Synthesis, Cytotoxic and Heparanase Inhibition Studies of 5-oxo-1-arylpyrrolidine-3- carboxamides of Hydrazides and 4-amino-5-aryl-4H-1,2,4-triazole-3-thiol

Hari, Swetha; Swaroop, Toreshettahally R.; Preetham, Habbanakuppe D.; Mohan, Chakrabhavi Dhananjaya; Muddegowda, Umashakara; Basappa, Basappa; Vlodavsky, Israël; Sethi, Gautam; Rangappa, Kanchugarakoppal S.

doi:10.2174/1570179417666200225123329

Cited by 6 publications

(3 citation statements)

References 35 publications

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“…Strikingly, treatment with compound 4-MMI resulted in a profound inhibition of tumor growth and burden in the aggressive MPC-11 myeloma (Figure 5). We also noted a profound reduction in VEGF levels in tumor sections derived from 4-MMI treated vs. untreated mice, likely due to inhibition of heparanasemediated VEGF gene expression and/or release [6,7,10]. Due to limited amounts of the 4-MMI compound, we could not perform dose-response and pharmacokinetic studies.…”

Section: Discussionmentioning

confidence: 88%

“…Importantly, the sulfated regions of HS serve as docking sites for ECM components, extrinsic proteins, growth-promoting factors (i.e., VEGF, FGF, HGF, TGFβ), chemokines, and cytokines [4,5], indicating that HSPG is crucial in maintaining tissue/cell architecture, growth, and differentiation [3,6]. Heparanase is the only β-endoglycosidase that partially degrades the HS saccharide side chains of HSPG to generate fragments of 4-7 kDa in length [7][8][9]. The degradation products of HS and, even more so, the liberated biologically active molecules, serve as a bioavailable source of HS-bound proteins that activate signal transduction and promote tissue remodeling, repair, neovascularization, and growth [8,9].…”

Section: Introductionmentioning

confidence: 99%

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New Heparanase-Inhibiting Triazolo-Thiadiazoles Attenuate Primary Tumor Growth and Metastasis

Barash

Rangappa²,

Mohan

et al. 2021

Cancers

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Compelling evidence ties heparanase, an endoglycosidase that cleaves heparan sulfate side (HS) chains of proteoglycans, with all steps of tumor development, including tumor initiation, angiogenesis, growth, metastasis, and chemoresistance. Moreover, heparanase levels correlate with shorter postoperative survival of cancer patients, encouraging the development of heparanase inhibitors as anti-cancer drugs. Heparanase-inhibiting heparin/heparan sulfate-mimicking compounds and neutralizing antibodies are highly effective in animal models of cancer progression, yet none of the compounds reached the stage of approval for clinical use. The present study focused on newly synthesized triazolo–thiadiazoles, of which compound 4-iodo-2-(3-(p-tolyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl)phenol (4-MMI) was identified as a potent inhibitor of heparanase enzymatic activity, cell invasion, experimental metastasis, and tumor growth in mouse models. To the best of our knowledge, this is the first report showing a marked decrease in primary tumor growth in mice treated with small molecules that inhibit heparanase enzymatic activity. This result encourages the optimization of 4-MMI for preclinical and clinical studies primarily in cancer but also other indications (i.e., colitis, pancreatitis, diabetic nephropathy, tissue fibrosis) involving heparanase, including viral infection and COVID-19.

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Section: Discussionmentioning

confidence: 88%

Section: Introductionmentioning

confidence: 99%

New Heparanase-Inhibiting Triazolo-Thiadiazoles Attenuate Primary Tumor Growth and Metastasis

Barash

Rangappa²,

Mohan

et al. 2021

Cancers

Self Cite

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“…At 6.69-7.51 ppm, broad multiplets were found and identified as aromatic protons. Signals at 9.10, 10.28, and 3.70 ppm represented the CH=N proton, OH, S-H thiophenol and S-H tetrazole, respectively [18].…”

Section: Synthesized Metal Ion Complexes (Co (1) To Co (3) )mentioning

confidence: 99%

Synthesis and Characterization of a Novel Azo-Dye Schiff Base and Its Metal Ion Complexes Based on 1,2,4-Triazole Derivatives

Ahmed Rasheed Al-qasii,

Bader,

Mosaa

2023

Indones. J. Chem.

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The study focused on producing and examining the properties of the 2-(((3-mercapto-5-(4-nitrophenyl)-4H-1,2,4-triazol-4-yl)imino)methyl)-4-(((4-mercaptophenyl) diazenyl)phenol) ligand (L) and its complexes with three transition metal ions, namely Ni(II), Co(II), and Cu(II). The ligand was formed through diazotization and coupling reactions between 4-aminobenzenethiol and a coupling Schiff base derived from 1,2,4-triazole. The characterization of the ligand and its metal ion complexes was carried out using analytical techniques such as FTIR, 1H- and 13C-NMR, UV-visible spectroscopy, and thermal analysis (TGA and DTG). Various physical methods were employed to synthesize and analyze the properties of the three mononuclear Co(II), Ni(II), and Cu(II) complexes with the azo-dye Schiff's base ligand. Based on the microanalysis and spectroscopic results, it was determined that the coordination between the azo Schiff base ligand and the central metal ion occurred through the NOS-donating atoms of the ligand. The analysis of the electronic spectra revealed that the synthesized Co(II) and Ni(II) complexes exhibited an octahedral geometry, while the Cu(II) complex had a distorted octahedral geometry. The implications of the finding regarding the octahedral and distorted-octahedral geometries include expanding the structural diversity in coordination chemistry, providing insights into ligand-metal interactions, and understanding the influence of geometry on properties.

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GC-MS-Guided Antimicrobial Defense Responsive Secondary Metabolites from the Endophytic Fusarium solani Isolated from Tinospora cordifolia and Their Multifaceted Biological Properties

Uzma,

Chowdappa,

Roy

et al. 2023

Appl Biochem Biotechnol

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Synthesis, Cytotoxic and Heparanase Inhibition Studies of 5-oxo-1-arylpyrrolidine-3- carboxamides of Hydrazides and 4-amino-5-aryl-4H-1,2,4-triazole-3-thiol

Cited by 6 publications

References 35 publications

New Heparanase-Inhibiting Triazolo-Thiadiazoles Attenuate Primary Tumor Growth and Metastasis

New Heparanase-Inhibiting Triazolo-Thiadiazoles Attenuate Primary Tumor Growth and Metastasis

Synthesis and Characterization of a Novel Azo-Dye Schiff Base and Its Metal Ion Complexes Based on 1,2,4-Triazole Derivatives

GC-MS-Guided Antimicrobial Defense Responsive Secondary Metabolites from the Endophytic Fusarium solani Isolated from Tinospora cordifolia and Their Multifaceted Biological Properties

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