ◽

Multidrug Resistant ◽

Breast Adenocarcinoma ◽

Gram Negative Bacteria ◽

Small Cell Lung ◽

Growth Inhibitory ◽

Growth Inhibitory Activity ◽

Mcf 7

A new spiculisporic acid derivative, spiculisporic acid E (2), and a new natural product 3-acetyl ergosterol 5, 8-endoperoxide (1), were isolated, together with ergosta-4, 6, 8 (14), 22-tetraen-3-one, glaucanic acid and glauconic acid, from the culture of the marine-sponge associated fungus Talaromyces trachyspermus (KUFA 0021). All the compounds were inactive against Gram-positive and Gram-negative bacteria, and Candida albicans, as well as multidrug-resistant isolates from the environment. Spiculisporic acid E (2), glaucanic acid and glauconic acid did not show in vitro growth inhibitory activity against the MCF-7 (breast adenocarcinoma), NCI-H460 (non-small cell lung cancer) and A375-C5 (melanoma) cell lines by the protein binding dye SRB method.

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Synergistic antibacterial efficacies of the combination of bovine lactoferrin or its hydrolysate with probiotic secretion in curbing the growth of meticillin-resistant Staphylococcus aureus

Journal of Medical Microbiology ◽

10.1099/jmm.0.052639-0 ◽

2013 ◽

Vol 62 (12) ◽

pp. 1845-1851 ◽

Cited By ~ 13

Author(s):

Po-Wen Chen ◽

Trista Tingyun Jheng ◽

Ching-Ling Shyu ◽

Frank Chiahung Mao

Keyword(s):

Staphylococcus Aureus ◽

Bifidobacterium Longum ◽

Multidrug Resistant ◽

Bovine Lactoferrin ◽

Bifidobacterium Animalis ◽

Growth Inhibitory ◽

Growth Inhibitory Activity ◽

Mrsa Infection ◽

Mrsa Strains

The occurrence of multidrug-resistant or meticillin-resistant Staphylococcus aureus (MRSA) has become an important issue in clinics. This study evaluated a combinatorial treatment approach by using the well-documented antibacterial protein apo-bovine lactoferrin (apo-bLf) or its hydrolysate and specific probiotic supernatants for controlling MRSA infection. Clinical MRSA strains were isolated from different patient specimens. Apo-bLf-hydrolysate possessed stronger anti-MRSA activity than complete bLf in that it inhibited the growth of most MRSA strains tested in vitro. Otherwise, the supernatants produced by Lactobacillus fermentum (ATCC 11739), Bifidobacterium longum subsp. longum (ATCC 15707) and Bifidobacterium animalis subsp. lactis (BCRC 17394) inhibited the growth of various MRSA strains. Further, L. fermentum or B. animalis subsp. lactis supernatant plus apo-bLf or bLf-hydrolysate led to partially synergistic to synergistic growth-inhibitory activity against MRSA strains. However, L. fermentum and not B. animalis subsp. lactis or B. longum subsp. longum was observed to resist the antibacterial activity of both apo-Lf and bLf-hydrolysate. Therefore, it is suggested that L. fermentum could be the best candidate to be used with apo-bLf or bLf-hydrolysate as a live supplement against MRSA infections.

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Modifications on the Tetrahydroquinoline Scaffold Targeting a Phenylalanine Cluster on GPER as Antiproliferative Compounds against Renal, Liver and Pancreatic Cancer Cells

Pharmaceuticals ◽

10.3390/ph14010049 ◽

2021 ◽

Vol 14 (1) ◽

pp. 49

Author(s):

David Méndez-Luna ◽

Loreley Araceli Morelos-Garnica ◽

Juan Benjamín García-Vázquez ◽

Martiniano Bello ◽

Itzia Irene Padilla-Martínez ◽

...

Keyword(s):

Binding Site ◽

Cell Lines ◽

Cancer Cell ◽

Inhibitory Activity ◽

In Silico ◽

Cancer Cell Lines ◽

Pancreatic Cancer Cells ◽

Growth Inhibitory ◽

Growth Inhibitory Activity ◽

New Compounds

The implementation of chemo- and bioinformatics tools is a crucial step in the design of structure-based drugs, enabling the identification of more specific and effective molecules against cancer without side effects. In this study, three new compounds were designed and synthesized with suitable absorption, distribution, metabolism, excretion and toxicity (ADME-tox) properties and high affinity for the G protein-coupled estrogen receptor (GPER) binding site by in silico methods, which correlated with the growth inhibitory activity tested in a cluster of cancer cell lines. Docking and molecular dynamics (MD) simulations accompanied by a molecular mechanics/generalized Born surface area (MMGBSA) approach yielded the binding modes and energetic features of the proposed compounds on GPER. These in silico studies showed that the compounds reached the GPER binding site, establishing interactions with a phenylalanine cluster (F206, F208 and F278) required for GPER molecular recognition of its agonist and antagonist ligands. Finally, a 3-(4,5-dimethylthiazol-2-yl)2,5-diphenyltetrazolium bromide (MTT) assay showed growth inhibitory activity of compounds 4, 5 and 7 in three different cancer cell lines—MIA Paca-2, RCC4-VA and Hep G2—at micromolar concentrations. These new molecules with specific chemical modifications of the GPER pharmacophore open up the possibility of generating new compounds capable of reaching the GPER binding site with potential growth inhibitory activities against nonconventional GPER cell models.

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New Antiproliferative Triflavanone from Thymelaea hirsuta—Isolation, Structure Elucidation and Molecular Docking Studies

Molecules ◽

10.3390/molecules26030739 ◽

2021 ◽

Vol 26 (3) ◽

pp. 739

Author(s):

Sameh S. Elhady ◽

Reda F. A. Abdelhameed ◽

Mayada M. El-Ayouty ◽

Amany K. Ibrahim ◽

Eman S. Habib ◽

...

Keyword(s):

Molecular Docking ◽

Liver Tumors ◽

Fold Increase ◽

In Vitro Cytotoxicity ◽

Mitogen Activated Protein Kinase ◽

Wild Plant ◽

Cytotoxic Activities ◽

Ic50 Values ◽

Thymelaea Hirsuta

In this study isolates from Thymelaea hirsuta, a wild plant from the Sinai Peninsula of Egypt, were identified and their selective cytotoxicity levels were evaluated. Phytochemical examination of the ethyl acetate (EtOAc) fraction of the methanolic (MeOH) extract of the plant led to the isolation of a new triflavanone compound (1), in addition to the isolation of nine previously reported compounds. These included five dicoumarinyl ethers found in Thymelaea: daphnoretin methyl ether (2), rutamontine (3), neodaphnoretin (4), acetyldaphnoretin (5), and edgeworthin (6); two flavonoids: genkwanin (7) and trans-tiliroside (8); p-hydroxy benzoic acid (9) and β sitosterol glucoside (10). Eight of the isolated compounds were tested for in vitro cytotoxicity against Vero and HepG2 cell lines using a sulforhodamine-B (SRB) assay. Compounds 1, 2 and 5 exhibited remarkable cytotoxic activities against HepG2 cells, with IC50 values of 8.6, 12.3 and 9.4 μM, respectively, yet these compounds exhibited non-toxic activities against the Vero cells. Additionally, compound 1 further exhibited promising cytotoxic activity against both MCF-7 and HCT-116 cells, with IC50 values of 4.26 and 9.6 μM, respectively. Compound 1 significantly stimulated apoptotic breast cancer cell death, resulting in a 14.97-fold increase and arresting 40.57% of the cell population at the Pre-G1 stage of the cell cycle. Finally, its apoptosis-inducing activity was further validated through activation of BAX and caspase-9, and inhibition of BCL2 levels. In silico molecular docking experiments revealed a good binding mode profile of the isolates towards Ras activation/pathway mitogen-activated protein kinase (Ras/MAPK); a common molecular pathway in the development and progression of liver tumors.

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Semi-Synthesis of Harringtonolide Derivatives and Their Antiproliferative Activity

Molecules ◽

10.3390/molecules26051380 ◽

2021 ◽

Vol 26 (5) ◽

pp. 1380

Author(s):

Xiutao Wu ◽

Lijie Gong ◽

Chen Chen ◽

Ye Tao ◽

Wuxi Zhou ◽

...

Keyword(s):

Antiproliferative Activity ◽

Normal Cell ◽

Selectivity Index ◽

Cytotoxic Activities ◽

Structure Activity ◽

Growth Inhibitory ◽

Growth Inhibitory Activity ◽

Hct 116 ◽

Systematic Structure

Harringtonolide (HO), a natural product isolated from Cephalotaxus harringtonia, exhibits potent antiproliferative activity. However, little information has been reported on the systematic structure−activity relationship (SAR) of HO derivatives. Modifications on tropone, lactone, and allyl positions of HO (1) were carried out to provide 17 derivatives (2–13, 11a–11f). The in vitro antiproliferative activity against four cancer cell lines (HCT-116, A375, A549, and Huh-7) and one normal cell line (L-02) was tested. Amongst these novel derivatives, compound 6 exhibited comparable cell growth inhibitory activity to HO and displayed better selectivity index (SI = 56.5) between Huh-7 and L-02 cells. The SAR results revealed that the tropone and lactone moieties are essential for the cytotoxic activities, which provided useful suggestions for further structural optimization of HO.

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A molecular architectural design that promises potent antimicrobial activity against multidrug-resistant pathogens

NPG Asia Materials ◽

10.1038/s41427-021-00287-y ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Bing Yuan ◽

Jiaojiao Liu ◽

Zhixiong Deng ◽

Lin Wei ◽

Wenwen Li ◽

...

Keyword(s):

Architectural Design ◽

Building Blocks ◽

Multidrug Resistant ◽

In Vitro Cytotoxicity ◽

Antimicrobial Drugs ◽

Minimal Inhibitory Concentrations ◽

Antimicrobial Efficiency ◽

Multidrug Resistant Pathogens

AbstractAddressing the devastating threat of drug-resistant pathogens requires the discovery of new antibiotics with advanced action mechanisms and/or novel strategies for drug design. Herein, from a biophysical perspective, we design a class of synthetic antibacterial complexes with specialized architectures based on melittin (Mel), a natural antimicrobial peptide, and poly(ethylene glycol) (PEG), a clinically available agent, as building blocks that show potent and architecture-modulated antibacterial activity. Among the complexes, the flexibly linear complex consisting of one Mel terminally connected with a long-chained PEG (e.g., PEG12k–1*Mel) shows the most pronounced improvement in performance compared with pristine Mel, with up to 500% improvement in antimicrobial efficiency, excellent in vitro activity against multidrug-resistant pathogens (over a range of minimal inhibitory concentrations of 2–32 µg mL−1), a 68% decrease in in vitro cytotoxicity, and a 57% decrease in in vivo acute toxicity. A lipid-specific mode of action in membrane recognition and an accelerated “channel” effect in perforating the bacterial membrane of the complex are described. Our results introduce a new way to design highly efficient and low-toxicity antimicrobial drugs based on architectural modulations with clinically available agents.

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