Synthesis and characterization of new aromatic aldehyde/ketone 4-(β-d-glucopyranosyl)thiosemicarbazones

doi:10.1016/j.carres.2009.05.010

Carbohydrate Research

Volume 344, Issue 11, 27 July 2009, Pages 1352-1364

Dedicated to the memory of our colleague and distinguished scientist Dr. Nikos G. Oikonomakos

https://doi.org/10.1016/j.carres.2009.05.010 Get rights and content

Abstract

A series of 22 aromatic aldehyde/ketone 4-(β-d-glucopyranosyl)thiosemicarbazones have been synthesized by condensation of 4-(per-O-acetylated-β-d-glucopyranosyl)thiosemicarbazide with an aldehyde or a ketone, and then, deacetylation of the resulting product. The compounds were fully characterized by spectroscopic techniques, elemental analysis, and for two derivatives by X-ray analysis. The data indicate the β configuration, and the E configuration pertaining to the stereochemistry of the C double bond N bond. However, a partial conversion of the E-form into the Z-form is possible in solution after several hours.

Graphical abstract

Section snippets

General

4-(2,3,4,6-Tetra-O-acetyl-β-d-glucopyranosyl)thiosemicarbazide (1) was synthesized in accordance with a known procedure by treatment of (2,3,4,6-tetra-O-acetyl-β-d-glucopyranosyl)isothiocyanate with dry hydrazine in ethanol.^5e The only modification in this procedure was the reaction temperature, which was kept at 5–10 °C in order to avoid the formation of a carbohydrate bearing diacylhydrazine framework.¹⁴ The above-mentioned isothiocyanate was prepared by the reaction of (per-O-acetylated-α-d

Supplementary data

Supplementary crystallographic data for the structural analysis have been deposited with the Cambridge Crystallographic Data Centre, CCDC-711876 (2d) and 711877 (3j). Copies of this information may be obtained free of charge from the Director, Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ, UK. (fax: +44-1223-336033, e-mail: [email protected] or via: www.ccdc.cam.ac.uk).

Acknowledgement

This work was supported by the EST Marie Curie program EURODESY, Contr. No. MEST-CT-2005-020575 (2006–2010).

References (19)

G. Zemplén et al.
Chem. Ber.
(1936)
H. Booth
Tetrahedron Lett.
(1965)
J.R. Dimmock et al.
Eur. J. Med. Chem.
(1990)
D.X. West et al.
Polyhedron
(1995)
P. Pelagatti et al.
J. Chem. Soc., Dalton Trans.
(1998)
J. Martínez et al.
J. Organomet. Chem.
(2006)
A.E. Graminha et al.
Spectrochim. Acta, Part A
(2008)
L. Szilágyi et al.
Carbohydr. Res.
(1986)
A. Pérez-Rebolledo et al.
Polyhedron
(2007)
D. Sriram et al.
Acta Crystallogr., Sect. C
(1997)
B. Yang et al.
Chem. Res. Chinese U.
(2005)
N.G. Oikonomakos
Curr. Protein Pept. Sci.
(2002)
N.G. Oikonomakos et al.
Curr. Opin. Investig. Drugs
(2008)
L. Somsák et al.
Curr. Med. Chem.
(2008)
M. Diéguez et al.
Chem. Rev.
(2004)
M. Diéguez et al.
Eur. J. Org. Chem.
(2007)
H. Beraldo et al.
Mini-Rev. Med. Chem.
(2004)
M. Belicchi-Ferrari et al.
J. Med. Chem.
(2005)
D. Kovala-Demertzi et al.
J. Inorg. Biochem.
(2006)
D. Kovala-Demertzi et al.
Eur. J. Med. Chem.
(2009)

There are more references available in the full text version of this article.

Cited by (29)

An efficient and concise synthesis of a selective small molecule non-peptide inhibitor of cathepsin L: KGP94
2021, Bioorganic Chemistry
KGP94 is a potent, selective, and competitive inhibitor of the lysosomal endopeptidase enzyme (Cathepsin L) currently in preclinical trials for the treatment of metastatic cancer, which is a leading cause of cancer-associated death. Herein, we report two new synthetic routes for synthesizing the target compound through four consecutive steps, using a Weinreb amide approach starting from a common 3-bromobenzoyl chloride. A key step in the approach is a coupling reaction of a readily available Grignard reagent with amide 4 to produce 6, a previously unreported coupling pattern. These new strategies offer an efficient and alternative approach to synthesis of target compound with an excellent overall yield.
Synthesis and biological screening of thiosemicarbazones of substituted 3-acetylcoumarins having D-glucose moiety
2020, Bioorganic and Medicinal Chemistry Letters
Thiosemicarbazones 5a-j were synthesized with yields of 45–68% by condensation of 3-acetylcoumarins 3a-j and tetra-O-acetyl-β-d-thiosemicarbazide 4. All obtained thiosemicarbazones were screened for anti-microorganic activities against bacteria (B. subtilis, S. aureus, S. epidermidis, E. coli, P. aeruginosa, K. pneumoniae, S. typhimurium) and fungi (A. niger, C. albicans, S. cerevisiae, and A. flavus). Some compounds had significant inhibitory activity with MICs of 0.78–3.125 μM in comparison with 5a, including 5e,h,i for S. aureus, and 5c,f,i for S. epidermidis (Gram-(+) bacteria), 5c,f,g for E.coli, 5f for K. pneumoniae, 5b,c,g for P. aeruginosa, and 5i for S. typhimurium (Gram-(−) bacteria), 5d,h,i for A. niger, 5i for A. flavus, 5b,d,e,h for C. albicans, and 5i for S. cerevisiae. Compounds exhibited excellent activity against tested microorganism with MIC = 0.78 μM, including 5h,i (against S. aureus), 5h (against C. albicans), and 5i (against S. cerevisiae).
Synthesis, molecular modeling studies and evaluation of antifungal activity of a novel series of thiazole derivatives
2018, European Journal of Medicinal Chemistry
In the search for new antifungal agents, a novel series of fifteen hydrazine-thiazole derivatives was synthesized and assayed in vitro against six clinically important Candida and Cryptococcus species and Paracoccidioides brasiliensis. Eight compounds showed promising antifungal activity with minimum inhibitory concentration (MIC) values ranging from 0.45 to 31.2 μM, some of them being equally or more active than the drug fluconazole and amphotericin B. Active compounds were additionally tested for toxicity against human embryonic kidney (HEK-293) cells and none of them exhibited significant cytotoxicity, indicating high selectivity. Molecular modeling studies results corroborated experimental SAR results, suggesting their use in the design of new antifungal agents.
Thio-functionalized carbohydrate thiosemicarbazones and evaluation of their anticancer activity
2017, Bioorganic and Medicinal Chemistry Letters
Thiosemicarbazides and their analogs have shown potential medical applications as antiviral, antibacterial and anticancer drugs. We designed, synthesized and evaluated in vitro anticancer activity against ovarian (A2780), cervix (HeLa), colon (LoVo), breast (MCF-7) and brain (MO59J) human cancer cell lines of seven novel compounds –S-glycosylated thiosemicarbazones. We assessed the cyto- and genotoxic properties of all novel compounds using a variety of methods including comet assay, XTT assay, various fluorescent assays and toxicology PathwayFinder expression array. We tried to evaluate their possible mechanism of action with particular attention to induction of DNA damage and repair, apoptosis, oxidative stress analysis and cellular response in terms of changes in gene expression. The most sensitive cell line was human ovarian cancer. The results revealed that the major activity against A2780 cancer cell line displayed by our compounds is induction of DNA damage. This effect is not associated with apoptosis or oxidative stress induction and the resulting damage will not lead to cell cycle arrest. We also observed up-expression of heat shock related genes and NQO1 gene in response to our compounds. The second effect seems to be specific to glycosylated S-bond compounds as we observed it earlier. Upregulation of heat shock protein encoding genes suggest that our compounds induce stressful conditions. The nature of this phenomena (heat shock, pH shift or hypoxia) needs further study.
Synthesis and biological evaluation of a water-soluble phosphate prodrug salt and structural analogues of KGP94, a lead inhibitor of cathepsin L
2017, Bioorganic and Medicinal Chemistry Letters
The magnitude of expression of cathepsin L, often upregulated in the tumor microenvironment, correlates with the invasive and metastatic nature of certain tumors. Inhibition of cathepsin L represents an emerging strategy for the treatment of metastatic cancer. A potent, small-molecule inhibitor (referred to as KGP94) of cathepsin L, and new KGP94 analogues were synthesized. (3,5-Dibromophenyl)-(3-hydroxyphenyl) ketone thiosemicarbazone (22), with an IC₅₀ value of 202 nM, exhibited similar inhibitory activity against cathepsin L compared to KGP94 (IC₅₀ = 189 nM). Due to limited aqueous solubility of KGP94, a water-soluble phosphate salt (KGP420) was prepared in order to facilitate future in vivo studies. Enzymatic hydrolysis with alkaline phosphatase (ALP) demonstrated that the phosphate prodrug, KGP420, was readily converted to the parent compound, KGP94.
Synthesis and evaluation of in vivo antioxidant, in vitro antibacterial, MRSA and antifungal activity of novel substituted isatin N-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)thiosemicarbazones
2016, European Journal of Medicinal Chemistry
Some new isatin N-(2,3,4,6-tetra-O-acetyl-β-d-glucopyranosyl)thiosemicarbazones 4a-t with different substituents at 1-, 5- and 7-positions of isatin ring have been synthesized by reaction of N-(2,3,4,6-tetra-O-acetyl-β-d-glucopyranosyl)thiosemicarbazide 2 with corresponding isatins 3a-t. Compounds 4a-t were evaluated in vivo for antioxidant activity and in vitro for anti-microorganism activities. The MIC values were found for Gram positive bacteria (MIC = 1.56–6.25 μM), for Gram negative bacteria (MIC = 12.5 μM), and for fungi Aspergillus niger (MIC = 3.12–12.5 μM), Fusarium oxysporum (MIC = 6.25–12.5 μM) and Saccharomyces cerevisiae (MIC = 6.25–12.5 μM). Regarding the antioxidant activity, the SOD, GHS-Px and catalase activities of 4c-i and 4m-r were MIC = 10.57–10.85, 0.27–0.93 and 345.45–399.75 unit/mg protein, respectively. Compounds 4e-h had MIC values of 0.78, 1.56, and 3.12 μM for three clinical MRSA isolates. Compound 4e showed the selective cytotoxic effects against some cancer (LU-1, HepG2, MCF7, P338, SW480, KB) cell lines and normal fibroblast cell line NIH/3T3.

View all citing articles on Scopus

View full text

NoteSynthesis and characterization of new aromatic aldehyde/ketone 4-(β-d-glucopyranosyl)thiosemicarbazones

Abstract

Graphical abstract

Section snippets

General

Supplementary data

Acknowledgement

Chem. Ber.

Tetrahedron Lett.

Eur. J. Med. Chem.

Polyhedron

J. Chem. Soc., Dalton Trans.

J. Organomet. Chem.

Spectrochim. Acta, Part A

Carbohydr. Res.

Polyhedron

Acta Crystallogr., Sect. C

Chem. Res. Chinese U.

Curr. Protein Pept. Sci.

Curr. Opin. Investig. Drugs

Curr. Med. Chem.

Chem. Rev.

Eur. J. Org. Chem.

Mini-Rev. Med. Chem.

J. Med. Chem.

J. Inorg. Biochem.

Eur. J. Med. Chem.

Note
Synthesis and characterization of new aromatic aldehyde/ketone 4-(β-d-glucopyranosyl)thiosemicarbazones