Permuted 2,4-thiazolidinedione (TZD) analogs as GLUT inhibitors and their in-vitro evaluation in leukemic cells

Tilekar, Kalpana; Upadhyay, Neha; Schweipert, Markus; Hess, Jessica D.; Macias, Lucasantiago Henze; Mrówka, Piotr; Meyer‐Almes, Franz‐Josef; Aguilera, Renato J.; Iancu, Cristina V.; Choe, Juhui; Ramaa, C. S.

doi:10.1016/j.ejps.2020.105512

Cited by 27 publications

(22 citation statements)

References 59 publications

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“…The synthetic strategy towards the synthesis of target compounds 1–21 is outlined in Scheme 1 . The intermediates VIa–f [ 28 ] , VIIa–f [ 29 ] , VIIIa–c [ 30 ] , and IXa–d [ 31 ] were synthesized, as stated previously, and their structures were confirmed by comparing their physical constants and spectral data to those previously recorded. As shown in Scheme 1 , ciprofloxacin undergoes a Mannich reaction with heterocycles I – VI and formaldehyde in refluxing ethanol to yield the target compounds 1 – 21 in yields ranging from 79% to 97%.…”

Section: Resultsmentioning

confidence: 99%

“…One hundred μL microbial suspension was spread over agar plates that suited the broth in which it was held. The selected colonies of each organism that may play a pathogenic function should be from the primary agar plates and tested by the disc diffusion method for susceptibility [ 30 , 31 ]. Plates inoculated with filamentous fungi as Aspergillus flavus were incubated at 25 °C for 48 h; Gram positive bacteria as Staphylococcus aureus (ATCC 12600, Microanalytical center, Cairo, Egypt), Bacillus subtilis (ATCC 6051); Gram negative bacteria as Escherichia coli (ATCC 11775), Pseudomonas aeuroginosa (ATCC 10145) were incubated at 35–37 °C for 24–48 h and yeast as Candida albicans (ATCC 7102) was incubated at 30 °C for 24–48 h and, then the diameters of the inhibition zones were measured in millimeters [ 28 ].…”

Section: Appendix A1 General Detailsmentioning

confidence: 99%

“…For the disc diffusion, the zone diameters were measured with slipping calipers of the National Committee for Clinical Laboratory Standards [ 30 ], and the results are given in Table 1 . Agar-based methods such as E-test and disk diffusion can be good alternatives because they are simpler and faster than broth-based methods [ 30 , 31 ].…”

Section: Appendix A1 General Detailsmentioning

confidence: 99%

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Design, Synthesis, and Antibacterial Screening of Some Novel Heteroaryl-Based Ciprofloxacin Derivatives as DNA Gyrase and Topoisomerase IV Inhibitors

et al. 2021

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A novel series of ciprofloxacin hybrids comprising various heterocycle derivatives has been synthesized and structurally elucidated using 1H NMR, 13C NMR, and elementary analyses. Using ciprofloxacin as a reference, compounds 1–21 were screened in vitro against Gram-positive bacterial strains such as Staphylococcus aureus and Bacillus subtilis and Gram-negative strains such as Escherichia coli and Pseudomonas aeruginosa. As a result, many of the compounds examined had antibacterial activity equivalent to ciprofloxacin against test bacteria. Compounds 2–6, oxadiazole derivatives, were found to have antibacterial activity that was 88 to 120% that of ciprofloxacin against Gram-positive and Gram-negative bacteria. The findings showed that none of the compounds tested had antifungal activity against Aspergillus flavus, but did have poor activity against Candida albicans, ranging from 23% to 33% of fluconazole, with compound 3 being the most active (33% of fluconazole). The most potent compounds, 3, 4, 5, and 6, displayed an IC50 of 86, 42, 92, and 180 nM against E. coli DNA gyrase, respectively (novobiocin, IC50 = 170 nM). Compounds 4, 5, and 6 showed IC50 values (1.47, 6.80, and 8.92 µM, respectively) against E. coli topo IV in comparison to novobiocin (IC50 = 11 µM).

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Section: Resultsmentioning

confidence: 99%

Section: Appendix A1 General Detailsmentioning

confidence: 99%

Section: Appendix A1 General Detailsmentioning

confidence: 99%

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Design, Synthesis, and Antibacterial Screening of Some Novel Heteroaryl-Based Ciprofloxacin Derivatives as DNA Gyrase and Topoisomerase IV Inhibitors

et al. 2021

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“…The compounds with promising HDAC4 inhibition viz. 5 h , 5 o , 5 u , 5 v , 5 w , 5 x , 5 y , and 5 z were further screened in the live cell imaging‐based Differential Nuclear Staining (DNS) assay [42] to find out the cytotoxic potential against a panel of 7 cell lines consisting of solid tumor cells (HeLa, MDA‐MB‐231, SH‐SY5Y), hematological tumor cells (CEM, Ramos, HL60) and noncancerous cells (HS‐27) as described previously . For this experiment, cells were exposed to experimental or control treatments in quadruplicate for 72 hours.…”

Section: Resultsmentioning

confidence: 99%

HDAC4 Inhibitors with Cyclic Linker and Non‐hydroxamate Zinc Binding Group: Design, Synthesis, HDAC Screening and in vitro Cytotoxicity evaluation.

et al. 2021

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Recent evidences highlight the usefulness of small molecule (Histone deacetylase 4) HDAC4 inhibitors in the several preclinical paradigms. Major toxicity and mutagenicity issues associated with hydroxamate HDAC inhibitors, stimulated us to develop potent non-hydroxamate inhibitors. In the present work a novel series of thiazolidinedione (TZD) derivatives with pyridine as cyclic linker and TZD ring as zinc binding group was designed and screened in a panel of isoenzymes of HDACs, wherein the most potent compounds exhibiting HDAC4 IC50values < 5 μM were 5 v, 5 w, 5 y and 5 z (IC 50 = 4.2 � 1 μM, 0.75 � 0.03 μM, 4.9 � 0.5 and 2.3 � 0.5 μM, respectively). The docking studies displayed the unique binding mode of this series of compound at active site of HDAC4, wherein TZD ring was indicated as zinc binding group. Further, 5 w and 5 y were found as the most potent antiproliferative agent in lymphoblastic leukemia (CCRF-CEM) and breast cancer MDA-MB-231 cells. Compound 5 y was found to induce the apoptosis and DNA fragmentation of CEM cells. The western blotting analysis of 5 y also showed the presence of cleaved caspases supporting their apoptotic nature. Further, Class IIa (HDAC4) selectivity of 5 y was also supported by western blotting observations, wherein 5 y caused the accumulation of acetylated H3 but not of acetylated Tubulin. Thus, our findings endorse the further investigation of this series of compounds for their potential as targeted cancer therapeutic agents.

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“…Tilekar et al . 78 , 79 found that compounds that inhibited both GLUT1 and GLUT4 hindered proliferation of CEM leukemia cells, both in vitro and in vivo. Thus, dual GLUT1 and GLUT4 inhibitors may have antileukemic potential.…”

Section: Discussionmentioning

confidence: 99%

GLUT3 inhibitor discovery through in silico ligand screening and in vivo validation in eukaryotic expression systems

Iancu

Bocci

Ishtikhar

et al. 2022

Sci Rep

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The passive transport of glucose and related hexoses in human cells is facilitated by members of the glucose transporter family (GLUT, SLC2 gene family). GLUT3 is a high-affinity glucose transporter primarily responsible for glucose entry in neurons. Changes in its expression have been implicated in neurodegenerative diseases and cancer. GLUT3 inhibitors can provide new ways to probe the pathophysiological role of GLUT3 and tackle GLUT3-dependent cancers. Through in silico screening of an ~ 8 million compounds library against the inward- and outward-facing models of GLUT3, we selected ~ 200 ligand candidates. These were tested for in vivo inhibition of GLUT3 expressed in hexose transporter-deficient yeast cells, resulting in six new GLUT3 inhibitors. Examining their specificity for GLUT1-5 revealed that the most potent GLUT3 inhibitor (G3iA, IC50 ~ 7 µM) was most selective for GLUT3, inhibiting less strongly only GLUT2 (IC50 ~ 29 µM). None of the GLUT3 inhibitors affected GLUT5, three inhibited GLUT1 with equal or twofold lower potency, and four showed comparable or two- to fivefold better inhibition of GLUT4. G3iD was a pan-Class 1 GLUT inhibitor with the highest preference for GLUT4 (IC50 ~ 3.9 µM). Given the prevalence of GLUT1 and GLUT3 overexpression in many cancers and multiple myeloma’s reliance on GLUT4, these GLUT3 inhibitors may discriminately hinder glucose entry into various cancer cells, promising novel therapeutic avenues in oncology.

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Permuted 2,4-thiazolidinedione (TZD) analogs as GLUT inhibitors and their in-vitro evaluation in leukemic cells

Cited by 27 publications

References 59 publications

Design, Synthesis, and Antibacterial Screening of Some Novel Heteroaryl-Based Ciprofloxacin Derivatives as DNA Gyrase and Topoisomerase IV Inhibitors

Design, Synthesis, and Antibacterial Screening of Some Novel Heteroaryl-Based Ciprofloxacin Derivatives as DNA Gyrase and Topoisomerase IV Inhibitors

HDAC4 Inhibitors with Cyclic Linker and Non‐hydroxamate Zinc Binding Group: Design, Synthesis, HDAC Screening and in vitro Cytotoxicity evaluation.

GLUT3 inhibitor discovery through in silico ligand screening and in vivo validation in eukaryotic expression systems

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