Synthesis of oxamide-hydrazone hybrid derivatives as potential anticancer agents

Mina Dehbid, Raheleh Tahmasvand, Marzieh Tasharofi, Fatemeh Shojaie, Mahmoudreza Aghamaali, Ali Almasirad , Mona Salimi

Abstract


Background and purpose: Considering various studies implying anticancer activity of the hydrazone and oxamide derivatives through different mechanisms such as kinases and calpain inhibition, herein, we report the synthesis, characterization, and evaluation of the antiproliferative effect of a series of hydrazones bearing oxamide moiety compounds (7a-7n) against a panel of cancer cell lines to explore a novel and promising anticancer agent (7k).

Experimental approach: Chemical structures of the synthesized compounds were confirmed by FTIR, 1H-NMR, 13C-NMR, and mass spectra. The antiproliferative activity and cell cycle progression of the target compound were investigated using the MTT assay and flow cytometry.

Findings/Results: Compound 7k with 2-hydroxybenzylidene structure was found to have a significant in vitro anti-proliferative influence on MDA-MB-231 (human adenocarcinoma breast cancer) and 4T1 (mouse mammary tumor) cells as the model of triple-negative breast cancer, with the IC50-72 h values of 7.73 ± 1.05 and 1.82 ± 1.14 µM, respectively. Following 72-h incubation with compound 7k, it caused MDA-MB-231 cell death through G1/S cell cycle arrest at high concentrations (12 and 16 µM).

Conclusion and implications: Conclusively, this study for the first time reports the anti-proliferative efficacy of compound 7k possessing 2-hydroxyphenyl moiety, which may serve as a potent candidate in triple-negative breast cancer treatment.


Keywords


Anti-proliferation; Cancer; Cell Cycle; Hydrazone; Oxamide.

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References


Ma X, Yu H. Global burden of cancer. Yale J Biol Med. 2006;79(3-4): 85-94.PMID: 17940618.

DeSantis CE, Ma J, Gaudet MM, Newman LA, Miller KD, Sauer AG, et al. Breast cancer statistics. CA Cancer J Clin. 2019;69(6):438-451.DOI: 10.3322/caac.21583.

Dent R, Trudeau M, Pritchard KI, Hanna WM, Kahn HK, Sawka CA, et al. Triple-negative breast cancer: clinical features and patterns of recurrence. Clin Cancer Res. 2007;13(15 Pt 1):4429-4434.DOI: 10.1158/1078-0432.CCR-06-3045.

Almansour NM. Triple-negative breast cancer: a brief review about epidemiology, risk factors, signaling pathways, treatment and role of artificial intelligence. Front Mol Biosci. 2022;9: 36417.DOI: 10.3389/fmolb.2022.836417.

Pernas S, Tolaney SM. HER2-positive breast cancer: new therapeutic frontiers and overcoming resistance. Ther Adv Med Oncol. 2019;11:1-16.DOI: 10.1177/1758835919833519.

Rollas S and Küçükgüzel SG. Biological activities of hydrazone derivatives. Molecules. 2007;12(8):1910-1939.

DOI: 10.3390/12081910.

Şenkardeş S, Han MI, Kulabaş N, Abbak M, Çevik Ö, Küçükgüzel I, et al. Synthesis, molecular docking and evaluation of novel sulfonyl hydrazones as anticancer agents and COX-2 inhibitors. Mol Divers. 2020;24(3):673-689.DOI: 10.1007/s11030-019-09974-z.

Sreenivasulu R, Reddy KT, Sujitha P, Kumar CG, Raju RR. Synthesis, antiproliferative and apoptosis induction potential activities of novel bis (indolyl) hydrazide-hydrazone derivatives. Bioorg Med Chem. 2019;27(6):1043-1055.DOI: 10.1016/j.bmc.2019.02.002.

Mousavi E, Tavakolfar S, Almasirad A, Kooshafar Z, Dehghani S, Afsharinasab A, et al. In vitro and in vivo assessments of two novel hydrazide compounds against breast cancer as well as mammary tumor cells. Cancer Chemother Pharmacol. 2017;79(6):1195-1203.DOI: 10.1007/s00280-017-3318-5.

Nam DH, Lee KS, Kim SH, Kim SM, Jung SY, Chung SH, et al. Design and synthesis of 4-quinolinone 2-carboxamides as calpain inhibitors. Bioorg Med Chem Lett. 2008;8(1):205-209.DOI: 10.1016/j.bmcl.2007.10.097

Zulkepli NA, Rou KVK, Sulaiman WNHW, Salhin A, Saad B, Seeni A. A synthetic hydrazone derivative acts as an apoptotic inducer with chemopreventive activity on a tongue cancer cell line. Asian Pac J Cancer Prev. 2011;12(1):259-263.PMID: 21517268.

Zheng LW, Wu LL, Zhao BX, Dong WL, Miao JY. Synthesis of novel substituted pyrazole-5-carbohydrazide hydrazone derivatives and discovery of a potent apoptosis inducer in A549 lung cancer cells. Bioorg Med Chem. 2009;17(5):1957-1962.DOI: 10.1016/j.bmc.2009.01.037.

do Amaral DN, Cavalcanti BC, Bezerra DP, Ferreira PMP, Castro RDP, Sabino JR, et al. Docking, synthesis and antiproliferative activity of N-acylhydrazone derivatives designed as combretastatin A4 analogues. PLoS One. 2014;9(3):e85380.DOI: 10.1371/journal.pone.0085380.

Takao H, Takeda Y, Haginoya N, Miyazaki M, Nagata M, Kitagawa M, et al. Discovery of novel thieno [2, 3-d] pyrimidin-4-yl hydrazone-based cyclin-dependent kinase 4 inhibitors: synthesis, biological evaluation and structure-activity relationships. Chem Pharm Bull (Tokyo). 2011;59(8):991-1002.DOI: 10.1248/cpb.59.991.

Fan C, Su H, Zhao J, Zhao B, Zhang S, Miao J. A novel copper complex of salicylaldehyde pyrazole hydrazone induces apoptosis through up-regulating integrin β4 in H322 lung carcinoma cells. Eur J Med Chem. 2010;45(4):1438-1446.DOI: 10.1016/j.ejmech.2009.12.048.

Effenberger K, Breyer S, Schobert R. Modulation of doxorubicin activity in cancer cells by conjugation with fatty acyl and terpenyl hydrazones. Eu J Med Chem. 2010;45(5):1947-1954.DOI: 10.1016/j.ejmech.2010.01.037.

Nasr T, Bondock S, Rashed HM, Fayad W, Youns M, Sakr TM. Novel hydrazide-hydrazone and amide substituted coumarin derivatives: synthesis, cytotoxicity screening, microarray, radiolabeling and in vivo pharmacokinetic studies. Eur J Med Chem. 2018;151:723-739.DOI: 10.1016/j.ejmech.2018.04.014.

Zhao Y, Hui J, Wang D, Zhu L, Fang JH, Zhao XD. Synthesis, cytotoxicity and pro-apoptosis of novel benzoisoindolin hydrazones as anticancer agents. Chem Pharm Bull (Tokyo). 2010;58(10):1324-1327.DOI: 10.1248/cpb.58.1324.

Rodrigues DA, Guerra FS, Sagrillo FS, Pinheiro PDSM, Alves MA, Thota S, et al. Design, synthesis, and pharmacological evaluation of first‐in‐class multitarget N‐acylhydrazone derivatives as selective HDAC6/8 and PI3Kα inhibitors. Chem Med Chem. 2020;15(6);539-551.DOI: 10.1002/cmdc.201900716.

Wada CK, Frey RR, Ji Z, Curtin ML, Garland RB, Holms JH, et al. α-Keto amides as inhibitors of histone deacetylase. Bioorg Med Chem Lett. 2003;13:3331-3335.DOI: 10.1016/s0960-894x(03)00685-1.

Lee KY, Lee KS, Jin C, Lee YS. Design and synthesis of calpain inhibitory 6-pyridone 2-carboxamide derivatives. Eur J Med Chem. 2009;44(3):1331-1334.DOI: 10.1016/j.ejmech.2008.02.023.

Tavakolfar S, Mousavi E, Almasirad A, Amanzadeh A, Atyabi SM, Yaghamii P, et al. In vitro anticancer effects of two new potent hydrazide compounds on leukemic cells. Anticancer Agents Med Chem. 2016;16(12):1646-1651.DOI: 10.2174/1871520616666160404112945.

Wang C, Li y, Liu T, Wang Z, Zhang Y, Bao K, et al. Design, synthesis and evaluation of antiproliferative and antitubulin activities of 5-methyl-4-aryl-3-(4-arylpiperazine-1-carbonyl)-4H-1, 2, 4-triazoles. Bioorg Chem. 2020;104:103909.DOI: 10.1016/j.bioorg.2020.103909.

Yousef T, El-Reash GA, Rakha T, El-Ayaan U. First row transition metal complexes of (E)-2-(2-(2-hydroxybenzylidene) hydrazinyl)-2-oxo-N-phenylacetamide complexes. Spectrochim Acta A Mol Biomol Spectrosc. 2011;83(1):271-278.DOI: 10.1016/j.saa.2011.08.030.

Zakalyuzhnyi M, Zakalyuzhnyi YM, Pershin G, Zykova T, Gus' kova T. Benzylidene-and nitrobenzylideneoxanyloyl-hydrazide and their antimicrobial activity. Pharm Chem J. 1973;7: 679-681.DOI: 10.1007/BF00757931.

Cremlyn RJ. Synthesis and spectral data for some derivatives of N-aryloxamic acid hydrazides. J Chem Eng Data.1974;19:288-294.DOI: 10.1021/je60062a005.

El-Gammal OA, El-Reash GA, Ahmed S. Synthesis, spectral characterization, molecular modeling and in vitro antibacterial activity of complexes designed from O2, NO and NO donor Schiff-base ligand. Spectrochim Acta A Mol Biomol Spectrosc. 2015;135:227-240. DOI: 10.1016/j.saa.2014.04.197.

Tierie G. Oxanilhydrazides. Rec Trav Chim. 1993;52(6):533-537.DOI: 10.1002/recl.19770960402.

Shah R. Ligational, potentiometric and floatation studies on Cu (II) complexes of hydrazones derived from p and o-vanillin condensed with diketo hydrazide. J Mol Liq. 2016;220:939-953. DOI: 10.1016/j.molliq.2016.04.047

Tahmasvand R, Bayat P, Vahdaniparast SM, Dehghani S, KooshafarZ, Khaleghi S, et al. Design and synthesis of novel 4-thiazolidinone derivatives with promising anti-breast cancer activity: synthesis, characterization, in vitro and in vivo results. Bioorg Chem. 2020;104:104276,1-13. DOI: 10.1016/j.bioorg.2020.104276.

Asadi M, Mohammadi-Khanaposhtani M, Hosseini FS, Gholami M, Dehpour AR, Amanlou M. Design, synthesis, and evaluation of novel racecadotril-tetrazole-amino acid derivatives as new potent analgesic agents. Res Pharm Sci. 2021;16(4):341-357.DOI: 10.4103/1735-5362.319573.

Mohareb RM, Fleita DH, Sakka OL. Novel synthesis of hydrazide-hydrazone derivatives and their utilization in the synthesis of coumarin, pyridine, thiazole and thiophene derivatives with antitumor activity. Molecules. 2011;16(1):16-27. DOI: 10.3390/molecules16010016.

Wu J, Zhang D, Chen L, Li J, Wang J, Ning C, et al. Discovery and mechanism study of SIRT1 activators that promote the deacetylation of fluorophore-labeled substrate. J Med Chem. 2013,56(3),761-780. DOI: 10.1021/jm301032j.

Cui Z, Li Y, Ling Y, Huang J, Cui J, Wang R, et al. New class of potent antitumor acylhydrazone derivatives containing furan. Eur J Med Chem. 2010;45(12):5576-5584. DOI: 10.1016/j.ejmech.2010.09.007


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