Login Register Cart 0
Generic placeholder image

Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1573-4064
ISSN (Online): 1875-6638

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Synthesis and Erythroid Induction Activity of New Thiourea Derivatives

Author(s): Hina Siddiqui*, Sarah Shafi, Hamad Ali and Syed Ghulam Musharraf

Volume 17, Issue 2, 2021

Published on: 14 May, 2020

Page: [121 - 133] Pages: 13

DOI: 10.2174/1573406416666200514085623

Price: $65

Abstract

Background: The use of medicinal agents to augment the fetal hemoglobin (HbF) accretion is an important approach for the treatment of sickle-cell anemia and β-thalassemia. HbF inducers have the potential to reduce the clinical symptoms and blood transfusion dependence in the patients of β- hemoglobinopathies.

Objective: The current study was aimed to examine the erythroid induction potential of newly synthesized thiourea derivatives.

Methods: Thiourea derivatives 1-27 were synthesized by using environmentally friendly methods. Compounds 3, 10 and 22 were found to be new. The structures of synthesized derivatives were deduced by using various spectroscopic techniques. These derivatives were then evaluated for their erythroid induction using the human erythroleukemic K562 cell line, as a model. The benzidine-H2O2 assay was used to evaluate erythroid induction, while HbF expression was studied through immunocytochemistry using the Anti-HbF antibody. Cytotoxicity of compounds 1-27 was also evaluated on mouse fibroblast 3T3 cell line and cancer Hela cell line using MTT assay.

Result: All the compounds (1-27) have not been reported for their erythroid induction activity previously. Compounds 1, 2, and 3 were found to be the potent erythroid inducing agents with % induction of 45± 6.9, 44± 5.9, and 41± 6.1, at 1.56, 0.78, and 0.78 μM concentrations, respectively, as compared to untreated control (12 ± 1 % induction). Furthermore, compound 1, 2, and 3 significantly induced fetal hemoglobin the expression up to 4.2-fold, 4.06-fold, and 3.52-fold, respectively, as compared to untreated control. Moreover, the compounds 1-4, 6-9, 11, 12, 15, 17, 19, 22, 23, and 25 were found to be non-cytotoxic against the 3T3 cell line.

Conclusion: This study signifies that the compounds reported here may serve as the starting point for the designing and development of new fetal hemoglobin inducers for the treatment of β- hemoglobinopathies.

Keywords: Thiourea derivatives, erythroid induction activity, cytotoxicity, β-thalassemia, HbF induction effect, sickle-cell anemia and β-thalassemia.

Next »
Graphical Abstract

[1]
Gambari R, Fibach E. Medicinal chemistry of fetal hemoglobin inducers for treatment of β-thalassemia. Curr Med Chem 2007; 14(2): 199-212.
[http://dx.doi.org/10.2174/092986707779313318 ] [PMID: 17266579]
[2]
Lozzio CB, Lozzio BB. Human chronic myelogenous leukemia cell-line with positive Philadelphia chromosome. Blood 1975; 45(3): 321-34.
[http://dx.doi.org/10.1182/blood.V45.3.321.321 ] [PMID: 163658]
[3]
Cioe L, McNab A, Hubbell HR, Meo P, Curtis P, Rovera G. Differential expression of the globin genes in human leukemia K562(S) cells induced to differentiate by hemin or butyric acid. Cancer Res 1981; 41(1): 237-43.
[PMID: 6934848]
[4]
Rutherford TR, Clegg JB, Weatherall DJ. K562 human leukaemic cells synthesise embryonic haemoglobin in response to haemin. Nature 1979; 280(5718): 164-5.
[http://dx.doi.org/10.1038/280164a0 ] [PMID: 95354]
[5]
Lowrey CH, Nienhuis AW. Brief report: treatment with azacitidine of patients with end-stage β-thalassemia. N Engl J Med 1993; 329(12): 845-8.
[http://dx.doi.org/10.1056/NEJM199309163291205 ] [PMID: 7689171]
[6]
Ali H, Iftikhar F, Shafi S, et al. Thiourea derivatives induce fetal hemoglobin production in vitro: A new class of potential therapeutic agents for β-thalassemia. Eur J Pharmacol 2019; 855: 285-93.
[http://dx.doi.org/10.1016/j.ejphar.2019.05.027 ] [PMID: 31100414]
[7]
Gambari R, Raschellà G, Biagini R, et al. Predominant expression of zeta and ε globin genes in human leukemia K-562(S6) variant cell line. Experientia 1983; 39(4): 415-6.
[http://dx.doi.org/10.1007/BF01963156 ] [PMID: 6832327]
[8]
Rodgers GP, Dover GJ, Uyesaka N, Noguchi CT, Schechter AN, Nienhuis AW. Augmentation by erythropoietin of the fetal-hemoglobin response to hydroxyurea in sickle cell disease. N Engl J Med 1993; 328(2): 73-80.
[http://dx.doi.org/10.1056/NEJM199301143280201 ] [PMID: 7677965]
[9]
Ikuta T, Atweh G, Boosalis V, et al. Cellular and molecular effects of a pulse butyrate regimen and new inducers of globin gene expression and hematopoiesis. Ann N Y Acad Sci 1998; 850(1): 87-99.
[http://dx.doi.org/10.1111/j.1749-6632.1998.tb10466.x ] [PMID: 9668531]
[10]
Fibach E, Burke LP, Schechter AN, Noguchi CT, Rodgers GP. Hydroxyurea increases fetal hemoglobin in cultured erythroid cells derived from normal individuals and patients with sickle cell anemia or beta-thalassemia. Blood 1993; 81(6): 1630-5.
[http://dx.doi.org/10.1182/blood.V81.6.1630.1630 ] [PMID: 7680923]
[11]
Schwartz EL, Ishiguro K, Sartorelli AC. Induction of leukemia cell differentiation by chemotherapeutic agents. Adv Enzyme Regul 1983; 21: 3-20.
[http://dx.doi.org/10.1016/0065-2571(83)90005-5 ] [PMID: 6400065]
[12]
Metzler-Nolte N. Medicinal applications of metal–peptide bioconjugates. CHIMIA Int J Chem 2007; 61(11): 736-41.
[http://dx.doi.org/10.2533/chimia.2007.736]
[13]
Pete UD, Zade CM, Bhosale JD, et al. Hybrid molecules of carvacrol and benzoyl urea/thiourea with potential applications in agriculture and medicine. Bioorg Med Chem Lett 2012; 22(17): 5550-4.
[http://dx.doi.org/10.1016/j.bmcl.2012.07.017 ] [PMID: 22850211]
[14]
Liav A, Angala SK, Brennan PJ, Jackson M. N-D-aldopentofuranosyl-N'-[p-(isoamyloxy)phenyl]-thiourea derivatives: potential anti-TB therapeutic agents. Bioorg Med Chem Lett 2008; 18(8): 2649-51.
[http://dx.doi.org/10.1016/j.bmcl.2008.03.033 ] [PMID: 18362068]
[15]
Cunha S, Macedo FC, Costa GA, et al. Antimicrobial activity and structural study of disubstituted thiourea derivatives. Monatshefte für Chemie-Chemical Monthly 2007; 138(5): 511-6.
[http://dx.doi.org/10.1007/s00706-007-0600-y]
[16]
Janakiramudu D, Rao DS, Madhu K, Madhava G, Raju CN, Chalapathi PV. Unsymmetrical urea and thiourea derivatives: An efficient nano BF 3-SiO 2 catalyzed PEG-400 mediated sonochemical synthesis and biological evaluation. Organic Communications 2017; 10(3): 201-15.
[17]
Fukuyama M, Miwa K, Ishikawa K. Material for elimination or detoxification of super antigens. US Patent No 5 1999 July; 27928:633.
[18]
Smith J, Liras JL, Schneider SE, Anslyn EV. Solid and solution phase organic syntheses of oligomeric thioureas. J Org Chem 1996; 61(25): 8811-8.
[http://dx.doi.org/10.1021/jo9614102 ] [PMID: 11667859]
[19]
Rowley PT, Ohlsson-Wilhelm BM, Farley BA. K562 human erythroleukemia cells demonstrate commitment. Blood 1985; 65(4): 862-8.
[http://dx.doi.org/10.1182/blood.V65.4.862.862 ] [PMID: 3919782]
[20]
Bianchi N, Ongaro F, Chiarabelli C, et al. Induction of erythroid differentiation of human K562 cells by cisplatin analogs. Biochem Pharmacol 2000; 60(1): 31-40.
[http://dx.doi.org/10.1016/S0006-2952(00)00297-5 ] [PMID: 10807942]
[21]
Viola G, Vedaldi D, Dall’Acqua F, et al. Induction of γ-globin mRNA, erythroid differentiation and apoptosis in UVA-irradiated human erythroid cells in the presence of furocumarin derivatives. Biochem Pharmacol 2008; 75(4): 810-25.
[http://dx.doi.org/10.1016/j.bcp.2007.10.007 ] [PMID: 18022602]
[22]
Iftikhar F, Ali H, Musharraf SG. Cinchona alkaloids as natural fetal hemoglobin inducing agents in human erythroleukemia cells. RSC Advances 2019; 9(31): 17551-9.
[http://dx.doi.org/10.1039/C9RA01744E]
[23]
Pauwels R, Balzarini J, Baba M, et al. Rapid and automated tetrazolium-based colorimetric assay for the detection of anti-HIV compounds. J Virol Methods 1988; 20(4): 309-21.
[http://dx.doi.org/10.1016/0166-0934(88)90134-6 ] [PMID: 2460479]
[24]
Calabrese EJ, Bachmann KA, Bailer AJ, et al. Biological stress response terminology: Integrating the concepts of adaptive response and preconditioning stress within a hormetic dose-response framework. Toxicol Appl Pharmacol 2007; 222(1): 122-8.
[http://dx.doi.org/10.1016/j.taap.2007.02.015 ] [PMID: 17459441]
[25]
Reynolds AR. Potential relevance of bell-shaped and u-shaped dose-responses for the therapeutic targeting of angiogenesis in cancerDose-Response 2010; 8(3)09-049.
[http://dx.doi.org/10.2203/dose-response.09-049.Reynolds]
[26]
Mattson MP. Hormesis defined. Ageing Res Rev 2008; 7(1): 1-7.
[http://dx.doi.org/10.1016/j.arr.2007.08.007 ] [PMID: 18162444]
[27]
Hotamisligil GS, Davis RJ. Cell signaling and stress responses. Cold Spring Harb Perspect Biol 2016; 8(10)a006072
[http://dx.doi.org/10.1101/cshperspect.a006072 ] [PMID: 27698029]
[28]
Park J-I, Choi H-S, Jeong J-S, Han J-Y, Kim I-H. Involvement of p38 kinase in hydroxyurea-induced differentiation of K562 cells. Cell Growth Differ 2001; 12(9): 481-6.
[PMID: 11571231]
[29]
Zhu J, Chin K, Aerbajinai W, Kumkhaek C, Li H, Rodgers GP. Hydroxyurea-inducible SAR1 gene acts through the Giα/JNK/Jun pathway to regulate γ-globin expression. Blood 2014; 124(7): 1146-56.
[http://dx.doi.org/10.1182/blood-2013-10-534842 ] [PMID: 24914133]

Rights & Permissions Print Cite
Article Metrics
14
1
© 2024 Bentham Science Publishers | Privacy Policy