Ukr.Biochem.J. 2020; Volume 92, Issue 4, Jul-Aug, pp. 55-62
doi: https://doi.org/10.15407/ubj92.04.055
Cytotoxic action of maleimide derivative 1-(4-Cl-benzyl)-3-chloro-4-(CF(3)-phenylamino)-1H-pyrrole-2,5-dione toward mammalian tumor cells and its capability to interact with DNA
N. S. Finiuk1,2, I. I. Ivasechko1, O. Yu. Klyuchivska1,
H. M. Kuznietsova3, V. K. Rybalchenko3, R. S. Stoika1,2,3*
1Institute of Cell Biology, National Academy of Sciences of Ukraine, Lviv;
2Ivan Franko National University of Lviv, Ukraine;
3Taras Shevchenko National University of Kyiv, Ukraine;
*e-mail: stoika@cellbiol.lviv.ua
Received: 21 November 2019; Accepted: 15 May 2020
Development of chemical compounds capable to supress tumor progression is a perspective strategy of cancer treatment. Heterocyclic compounds possess a broad spectrum of biological activities, including anticancer one. According to the previous results of in silico modeling maleimide derivative 1-(4-Cl-benzil)-3-Cl-4-(CF3-phenylamino)-1Н-pyrrole-2,5-dione (MI-1) has a potential effect as an inhibitor of tyrosine protein kinases. The present study was aimed at in vitro evaluation of MI-1 cytotoxic effects toward tumor cells of various lines. The viability of tumor cells after incubation with MI-1 was measured by means of 3,4,5-dymetyltiazol-2-yl-2,5-diphenyl-tetrazolium bromide (MTT) test. The MI-1 compound was shown to be toxic for a majority of studied tumor cell lines with IC50 value ranging from 0.8 to 62.2 μg/ml depending on the tissue origin of cells. The most prominent effect of MI-1 towards human cervix carcinoma (KB3-1 and KBC-1) cells with six times higher toxicity towards the multidrug resistant sub-line KBC-1 cells comparing with the action of Doxorubicin was demonstrated. MI-1 inhibited the viability of human pancreatic, hepatocarcinoma, and colon carcinoma cells only in high doses, while human and rat glioblastoma cells were not sensitive to MI-1. Thus, the MI-1 anticancer activity dropped in the following rank of tumor cells: cervix > breast > pancreatic carcinoma > liver carcinoma > colon carcinoma > glioblastoma. Experiments on replacement of methyl green dye from DNA-methyl green complex showed that MI-1 intercalated into DNA molecule structure. The increase of the amount of the additional band of super-spiral DNA in the presence of MI-1 was revealed by means of DNA retardation at electrophoresis in the agarose gel and this effect was more pronounced than the effect of doxorubicin. The data presented indicate a new DNA-targeting mechanism of maleimide derivative 1-(4-Cl-benzil)-3-Cl-4-(CF3-phenylamino)-1Н-pyrrole-2,5-dione anticancer action.
Keywords: 1-(4-Cl-benzil)-3-Cl-4-(CF3-phenylamino)-1Н-pyrrole-2.5-dione, anticancer activity, МТТ
References:
- El-Moghazy SM, George RF, Osman EEA, Elbatrawy AA, Kissova M, Colombo A, Crespan E, Maga G. Novel pyrazolo[3,4-d]pyrimidines as dual Src-Abl inhibitors active against mutant form of Abl and the leukemia K-562 cell line. Eur J Med Chem. 2016;123:1-13. PubMed, CrossRef
- Bhullar KS, Lagarón NO, McGowan EM, Parmar I, Jha A, Hubbard BP, Rupasinghe HPV. Kinase-targeted cancer therapies: progress, challenges and future directions. Mol Cancer. 2018;17(1):48. PubMed, PubMedCentral, CrossRef
- Pat. 22204 UA. Compound of 1,4-disubstituted 5-amino-1,2-dihydropyrrole-3-one having anticancer activity / Dubinina G. G., Volovenko Yu. M. Publ. 25.04.2007.
- Dubinina GG, Chupryna OO, Platonov MO, Borisko PO, Ostrovska GV, Tolmachov AO, Shtil AA. In silico design of protein kinase inhibitors: successes and failures. Anticancer Agents Med Chem. 2007;7(2):171-188. PubMed, CrossRef
- Zhang J, Yang PL, Gray NS. Targeting cancer with small molecule kinase inhibitors. Nat Rev Cancer. 2009;9(11):28-39. PubMed, CrossRef
- Dubinina GG, Golovach SM, Kozlovsky VO, Tolmachov AO, Volovenko YuM. Antiproliferative action of the new derivatives of l-(4-R-benzyl)-3-R1-4-(R2-phenylamino)-1H-pyrrol-2,5-dione. J Organ Pharm Chem. 2007;5(1):39-49. (In Ukrainian).
- Kuznietsova HM, Lynchak OV, Danylov MO, Kotlyar IP, Rybalchenko VK. Effect of dihydropyrrol and maleimide derivatives on the state of liver and colon in normal rats and those with colorectal carcinogenesis induced by dimethylhydrazine. Ukr Biokhim Zhurn. 2013;85(3):74-84. (In Ukrainian).
PubMed, CrossRef - Yablonska S, Lynchak О, Filinska О. Proc. 34th FEBS congress “Manifestation of antiproliferative effects of new kinase inhibitor in respect of normal cell”. Prague, Czech Republic, 2009. P. 352.
- Kuznietsova HM, Yena MS, Kotlyar IP, Ogloblya OV, Rybalchenko VK. Antiinflammatory effects of protein. Sci World J. 2016;2016:2145753.
- Kharchuk IV, Andrukhova OO, Rybal’chenko VK, Andrukhov O. Mechanisms of nephrotoxicityof novel anticancer compound maleimide derivative МІ-1. Fiziol J. 2013;59(3):50-57. (In Ukrainian). PubMed, CrossRef
- Kuznietsova HM, Dziubenko NV, Lynchak OV, Tykhoniuk OI, Milokhov DS, Khilya OV, Rybalchenko VK. Hepatoprotective effect of protein kinase inhibitor 1-(4-cl-benzyl)-3-chloro-4-(cf3-phenylamino)-1h-pyrrole-2,5-dione on rats’ acute cholangitis. Rep Nat Acad Sci Ukr. 2018;(5):83-90. (In Ukrainian). CrossRef
- Kannaiyan R, Mahadevan D. A comprehensive review of protein kinase inhibitors for cancer therapy. Expert Rev Anticancer Ther. 2018;18(12):1249-1270. PubMed, PubMedCentral, CrossRef
- Ismail NSM, Ali GME, Ibrahim DA, Elmetwali AM. Medicinal attributes of pyrazolo[1,5-a]pyrimidine based scaffold derivatives targeting kinases as anticancer agents. Future J Pharm Sci. 2016;2(2):60-70. CrossRef
- Köstler WJ, Zielinski CC. Targeting receptor tyrosine kinases in cancer. In Receptor Tyrosine Kinases: Structure, Functions and Role in Human Disease. New York: Spring, 2015. P. 225-278. CrossRef
- Mudgapalli N, Nallasamy P, Chava H, Chava S, Pathania AS, Gunda V, Gorantla S, Pandey MK, Gupta SC, Challagundla KB. The role of exosomes and MYC in therapy resistance of acute myeloid leukemia: Challenges and opportunities. Mol Aspects Med. 2019;70:21-32. PubMed, CrossRef
- Druker BJ, Guilhot F, O’Brien SG, Gathmann I, Kantarjian H, Gattermann N, Deininger MWN, Silver RT, Goldman JM, Stone RM, Cervantes F, Hochhaus A, Powell BL, Gabrilove JL, Rousselot P, Reiffers J, Cornelissen JJ, Hughes T, Agis H, Fischer T, Verhoef G, Shepherd J, Saglio G, Gratwohl A, Nielsen JL, Radich JP, Simonsson B, Taylor K, Baccarani M, So C, Letvak L, Larson RA, IRIS Investigators. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. 2006;355(23):2408-2417. PubMed, CrossRef
- Kumar A, Ahmad I, Chhikara BS, Tiwari R, Mandal D, Parang K. Synthesis of 3-phenylpyrazolopyrimidine-1,2,3-triazole conjugates and evaluation of their Src kinase inhibitory and anticancer activities. Bioorg Med Chem Lett. 2011;21(5):1342-1346. PubMed, CrossRef
- Lombardo LJ, Lee FY, Chen P, Norris D, Barrish JC, Behnia K, Castaneda S, Cornelius LAM, Das J, Doweyko AM, Fairchild C, Hunt JT, Inigo I, Johnston K, Kamath A, Kan D, Klei H, Marathe P, Pang S, Peterson R, Pitt S, Schieven GL, Schmidt RJ, Tokarski J, Wen ML, Wityak J, Borzilleri RM. Discovery of N-(2-chloro-6-methyl-phenyl)-2-(6-(4-(2-hydroxyethyl)-piperazin-1-yl)-2-methylpyrimidin-4-ylamino) thiazole-5-carboxamide (BMS-354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays. J Med Chem. 2004;47(27):6658-6661. PubMed, CrossRef
- Fabian MA, Biggs WH, Treiber DK, Atteridge CE, Azimioara MD, Benedetti MG, Carter TA, Ciceri P, Edeen PT, Floyd M, Ford JM, Galvin M, Gerlach JL, Grotzfeld RM, Herrgard S, Insko DE, Insko MA, Lai AG, Lélias JM, Mehta SA, Milanov ZV, Velasco AM, Wodicka LM, Patel HK, Zarrinkar PP, Lockhart DJ.
A small molecule–kinase interaction map for clinical kinase inhibitors. Nat Biotechnol. 2005;23(3):329-336. PubMed, CrossRef - Finiuk NS, Ostapiuk YuV, Hreniukh VP, Shalai YaR, Matiychuk VS, Obushak MD, Stoika RS, Babsky AM. Evaluation of antiproliferative activity of pyrazolothiazolopyrimidine derivatives. Ukr Biochem J. 2018;90(2):25-32. CrossRef
- Finiuk NS, Ivasechko II, Klyuchivska OYu, Ostapiuk YuV, Hreniukh VP, Shalai YaR, Matiychuk VS, Obushak MD, Babsky AM, Stoika RS. Apoptosis induction in human leukemia cells by novel 2-amino-5-benzylthiazole derivatives. Ukr Biochem J. 2019;91(2):29-39. CrossRef
- Filak LK, Mühlgassner G, Jakupec MA, Heffeter P, Berger W, Arion VB, Keppler BK. Organometallic indolo[3,2-c]quinolines versus indolo[3,2-d]benzazepines: synthesis, structural and spectroscopic characterization, and biological efficacy. J Biol Inorg Chem. 2010;15(6):903-918. PubMed, PubMedCentral, CrossRef
- Schlacher K. A new road to cancer-drug resistance. Nature. 2018;563(7732):478-480. PubMed, CrossRef
- Housman G, Byler S, Heerboth S, Lapinska K, Longacre M, Snyder N, Sarkar S. Drug resistance in cancer: an overview. Cancers (Basel). 2014;6(3):1769-1792. PubMed, PubMedCentral, CrossRef
- Palchaudhuri R., Hergenrother PJ. DNA as a target for anticancer compounds: methods to determine the mode of binding and the mechanism of action. Curr Opin Biotechnol. 2007;18(6):497-503. PubMed, CrossRef
- Hurley LH. DNA and its associated processes as targets for cancer therapy. Nat Rev Cancer. 2002;2(3):188-200. PubMed, CrossRef
- Mitra S, Nguyen LN, Akter M, Park G, Choi EH, Kaushik NK. Impact of ROS generated by chemical, physical, and plasma techniques on cancer attenuation. Cancers (Basel). 2019;11(7):1030. PubMed, PubMedCentral, CrossRef
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