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Anti-Cancer Agents in Medicinal Chemistry

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ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

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Research Article

Biological Activity, Apoptotic Induction and Cell Cycle Arrest of New Hydrazonoyl Halides Derivatives

Author(s): Magda F. Mohamed*, Hamdi M. Hassaneen*, Emad M. Elzayat, Salwa M. El-Hallouty, May El-Manawaty, Fatma M. Saleh, Yasmin Mohamed, Dina El-Zohiry, Ghada Fahmy, Nesma Abdelaal, Nouran Hassanin and Nouran Hossam

Volume 19, Issue 9, 2019

Page: [1141 - 1149] Pages: 9

DOI: 10.2174/1871520619666190306123658

Price: $65

Abstract

Background: The hydrazonoyl halides are presently an important target in the field of medicinal chemistry. The interest in the chemistry of hydrazonoyl halides is a consequence of the fact that they undergo a wide variety of reactions which provide routes to a myriad of both heterocyclic and acyclic compounds. In addition, they have diverse biological activities such as antiviral, anthelmintic, antiarthropodal, fungicidal, herbicidal, insecticidal, pesticidal, acaricidal and miticidal Activity correlated to the presence of hydrazonoyl halides. Moreover, many applications in both industrial and pharmaceutical fields have been found to be associated with these halides. Depending on the above facts and continuation to our work, we herein report on the evaluation of the anticancer activity of these two halides prepared according to the published work and trying to know their molecular mechanism that they proceed to stop proliferation and metastasis of tumor cells by molecular tools such as real time PCR using different apoptotic genes, and cell cycle assay.

Objective: The goal of this present study is to bring attention to the biological activities of hydrazonoyl halides and the molecular pathway they follow to exert their role in apoptotic death of cancer cell.

Methods: Synthesis of hydrazonoyl halides 2c and 2f. The cytotoxic effect against different human cancer cell lines PC3, HepG-2, HCT-116, MCF-7 and also on normal human cell lines as MCF-10 and MCF-12 in a monolayer culture model was evaluated. Their mechanism of action inside cancer cell was evaluated using different molecular tools.

Conclusion: Strong and promising chemotherapeutic hydrazonoyl halides (2a-2f) were evaluated for their different biological activities. As antimicrobial agents, results indicated that three compounds 2a, 2e and 2f exhibited high activity against two tested gram positive bacteria Staphylococcus aureus, Bacillus subtilis, and gram negative ones Escherichia coli, and Pseudomonas aeruginosa, the rest of the compounds were found to be moderately active against the tested microorganisms. Regarding their antifungal effect, compound 2c exhibited potent and promising effect against Candida albicans, while 2b was the most potent toward Aspergillus flavus Link. The compound 2f has repellent effect. With respect to the in vitro antitumor screening, this was done on different human cancer cell lines; namely PC3, HepG-2, HCT-116, MCF-7 and also on normal human cell lines; as MCF-10 and MCF-12 (normal breast epithelial cell and non-tumorigenic breast epithelial cell line) in a monolayer culture model where screening has been conducted at 100μg/ml (single dose test). Single dose test (100μg/ml) showed that, in case of PC3, all compounds have cytotoxic activity over 90% inhibition, 4 compounds have cytotoxic activity with 100% inhibition with Human colon cancer cell line, 4 compounds showed over 90% inhibition with MCF7 cell line and 4 compounds showed cytotoxic activity over 90% inhibition with HepG-2. Results of IC50 values for most promising compounds showed compounds with values lower than 20μM for all tested human cancer cell line. The promising hydrazonoyl halide 2c and 2f were selected for molecular study to know how they could act inside cancer cell causing death. Two biochemical tests were performed using the two halides 2c and 2f to predict their mechanism of action against breast carcinoma. Real time PCR analysis indicates that the two compounds induced the apoptosis of MCF7 cells through the up regulation of caspase-3, BAX mediated P53 mechanism but unfortunately, they promote the expression of anti-apoptotic protein BCL2. Also, cell cycle assay was performed using two different cell lines MCF7 and HCT116 and data revealed that the two compounds 2c and 2f induced apoptotic cells death of both lines via cell growth arrest at G2/M phase. In addition, it was noted that 2c induced arrest in the two lines more efficiently than 2f at G2/M phase.

Keywords: Antimicrobial activity, cytotoxicity, hydrazonoyl halides, p53, BAX, caspase3, Bcl-2, cell cycle arrest, PC3, HCT-116, MCF, HepG-2.

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[1]
Habib, H.M. The antiviral effect of some substituted α-Keto hydrazidoyl bromides. Egypt. J. Microbiol., 1987, 22(1), 129-142.
[2]
Folz, S.D.; Rector, D.L.; Geng, S. Efficacy of P-Toluoyl chloride phenylhydrazone against gastrointestinal helminths in ovines. J. Parasitol., 1976, 62(2), 281-285.
[3]
Folz, S.D.; Pax, R.A.; Thomas, E.M.; Bennett, J.L.; Lee, B.L.; Conder, G.A. Detecting in vitro anthelmintic effects with a micromotility meter. Vet. Parasitol., 1987, 24, 241-250.
[4]
Folz, S.D.; Pax, R.A.; Klei, T.R.; Thomas, E.M.; Ash, K.A.; Conder, G.A.; Bennett, J. Development of a novel in vitro equine anthelmintic assay. J. Vet. Pharmacol. Ther., 1988, 11(2), 177-182.
[5]
Molodykh, Z.V.; Buzykin, B.I.; Kudrina, M.A.; Sysoeva, L.P.; Gazetdimova, N.G.; Neklesova, I.D.; Kitaev, Y.P. Antimicrobial activity of certain aryl hydrazones of acyl halides and aryl hydrazides of carboxylic acids. Khimiko-Farmatsevticheskii Z., 1980, 14(3), 33-42.
[6]
Kaugars, G. Halogen substituted pyrininealdehyde phenyl hydrazones. U.S. Patent 3699111A, 1972.
[7]
Kaugars, G. Thiophenecarbonyl chloride phenylhydrazones. U.S. Patent 3809703A,, 1974.
[8]
Moon, M.W. Chlorination of aldehyde and ketone phenylhydrazones. J. Org. Chem., 1972, 37(3), 383-385.
[9]
Shawali, A.S.; Samy, N.A. Hydrazonoyl halides: Their versatile biological activities. Open Bioactive Compd. J., 2009, 2(1), 8-16.
[10]
Shawali, A.S.; Párkanyi, C. Hydrazidoyl halides in the synthesis of heterocycles. J. Heterocycl. Chem., 1980, 17(5), 833-854.
[11]
Shawali, A.S. Reactions of hydrazidoyl halides with sulfur compounds. Heterocycles, 1983, 20, 2239-2285.
[12]
Shawali, A.S. Reactions of heterocyclic compounds with nitrilimines and their precursors. Chem. Rev., 1993, 93(8), 2731-2777.
[13]
Shawali, A.S.; Abdallah, M.A. The chemistry of heterocyclic hydrazonoyl halides. Adv. Heterocycl. Chem., 1995, 63, 277-338.
[14]
Shawali, A.S.; Elsheikh, S.M. Annelated[1,2,4,5]Tetrazines. J. Heterocycl. Chem., 2001, 38(3), 541-559.
[15]
Shawali, A.S.; Mosselhi, M.A.N. Hydrazonoyl halides: Useful building blocks for the synthesis of arylazoheterocycles. J. Heterocycl. Chem., 2003, 40(4), 725-746.
[16]
Shawali, A.S.; Mosselhi, M.A.N. The chemistry of thiohydrazonates and their utility in organic synthesis. J. Sulfur Chem., 2005, 26(3), 267-303.
[17]
Shawali, A.S.; Edrees, M.M. Reactions of nitrilimines with heterocyclic amines and enamines. convenient methodology for synthesis and annulation of heterocycles. Gen. Pap. Ark., 2006, IX, 292-365.
[18]
Shawali, A.S.; Sherif, S.M. The chemistry of hydrazonates. Curr. Org. Chem., 2007, 11(9), 773-799.
[19]
Shawali, A.S.; Farghaly, T.A. Reactions of hydrazonoyl halides with heterocyclic thiones. convenient methodology for heteroannulation, synthesis of spiroheterocycles and heterocyclic ring. ARKIVOC, 2008, 2008, 18-64.
[20]
Shawali, A.S. Tandem in situ generation and 1, 5-electrocyclization of n-hetaryl nitrilimines. a facile methodology for synthesis of annulated 1, 2, 4-triazoles and their acyclo c-nucleosides. ARKIVOC, 2010, 2010, 18-64.
[21]
Shawali, S.A.; Abdelhamid, O.A. Synthesis of spiro-heterocycles via 1,3-dipolar cycloadditions of nitrilimines to exoheterocyclic enones. site-, regio- and stereo-selectivities overview. Curr. Org. Chem., 2012, 16(22), 2673-2689.
[22]
Butler, R.N.; Scott, F.L. Versatile reactive intermediates-hydrazidic halides. Chem. Ind., 1970, 38, 1216-1221.
[23]
Chattaway, F.D.; Farinholt, L.H. XVI. The formation of glyoxalosazones by the interaction of dichloroacetaldehyde and aryl hydrazines. J. Chem. Soc., 1930, 94-98.
[24]
Farag, A.M.; Kheder, N.A.; Budesinsky, M. Regioselective synthesis of polysubstituted 3, 3′-bi-1h-pyrazole derivatives via 1, 3-dipolar cycloaddition reactions. Tetrahedron, 1997, 53(27), 9293-9300.
[25]
Shawali, A.S.; Farag, A.M.; Albar, H.A.; Dawood, K.M. Facile syntheses of bi-1,2,4-triazoles via hydrazonyl halides. Tetrahedron, 1993, 49(13), 2761-2766.
[26]
Farag, M.A.; Shawali, S.A.; Algharib, S.M.; Dawood, M.K. One-step synthesis of novel 2,2′-bi(4,5-dihydro-1,3,4-thiadiazole) and 2,3-disubstituted 1,4-benzothiazine derivatives. Tetrahedron, 1994, 50(17), 5091-5098.
[27]
Farag, A.M.; Kandeel, Z.E.; Dawood, K.M.; Algharib, M.S. A facile, one-pot synthesis of novel 2, 2′-bi (4, 5-dihydro-1, 3, 4-selenadiazole) derivatives via dihydrazonoyl dihalides. Phosphorus Sulfur Silicon Relat. Elem., 1994, 91(1-4), 129-136.
[28]
Dawood, K. One-pot synthesis of novel polysubstituted pyrazole and pyrrolo [2, 1-b] benzothiazole derivatives. J. Chem. Res. Synopses, 1998, 128-129.
[29]
Hassaneen, H.M.; Saleh, F.M.; Mohammed, Y.S.; Awad, E.M. A convenient regioselective synthesis of novel 1,4‐phenylenemethylene-6,6′-bis-([1,2,4‐triazolo]-[4,3-b][1,2,4] -triazin-7(1H)‐ones). J. Heterocycl. Chem., 2017, 54(6), 3015-3022.
[30]
Mabkhot, Y.N.; Barakat, A.; Al-Majid, A.M.; Alshahrani, S.; Yousuf, S.; Choudhary, M.I. Synthesis, reactions and biological activity of some new bis-heterocyclic ring compounds containing sulphur atom. Chem. Cent. J., 2013, 7(1), 112.
[31]
Padmavathi, V.; Mahesh, K.; Subbaiah, D.R.C.V.; Deepti, D.; Reddy, G.S. Synthesis and biological activity of a new class of sulfone linked bis (heterocycles). ARKIVOC, 2009, 2009, 195-208.
[32]
Nagaraju, K.; Harikrishna, N.; Vasu, K.; Rao, C.V. Synthesis and biological activity of novel bis and mono heterocycles of thienopyrimidine derivatives. Indo Am. J. Pharm. Res., 2015, 5(4), 1604-1612.
[33]
Mabkhot, Y.N.; Barakat, A.; Al-Majid, A.M.; Choudhary, M.I. Synthesis of thieno [2, 3-b] thiophene containing bis-heterocycles-novel pharmacophores. Int. J. Mol. Sci., 2013, 14(3), 5712-5722.
[34]
Bisceglia, J.Á.; García, M.B.; Massa, R.; Magri, M.L.; Zani, M.; Gutkind, G.O.; Orelli, L.R. Synthesis, characterization and biological activity of bis(3-aryl-1-hexahydropyrimidinyl)methanes. novel heterocyclic polyamine derivatives. J. Heterocycl. Chem., 2004, 41(1), 85-90.
[35]
Hu, L.M.; Li, X.S.; Chen, Z.Y.; Liu, Z.J. Synthesis and biological activity of novel bis-heterocyclic compounds containing 1h-pyrazole and thiazole. Ch. J. Org. Chem., 2003, 23(10), 1131-1134.
[36]
Jwad, R.S. Synthesis of some new bis-heterocyclic derivatives based on 1, 2, 3-triazoline and study their antibacterial activity. J. Al-Nahrain Univ., 2012, 15(2), 55-62.
[37]
Abdella, A.M.; Mohamed, M.F.; Mohamed, A.F.; Elwahy, A.H.M.; Abdelhamid, I.A. Novel bis(dihydropyrano[3,2-c]chromenes): Synthesis, antiproliferative effect and molecular docking simulation. J. Heterocycl. Chem., 2018, 55(2), 498-507.
[38]
Mohamed, M.F.; Ibrahim, N.S.; Elwahy, A.H.M.; Abdelhamid, I.A. Molecular studies on novel antitumor bis 1,4-dihydropyridine derivatives against lung carcinoma and their limited side effects On normal melanocytes. Anticancer. Agents Med. Chem., 2018, 18(5), 2156-2168.
[39]
Ibrahim, N.S.; Mohamed, M.F.; Elwahy, A.H.M.; Abdelhamid, I.A. biological activities and docking studies on novel bis 1,4-DHPS linked to arene core via ether or ester linkage. Lett. Drug Des. Discov., 2018, 15, 1036-1045.
[40]
Salama, S.K.; Mohamed, M.F.; Darweesh, A.F.; Elwahy, A.H.M.; Abdelhamid, I.A. Molecular docking simulation and anticancer assessment on human breast carcinoma cell line using novel bis(1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile) and bis(1,4-dihydropyrazolo[4′,3′:5,6]pyrano[2,3-b]pyridine-6-carbonitrile) derivatives. Bioorg. Chem., 2017, 71, 19-29.
[41]
Mohamed, M.F.; Darweesh, A.F.; Elwahy, A.H.M.; Abdelhamid, I.A. Synthesis, characterization and antitumor activity of novel tetrapodal 1,4-dihydropyridines: p53 induction, cell cycle arrest and low damage effect on normal cells induced by genotoxic factor H2O2. RSC Adv., 2016, 6(47), 40900-40910.
[42]
Mohamed, M.F.; Abdelmoniem, A.M.; Elwahy, A.H.M.; Abdelhamid, I.A. DNA fragmentation, cell cycle arrest, and docking study of novel bis spiro-cyclic 2-oxindole of pyrimido[4,5-b]quinoline-4,6-dione derivatives against breast carcinoma. Curr. Cancer Drug Targets, 2018, 18(4), 372-381.
[43]
Akbas, E.; Berber, I. Antibacterial and antifungal activities of new pyrazolo [3, 4-d] pyridazin derivatives. Eur. J. Med. Chem., 2005, 40(4), 401-405.
[44]
Bildirici, İ.; Şener, A.; Tozlu, İ. Further derivatives of 4-benzoyl-1, 5-diphenyl-1h-pyrazole-3-carboxylic acid and their antibacterial activities. Med. Chem. Res., 2007, 16(7-9), 418-426.
[45]
Bildirici, İ.; Şener, A.; Atalan, E.; Battal, A.; Genç, H. Synthesis and antibacterial activity of 4-benzoyl-1-(4-carboxy-phenyl)-5-phenyl-1h-pyrazole-3-carboxylic acid and derivatives. Med. Chem. Res., 2009, 18(5), 327-340.
[46]
Hassaneen, H.M.; Shawali, A.S. Regioselective synthesis of some functionalized 3, 4′-bis-(pyrazolyl) ketones and chemoselectivity in their reaction with hydrazine hydrate. Eur. J. Chem., 2013, 4(2), 102-109.
[47]
Jain, A.K.; Sharma, S.; Vaidya, A.; Ravichandran, V.; Agrawal, R.K. 1,3,4-thiadiazole and its derivatives: A review on recent progress in biological activities. Chem. Biol. Drug Des., 2013, 81(5), 557-576.
[48]
Parveen, R.; Ahmad, S.; Mishra, R.; Alam, S. A potential review on thiadiazoles. Int. J. ChemTech Res., 2013, 5(6), 2917-2923.
[49]
Ajay Kumar, K.; Kumar, V.; Renuka, N. Thiadiazoles: Molecules of diverse applications-a review. Int. J. Pharm. Tech. Res., 2013, 5(1), 239-248.
[50]
Hassaneen, H.M.; Hilal, R.H.; Elwan, N.M.; Harhash, A.; Shawali, A.S. The regioselectivity in the formation of pyrazolines and pyrazoles from nitrile imines. J. Heterocycl. Chem., 1984, 21(4), 1013-1016.
[51]
Wolkoff, P. A new method of preparing hydrazonyl halides. Can. J. Chem., 1975, 53(9), 1333-1335.
[52]
Rector, D.L.; Folz, S.D.; Conklin, R.D.; Nowakowski, L.H.; Kaugars, G. Structure-activity relationships in a broad-spectrum anthelmintic series. acid chloride phenylhydrazones. I. aryl substitutions and chloride variations. J. Med. Chem., 1981, 24(5), 532-538.
[53]
Bazian, A.; Taheri, M.; Alavi, H. Synthesis of 4′-[3-Methyl-5-thioxo-1H-1,2,4-triazol-4(5H)-Yl]-2′,5′-diphenyl-2′,4′-dihydro spiro[indolin-3,3′[1,2,4]triazol]-2-one derivatives. Russ. J. Gen. Chem., 2014, 84(3), 586-592.
[54]
Stille, J.K.; Harris, F.W. Polymers from 1,3-dipole addition reactions: The nitrilimine dipole. J. Polym. Sci. Part B Polym. Lett.,, 1966, 4(5), 333-336.
[55]
Shier, W. Mammalian cell culture on $5 a day: A laboratory manual of low cost methods. Los Banos, Univ. Philipp., 1991, 64
[56]
Bauer, A.W.; Kirby, W.M.; Sherris, J.C.; Turck, M. Antibiotic susceptibility testing by a standardized single disk method. Am. J. Clin. Pathol., 1966, 45(4), 493-496.
[57]
Ncclss. Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts ; Approved Standard — Second Edition Serving the World ’ s Medical Science Community Through Voluntary Consensus;, 2002, Vol. 22
[58]
Rex, J.H.; Johnson, E.M.; Ghannoum, M.A.; Knapp, C.C.; Alexander, B.D.; Motyl, M.R.; Andes, D.; Ostrosky-Zeichner, L.; Brown, S.D.; Pfaller, M.A. Method for antifungal disk diffusion susceptibility testing of yeasts: Approved Guideline M44-A. , 2009; Vol. 24, .
[59]
El-Menshawi, B.; Fayad, W.; Mahmoud, K. Screening of natural products for therapeutic activity against solid tumors. Indian J. Exp. Biol., 2010, 48, 258-264.
[60]
Grever, M.R.; Schepartz, S.A.; Chabner, B.A. The national cancer institute: Cancer drug discovery and development program. Semin. Oncol., 1992, 19(6), 622-638.
[61]
Boyd, M.R.; Paull, K.D. Some practical considerations and applications of the national cancer institute in vitro anticancer drug discovery screen. Drug Dev. Res., 1995, 34(2), 91-109.
[62]
Mohamed, M.F.; Hassaneen, H.M.; Abdelhamid, I.A. Cytotoxicity, molecular modeling, cell cycle arrest, and apoptotic induction induced by novel tetrahydro-[1,2,4]triazolo[3,4-a]isoquinoline chalcones. Eur. J. Med. Chem., 2018, 143(1), 532-541.
[63]
El-Sawy, E.R.; Ebaid, M.S.; Abo-Salem, H.M.; El-Hallouty, S.; Kassem, E.M.; Mandour, A.H. Synthesis and biological activity of novel series of 4-methoxy, and 4,9-dimethoxy-5-substituted furo[2,3-g]-1,2,3-benzoxathiazine-7,7-dioxide derivatives. J. Adv. Res., 2014, 5(3), 337-346.

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