Arene-metal Complexes Based on Naproxen for Antitumor and Anti-inflammatory Applications †

doi:10.7503/cjcu20190534

Abstract

Abstract:

Naproxen(NPX) was used as precursors to prepare three arene complexes[Ru(η ⁶-p-cymene)·(NPX-bpy)Cl]Cl(1), [Os(η ⁶-p-cymene)(NPX-bpy)Cl]Cl(2) and [Ir(η ⁵-Cp ^*)(NPX-bpy)Cl]Cl(3) with arene ruthenium(Ru), osmium(Os) and iridium(Ir) dimers. The complexes were characterized by elemental analysis, electrospray ionization mass spectrometry and nuclear magnetic resonance spectroscopy. The cytotoxicity results showed that the three complexes exhibited little cytotoxic activity against the tumor cell lines(IC₅₀>100 μmol/L), except that complex 1 has moderate activity on NB-4 cells(IC₅₀=45.2 μmol/L), which may be attributed to the higher enrichment of complex 1 in the nucleus than complex 2 and 3. In addition, the three complexes could effectively inhibit the expression of COX-2, equivalent to the anti-inflammatory properties of naproxen, and achieved the multi-functional application of anticancer and anti-inflammatory threapy of arene-metal complexes.

Key words: Arene-metal complex, Anticancer drug, Anti-inflammation, Cyclooxygenase-2

CLC Number:

O614

TrendMD:

XUE Xuling,CHEN Jun,ZHANG Ziyou,WANG Mengmeng,Lü Mengdi,HAO Yuanyuan,HU Jiongsheng,GE Chao,SU Zhi,QIAN Yong,LIU Hongke. Arene-metal Complexes Based on Naproxen for Antitumor and Anti-inflammatory Applications ^†[J]. Chem. J. Chinese Universities, 2020, 41(2): 243.

Figures/Tables 8

Scheme 1 Synthetic routes of target complexes 1—3

Complex	IC₅₀/(μmol·L^-1)
Complex	HeLa	A549	A2780	NB-4
NPX-bpy	>200	>200	>200	>200
1	>200	>200	120.3±1.9	45.2±2.0
2	>200	>200	108.4±4.2	78.6±2.3
3	167.8±2.4	118.3±4.7	109.8±3.3	101.4±1.9
CDDP	1.6±1.2	17.9±0.9	10.0±1.7	4.2±1.1

Fig.2 Inhibition of COX-2 activity after treated with different concentrations of complexes 1—3

Fig.3 Fluorescent spectra of complex 1—3 in aqueous solution(containing 5% DMSO) λex=270 nm.

Fig.4 UV-Vis spectra of complexes 1(A), 2(B) and 3(C) in H2O solution(containing 5% DMSO) incubation for 24 h at 298 K to detect the hydrolysis of the complexes and the absorbance intensity statistics of the complexes 1—3 for different incubation time(D)

Fig.5 CD spectra of CT-DNA bound by complexes 1—3(A—C) with different [complex]/[DNA] values

Fig.6 Gel electrophoresis assay of pBR322 DNA treated with different concentrations of complexes 1—3(A—C)

Fig.7 Intracellular concentrations of metal ions(Ru, Os and Ir) in different organelles after treated with complexes 1—3 using ICP-MS detection

References 50

[1]	Rosenberg B., Vancamp L., Trosko J. E., Mansour V. ., Nature, 1969,222, 385— 386 doi: 10.1038/222385a0 URL
[2]	Fricker S. P., Dalton Trans., 2007,43, 4903— 4917
[3]	Habtemariam A., Melchart M., Fernandez R., ParsonsIain S., Oswald D. H., Parkin A., Fabbiani F. P. A., Davidson J. E., Dawson A., Aird R. E., Jodrell D. I., Sadler P. J., J. Med. Chem., 2006,49(23), 6858— 6868 doi: 10.1021/jm060596m URL
[4]	Pettinari C., Marchetti F., Cerquetella A., Pettinari R., Monari M., Mac Leod T. C. O., Martins L. M. D. R. S., Pombeiro A. J. L., Organomet., 2011,30(6), 1616— 1626 doi: 10.1021/om101146q URL
[5]	Garcia-Fernandez A., Diez J., Manteca A., Sánchez J., García-Navas R., Sierra B. G., Mollinedo F., Gamasa M. P., Lastraet E., Dalton Trans., 2010,39, 10186— 10196 doi: 10.1039/c0dt00206b URL
[6]	Hanif M., Henke H., Meier S. M. Martic S., Labib M., Kandioller W., Jakupec M. A., Arion V. B., Kraatz H. B., Keppler B. K., Hartinger C. G., Inorg. Chem., 2010,49(17), 7953— 7963 doi: 10.1021/ic1009785 URL
[7]	Hartinger C. G., Jakupec M. A., Zorbas S. S., Groessl M., A. Egge., Berger W., Zorbas H., Dyson P. J., Keppler B. K., Chem. & Biodivers., 2008,5(10), 2140— 2155
[8]	Alessio E., Mestroni G., Bergamo A., Gianni S., Curr. Top. Med. Chem., 2004,4(11), 1525— 1535 doi: 10.2174/1568026043387421 URL
[9]	Bergamo A., Sava G., Dalton Trans., 2007,13, 1267— 1272
[10]	Rademaker L. J. M., van-den-Bongard D., Pluim D., Beijnen J. H., Schellens J. H. M., Clin. Cancer Res., 2004,10(11), 3717— 3727 doi: 10.1158/1078-0432.CCR-03-0746 URL
[11]	Clarke M. J., Bitler S., Rennert D., Buchbinder M., Kelman A. D., J. Inorg. Biochem., 1980,12(1), 79— 87 doi: 10.1016/S0162-0134(00)80045-8 URL
[12]	Jakupec M. A., Reisner E., Eichinger A., Pongratz M., Arion V. B., Galanski M., Hartinger C. G., Keppler B. K., J. Med. Chem., 2005,48(8), 2831— 2837 doi: 10.1021/jm0490742 URL
[13]	Groessl M., Reisner E., Hartinger C. G.., Eichinger R., Semenova O., Timerbaev A. R., Jakupec M. A., Arion V. B., Keppler B. K., J. Med. Chem., 2007,50(9), 2185— 2193 doi: 10.1021/jm061081y URL
[14]	Vargiu A. V., Robertazzi A., Magistrato A., Ruggerone P., Carloni P., J. Phys. Chem. B, 2008,112(14), 4401— 4409 doi: 10.1021/jp710078y URL
[15]	Banerjee S., Soldevila-Barreda J. J., Wolny J. A., Wootton C. A., Habtemariam A., Canelón I. R., Chen F., Clarkson G. J., Prokes I., Song L. J., O'Connor P. B., Schünemann V., Sadler P. J., Chem. Sci., 2018,9(12), 3177— 3185 doi: 10.1039/C7SC05058E URL
[16]	Peacock A. F. A., Melchart M., Deeth R. J., Habtemariam A., Parsons S., Sadler P. J., Chem. Eur. J., 2007,13, 2601— 2613 doi: 10.1002/(ISSN)1521-3765 URL
[17]	Romero-Canelon, Isolda, Sadler P. J., Inorg. Chem., 2013,52(21), 12276— 12291 doi: 10.1021/ic400835n URL
[18]	Chen H., Parkinson J. A., Morris R. E., Sadler P. J., J. Am. Chem. Soc., 2003,125(1), 173— 186 doi: 10.1021/ja027719m URL
[19]	Hartinger C. G., Dyson P. J., Chem. Soc. Rev., 2009,38, 391— 401 doi: 10.1039/B707077M URL
[20]	Batchelor L. K., Ortiz D., Dyson P. J., Inorg. Chem., 2019,58(4), 2501— 2513 doi: 10.1021/acs.inorgchem.8b03069 URL
[21]	Pettinari R., Marchetti F., Pettinari C., Condello F., Petrini A., Scopelliti R., Riedel T., Dyson P. J., Dalton Trans., 2015,44, 20523— 20531 doi: 10.1039/C5DT03037D URL
[22]	Liu H. K., Sadler P. J., Acc. Chem. Res., 2011,44(5), 349— 359 doi: 10.1021/ar100140e URL
[23]	Liu H. K., Parkinson J. A., Bella J., Wang F. Y., Sadler P. J., Chem. Sci., 2010,1, 258— 270 doi: 10.1039/c0sc00175a URL
[24]	Liu H. K., Price B. S. J., Wang F. Y., Parkinson J. A., Xu J. J., Bella J., Sadler P. J., Angew. Chem. Int. Ed., 2006,45(48), 8153— 8156 doi: 10.1002/(ISSN)1521-3773 URL
[25]	Li J., Zhang P. P., Xu Y., Su Z., Qian Y., Li S. L., Yu T., Sadler P. J., Liu H. K., Dalton Trans., 2017,46, 16205— 16215 doi: 10.1039/C7DT03374E URL
[26]	Wu Q., Liu L. Y., Li S. L., Wang F. X., Li J., Qian Y., Su Z., Mao Z. W., Sadler P. J., Liu H. K., J. Inorg. Biochem., 2018,189, 30— 39 doi: 10.1016/j.jinorgbio.2018.08.013 URL
[27]	Hao Y. Y., Wu Q., Li J., Ge C., Ma C. Y., Qian Y., Su Z., Liu H. K., Chem. J. Chinese Universities, 2018,39(4), 614— 622
	( 郝元元, 吴琪, 李季, 葛超, 马超盈, 钱勇, 苏志, 刘红科 . 高等学校化学学报, 2018,39(4), 614— 622)
[28]	Carlsen R., Wohlgemuth N., Carlson L., Ess D. H., J. Am. Chem. Soc., 2018,140(35), 11039— 11045 doi: 10.1021/jacs.8b05238 URL
[29]	Yao Z. J., Yu W. B., Lin Y. J., Huang S. L., Li Z. H., Jin G. X., J. Am. Chem. Soc., 2014,136(7), 2825— 2832 doi: 10.1021/ja4115665 URL
[30]	Han Y. F., Jin G. X., Chem. Soc. Rev., 2014,43, 2799— 2823 doi: 10.1039/C3CS60343A URL
[31]	Kong Y. Q., Chen F., Su Z., Qian Y., Wang F. X., Wang X. X., Zhao J., Mao Z. W., Liu, H. K., J. Inorg. Biochem., 2018,182, 194— 199
[32]	Coussens L. M., Werb Z., Nature, 2002,420, 860— 867
[33]	Alberto Mantovani, Paola Allavena, Antonio Sica, Frances Balkwill ., Nature, 2008,454, 436— 444 doi: 10.1038/nature07205 URL
[34]	Ulrich C. M., Bigler J., Potter J. D., Nat. Rev. Cancer, 2006,6, 130— 140
[35]	Mandal P., Kundu B. K., Vyas K., Sabu V., Helen A., Dhankhar S. S., Nagaraja C. M., Bhattacherjee D., Bhabake K. P., Mukhopadhyay S., Dalton Trans., 2018,47, 517— 527
[36]	Tabrizi L., Olasunkanmi L. O., Fadare O. A., Dalton Trans., 2019,48, 728— 740
[37]	Ryan D. M, Coggins M. K., Concepcion J. J., Ashford D. L., Zhen F, Alibabaei L., Ma D., Meyer T. J., Waters M. L., Inorg. Chem., 2014,53(15), 8120— 8128 doi: 10.1021/ic5011488 URL
[38]	Cook T. R., Zheng Y. R., Stang P. J., Chem. Rev., 2012,113(1), 734— 777
[39]	Smith W. L., Malkowski M. G., J. Biol. Chem., 2019,294(5), 1697— 1705
[40]	Zhao C. C., Zheng W. F., Li M. Q., Chinese Journal of Pharmaceuticals., 2003,34(3), 137— 142
	( 赵长春, 郑维发, 李梦秋 . 中国医药工业杂志, 2003,34(3), 137— 142)
[41]	He R., Song H., Wei Z., Inorg. Chim. Acta, 2010,363(11), 2631— 2636
[42]	Liu Z., Habtemariam A., Pizarro A. M., Fletcher S. A., Kisova A., Vrana O., Salassa L., Bruijnincx P. C. A., Clarkson G. J., Brabec V., Sadler P. J., J. Med. Chem. 2011,54(8), 3011— 3026
[43]	Ang W. H., Casini A., Gianni S., Dyson P. J., J. Organomet. Chem., 2011,696(5), 989— 998
[44]	Liu Z., Sadler P. J., Acc. Chem. Res., 2014,47(4), 1174— 1185
[45]	Peacock A. F. A., Habtemariam A., Fernández R., Walland V., Fabbiani F. P. A., Parsons S., Aird R. E., Jodrell D. I., Sadler P. J., J. Am. Chem. Soc., 2006,128(5), 1739— 1748
[46]	Kypr J., Kejnovska I., Renciuk D., Vorlícková M., Nucleic Acids Res., 2009,37(6), 1713— 1725
[47]	Su W., Qian Q., Li P., Li P. Y., Lei X. L., Xiao Q., Huang S., Huang C. S., Cu J. G., Inorg. Chem., 2013,52(21), 12440— 12449
[48]	Grguric-Sipka S. R., Vilaplana R. A., Perez J. M., Fuertes M. A., Alonso C., Alvarez Y., Sabo T. J., Vílchez F. G., J. Inorg. Biochem., 2003,97(2), 215— 220
[49]	Yan Y. K., Melchart M., Habtemariam A., Sadler P. J., Chem. Commun., 2005,38, 4764— 4776
[50]	Meier-Menches S. M., Gerner C., Berger W., Hartinger C. G., Keppler B. K., Chem. Soc. Rev., 2018,47(3), 909— 928