Design, synthesis and antitumor activity evaluation of novel 2,6-dichloro-3,5-dinitrotoluene derivatives

doi:10.5246/jcps.2018.03.017

Abstract

Abstract:

A series of novel 2,6-dichloro-3,5-dinitrotoluene derivatives were designed, synthesized in the present study, and their antitumor activities against five cell lines (A431, HepG2, A549, HT-29 and HEK-293) were tested. Most of the compounds exhibited moderate-to-significant cytotoxicity and high selectivity against one or more cell lines in comparison with cisplatin. Studies on their preliminary structure-activity relationships (SARs) indicated that compounds containing phenyl (piperazin-1-yl) methanone groups, especially chlorine atom at 4-position of the phenyl ring, were more effective. Compound 4g was found to be the most potent derivative with IC₅₀values of 1.04, 3.20, 6.93, 4.10 and 20.15 μmol/L against A431, Hep G2, A549, HT-29 and HEK-293 cell lines, respectively, which was better than positive control cisplatin, one of the most clinically used chemotherapeutic drugs.

Key words: 2,6-Dichloro-3,5-dinitrotoluene, Cytotoxic activity, Structure-activity relationships

CLC Number:

R916

Supporting:

Jiayuan Jiao, Hao Hu, Siyuan Wei, Wanqiu Wang, He Lin, Baoshan Chai. Design, synthesis and antitumor activity evaluation of novel 2,6-dichloro-3,5-dinitrotoluene derivatives[J]. Journal of Chinese Pharmaceutical Sciences, 2018, 27(3): 159-169.

References

[1] Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer Statistics, 2017. CA Cancer J. Clin. 2017, 67, 7-30.

[2] Torre, L.A.; Siegel, R.L.; Ward, E.M.; Jemal, A. Global cancer incidence and mortality rates and trends-an update. Cancer Epidemiol. Biomarkers Prev. 2016, 25, 16-27.

[3] Que, L.L.; Wang, H.X.; Cao, B.S.; Yang, X.D.; Wang, K.; Yu, S.W. The regulation and functions of transcription factor Nrf2 in cancer chemoprevention and chemoresistance. J. Chin. Pharm. Sci. 2011, 20, 5-19.

[4] Miller, K.D.; Siegel, R.L.; Lin, C.C.; Mariotto, A.B.; Kramer, J.L.; Rowland, J.H.; Stein, K.D.; Alteri, R.; Jemal, A. Cancer treatment and survivorship statistics, 2016. CA Cancer J. Clin. 2016, 66, 271-289.

[5] Brawley, O.W. The role of government and regulation in cancer prevention. Lancet Oncol. 2017, 18, e483-e493.

[6] Raether, W.; Hänel, H. Nitroheterocyclic drugs with broad spectrum activity. Parasitol. Res. 2003, 90, S19-39.

[7] Tocher, J.H. Reductive activation of nitroheterocyclic compounds. Gen. Pharmac. 1997, 28, 485-487.

[8] Man, C.C.; Priscila, L.B.; Jean, L.D. A prodrug approach to improve the physico-chemical properties and decrease the genotoxicity of nitro compounds. Curr. Pharm. Des. 2011, 17, 3515-3526.

[9] Li, H.C.; Guan, A.Y.; Huang, G.; Liu, C.L.; Li, Z.N.; Xie, Y.; Lan, J. Design, synthesis and structure-activity relationship of novel diphenylamine derivatives. Bioorg. Med. Chem. 2016, 24, 453-461.

[10] Zhong, K.; Li, X.; Xie, C.; Zhang, D.F.; Chen, X.Y. Effects of renal impairment on the pharmacokinetics of morinidazole: uptake transporter-mediated renal clearance of the conjugated metabolites. Antimicrob. Agents Chemother. 2014, 58, 4153-4161.

[11] Cen, J.D.; Zhong, H.J. α-Substituted of 2-methyl-5-nitro imidazole-1-Ethanol derivatives. CN 200310100057.0, 2003.

[12] Thompson, A.M.; O’Connor, P.D.; Marshall, A.J.; Yardley, V.; Maes, L.; Gupta, S.; Launay, D.; Braillard, S.; Chatelain, E.; Franzblau, S.G.; Wan, B.; Wang, Y.H.; Ma, Z.K.; Cooper, C.B.; Denny, W.A. 7-Substituted 2-nitro-5, 6-dihydroimidazo [2, 1-b] [1, 3] oxazines: novel antitubercular agents lead to a new preclinical candidate for visceral leishmaniasis. J. Med. Chem. 2017, 60, 4212-4233.

[13] Mukherjee, A.; Dutta, S.; Sanyal, U. Evaluation of antitumor efficacy and toxicity of novel 6-nitro-2-(3-chloropropyl)-1H-benz [de] isoquinoline-1, 3-dione in vivo in mouse. J. Cancer Res. Ther. 2013, 9, 442-446.

[14] LaVoie, E.J.; Singh, S.K.; Liu, L.F. Nitro and amino substituted heterocycles as topoisomerase I targeting agents. WO 2004014862, 2004.

[15] Feng, Q.; Wang, M.Z.; Xiong, L.X.; Liu, Z.L.; Li, Z.M. Synthesis and insecticidal activities of novel analogues of chlorantraniliprole containing nitro group. Chem. Res. Chin. Univ. 2011, 27, 610-613.

[16] Yang, J.C.; Li, M.; Wu, Q.; Chang, X.H.; Liu, C.L. Design, synthesis and insecticidal evaluation of aryloxy dihalopropene derivatives. Bioorg. Med. Chem. 2016, 24, 383-390.

[17] Guan, A.Y.; Liu, C.L.; Huang, G.; Li, H.C.; Hao, S.L.; Xu, Y.; Li, Z.N. Design, synthesis, and structure-activity relationship of novel aniline derivatives of chlorothalonil. J. Agric. Food Chem. 2013, 61, 11929-11936.

[18] Guan, A.Y.; Liu, C.L.; Yang, X.P.; Dekeyser, M. Application of the intermediate derivatization approach in agrochemical discovery. Chem. Rev. 2014, 114, 7079-7107.

[19] Liu, C.L.; Guan, A.Y.; Yang, J.D.; Chai, B.S.; Li, M.; Li, H.C.; Yang, J.C.; Xie, Y. Efficient approach to discover novel agrochemical candidates: intermediate derivatization method. J. Agric. Food Chem. 2016, 64, 45-51.

[20] Li, L.; Li, M.; Chi, H.W.; Yang, J.C.; Li, Z.N.; Liu, C.L. Discovery of flufenoxystrobin: Novel fluorine-containing strobilurin fungicide and acaricide. J. Fluor. Chem. 2016, 185, 173-180.

[21] López, S.; Carilla, J.; Fajarí, L.; Julià, L.; Brillas, E.; Labarta, A. Inert carbon free radicals. 13. New free radicals of PTM (perchlorotriphenylmethyl) series with meta functionalization. Tetrahedron. 1995, 51, 7301-7312.

[22] Christophe, D.; Raphaeel, S.; Yves, F. Nickel (0)/dihydroimidazol-2-ylidene complex catalyzed coupling of aryl chlorides and amines. J. Org. Chem. 2002, 67, 3029-3036.

[23] Michael, H.; Jeffrey, E.; Dinesh, G. Sequential mono-N-arylation of piperazine nitrogens. Part 1: A simplified method and its application to the preparation of a key N,N’-biaryl piperazine antifungal intermediate. Tetrahedron Lett. 1999, 40, 5655-5659.

[24] Ramachary, D.B.; Narayana, V.V. Sequential Combination of Ruthenium-, Base-, and Gold-Catalysis-A New Approach to the Synthesis of Medicinally Important Heterocycles. Eur. J. Org. Chem. 2011, 19, 3514-3522.

[25] Ahmed, K.; Surendranadha, R.J.; Vijaya, B.E.; Dastagiri, D. Base-free monosulfonylation of amines using tosyl or mesyl chloride in water. Tetrahedron Lett. 2008, 49, 348-353.

[26] Brown, G.D.; David, H.; Colin, S.; Sajinder, L.; Price, P.M.; Frank, B. Two routes to [11C-carbonyl] organo-isocyanates utilizing [11C] phosgene ([11C] organo-isocyanates from [11C] phosgene). Nucl. Med. Biol. 2001, 28, 991-998.
[27] Muthukumaran, N.; Gandhi, S.; Periasamy, V.; Roberta, B.; Paolo, S.; Grzegorz, M.J. Organonickel complexes encum-bering bis-imidazolylidene carbene ligands: Synthesis, X-ray structure and catalytic insights on Buchwald-Hartwig amina-tion reactions. J. Organometal. Chem. 2017, 831, 1-10.