Ukr.Biochem.J. 2020; Volume 92, Issue 2, Mar-Apr, pp. 108-119
doi: https://doi.org/10.15407/ubj92.02.108
Synthesis and anti-leukemic activity of pyrrolidinedione-thiazolidinone hybrids
A. Kryshchyshyn1*, D. Kaminskyy1, O. Roman1, R. Kralovics2, O. Karpenko3, R. Lesyk1
1Department of Pharmaceutical, Organic and Bioorganic Chemistry, Danylo Halytsky Lviv National Medical University, Ukraine;
2Research Center for Molecular Medicine, Austrian Academy of Sciences, Vienna, Austria;
3Enamine Ltd., Kyiv, Ukraine;
*e-mail: kryshchyshyn.a@gmail.com
Received: 22 December 2019; Accepted: 27 March 2020
A series of novel 2-(5-ylidene-4-oxo-2-thioxo-thiazolidin-3-yl)-succinimides and 5-ylidene-3-(1-arylpyrrolidine-2,5-dione)-thiazolidine-2,4-diones were synthesized. An efficient simple protocol for rhodanine-pyrrolidinedione hybrids synthesis which allows avoiding the step of anhydride formation was proposed. Following the previous data on antileukemic properties of related thiazolidinone derivatives, the activity of 19 target compounds was investigated towards four leukemia cell lines: Dami, HL-60, Jurkat, and K562. Among the tested compounds, 3-[5-(4-chloro-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-1-phenyl-pyrrolidine-2,5-dione (Compound 1) possessed good and selective antiproliferative action against Dami and HL-60 cell lines and satisfactory toxicity level (acute toxicity evaluated in vivo in mice).
Keywords: 4-thiazolidinone, anti-leukemic activity, anticancer activity, pyrrolidinedione
References:
- Kaminskyy D, Zimenkovsky B, Lesyk R. Synthesis and in vitro anticancer activity of 2,4-azolidinedione-acetic acids derivatives. Eur J Med Chem. 2009; 44(9): 3627-3636. PubMed, CrossRef
- Senkiv J, Finiuk N, Kaminskyy D, Havrylyuk D, Wojtyra M, Kril I, Gzella A, Stoika R, Lesyk R. 5-Ene-4-thiazolidinones induce apoptosis in mammalian leukemia cells. Eur J Med Chem. 2016; 117: 33-46. PubMed, CrossRef
- Kaminskyy D, den Hartog GJM, Wojtyra M, Lelyukh M, Gzella A, Bast A, Lesyk R. Antifibrotic and anticancer action of 5-ene amino/iminothiazolidinones. Eur J Med Chem. 2016; 112: 180-195. PubMed, CrossRef
- Kaminskyy D, Kryshchyshyn A, Lesyk R. 5-Ene-4-thiazolidinones – an efficient tool in medicinal chemistry. Eur J Med Chem. 2017; 140: 542-594. PubMed, PubMedCentral, CrossRef
- Kaminskyy D, Kryshchyshyn A, Lesyk R. Recent developments with rhodanine as a scaffold for drug discovery. Expert Opin Drug Discov. 2017; 12(12): 1233-1252. PubMed, CrossRef
- Kaminskyy DV, Lesyk RB. Structure-anticancer activity relationships among 4-azolidinone-3-carboxylic acids derivatives. Biopolym Cell. 2010; 26(2): 136-145. CrossRef
- Kaminskyy DV, Roman OM, Atamanyuk DV, Lesyk RB. 5-Ylidene-2-thioxo-4-thiazolidinone-3-succinic acids and their derivatives: synthesis, anticancer activity, QSAR-analysis. J Org Pharm Chem. 2006; 4(1(13)): 41-48. (In Ukrainian).
- Zheng CJ, Song MX Sun L, Wu Y, Hong L, Piao HR. Synthesis and biological evaluation of 5-aryloxypyrazole derivatives bearing a rhodanine-3-aromatic acid as potential antimicrobial agents. Bioorg Med Chem Lett. 2012; 22(23): 7024-7028. PubMed, CrossRef
- Liu JC, Zheng CJ, Wang MX, Li YR, Ma LX, Hou S, Piao HR. Synthesis and evaluation of the antimicrobial activities of 3-((5-phenyl-1,3,4-oxadiazol-2-yl)methyl)-2-thioxothiazolidin-4-one derivatives. Eur J Med Chem. 2014; 74: 405-410. PubMed, CrossRef
- Jin X, Zheng CJ, Song MX, Wu Y, Sun LP, Li YJ, Yu LJ, Piao HR. Synthesis and antimicrobial evaluation of L-phenylalanine-derived C5-substituted rhodanine and chalcone derivatives containing thiobarbituric acid or 2-thioxo-4-thiazolidinone. Eur J Med Chem. 2012; 56: 203-209. PubMed, CrossRef
- Liu XF, Zheng CJ, Sun L, Liu XK, Piao HR. Synthesis of new chalcone derivatives bearing 2,4-thiazolidinedione and benzoic acid moieties as potential anti-bacterial agents. Eur J Med Chem. 2011; 46(8): 3469-3473. PubMed, CrossRef
- Tomašić T, Kovač A, Simčič M, Blanot D, Grdadolnik SG, Gobec S, Kikelj D, Mašič LP. Novel 2-thioxothiazolidin-4-one inhibitors of bacterial MurD ligase targeting D-Glu- and diphosphate-binding sites. Eur J Med Chem. 2011; 46(9): 3964-3975. PubMed, CrossRef
- Orchard MG, Neuss JC, Galley CMS, Carr A, Porter DW, Smith P, Scopes DIC, Haydon D, Vousden K, Stubberfield CR, Young K, Page M. Rhodanine-3-acetic acid derivatives as inhibitors of fungal protein mannosyl Transferase 1 (PMT1). Bioorg Med Chem Lett. 2004; 14(15): 3975-3978. PubMed, CrossRef
- Pudhom K, Kasai K, Terauchi H, Inoue H, Kaiser M, Brun R, Ihara M, Takasu K. Synthesis of three classes of rhodacyanine dyes and evaluation of their in vitro and in vivo antimalarial activity. Bioorg Med Chem. 2006; 14(24): 8550-8563. PubMed, CrossRef
- Smith TK, Young BL, Denton H, Hughes DL, Wagner GK. First small molecular inhibitors of T. brucei dolicholphosphate mannose synthase (DPMS), a validated drug target in African sleeping sickness. Bioorg Med Chem Lett. 2009; 19(6): 1749-1752. PubMed, PubMedCentral, CrossRef
- Choi J, Ko Y, Lee HS, Park YS, Yang Y, Yoon S. Identification of (b-carboxyethyl)-rhodanine derivatives exhibiting peroxisome proliferator-activated receptor γ activity. Eur J Med Chem. 2010; 45(1): 193-202. PubMed, CrossRef
- Maccari R, Paoli P, Ottanà R, Jacomelli M, Ciurleo R, Manao G, Steindl T, Langer T, Vigorita MG, Camici G. 5-Arylidene-2,4-thiazolidinediones as inhibitors of protein tyrosine phosphatases. Bioorg Med Chem. 2007; 15(15): 5137-5149. PubMed, CrossRef
- Kaminskyy D, Bednarczyk-Cwynar B, Vasylenko O, Kazakova O, Zimenkovsky B, Zaprutko L, Lesyk R. Synthesis of new potential anticancer agents based on 4-thiazolidinone and oleanane scaffolds. Med Chem Res. 2012; 21(11): 3568-3580. CrossRef
- Suresh N, Nagesh HN, Sekhar KVG, Kumar A, Shirazi AN, Parang K. Synthesis of novel ciprofloxacin analogues and evaluation of their anti-proliferative effect on human cancer cell lines. Bioorg Med Chem Lett. 2013; 23(23): 6292-6295. PubMed, CrossRef
- Sun CL, Christensen JG, McMahon G. Chapter 1. In: Li R, Stafford JA, eds. Kinase Inhibitor Drugs. Hoboken, New Jersey.: John Wiley Sons, Inc, 2009. CrossRef
- Szychowski KA, Leja ML, Kaminskyy DV, Binduga UE, Pinyazhko OR, Lesyk RB, Gmiński J. Study of novel anticancer 4-thiazolidinone derivatives. Chem Biol Interact. 2017; 262: 46-56. PubMed, CrossRef
- Salamone S, Colin C, Grillier-Vuissoz I, Kuntz S, Mazerbourg S, Flament S, Martin H, Richert L, Chapleur Y, Boisbrun M. Synthesis of new troglitazone derivatives: anti-proliferative activity in breast cancer cell lines and preliminary toxicological study. Eur J Med Chem. 2012; 51: 206-215. PubMed, CrossRef
- Jain VS, Vora DK, Ramaa CS. Thiazolidine-2,4-diones: progress towards multifarious applications. Bioorg Med Chem. 2013; 21(7): 1599-1620. PubMed, CrossRef
- Szychowski KA, Leja ML, Kaminskyy DV, Kryshchyshyn AP, Binduga UE, Pinyazhko OR, Lesyk RB, Tobiasz J, Gmiński J. Anticancer properties of 4-thiazolidinone derivatives depend on peroxisome proliferator-activated receptor gamma (PPARγ). Eur J Med Chem. 2017; 141: 162-168. PubMed, CrossRef
- Chandrappa S, Kavitha CV, Shahabuddin MS, Vinaya K, Kumar CSA, Ranganatha SR, Raghavan SC, Rangappa KS. Synthesis of 2-(5-((5-(4-chlorophenyl)furan-2-yl)methylene)-4-oxo-2-thioxo-thiazolidin-3-yl)acetic acid derivatives and evaluation of their cytotoxicity and induction of apoptosis in human leukemia cells. Biorg Med Chem. 2009; 17(6): 2576-2584. PubMed, CrossRef
- Michalic L, Desverge B, Wahli W. Peroxisome-proliferator-activated receptors and cancers: complexes stories. Nat Rev Cancer. 2004; 4(1): 61-70. PubMed, CrossRef
- Kubota T, Koshizuka K, Williamson EA, Asou H, Said JW, Holden S, Miyoshi I, Koeffler P. Ligand for peroxisome proliferator-activated receptor γ (Troglitazone) has potent antitumor effect against human prostate cancer both in vitro and in vivo. Cancer Res. 1998; 58(15): 3344-3352. PubMed
- Ammazzalorso A, De Filippis B, Giampietro L, Amoroso R. Blocking the peroxisome proliferator‐activated receptor (PPAR): an overview. Chem Med Chem. 2013; 8(10): 1609-1616. PubMed, CrossRef
- Panigrahy D, Huang S, Kieran MW, Kaipainen A. PPARγ as a therapeutic target for tumor angiogenesis and metastasis. Cancer Biol Ther. 2005; 4(7): 687-693. PubMed, PubMedCentral, CrossRef
- Cutshall NS, O’Day C, Prezhdo M. Rhodanine derivatives as inhibitors of JSP-1. Bioorg Med Chem Lett. 2005; 15(14): 3374-3379. PubMed, CrossRef
- Fu H, Hou X, Wang L, Dun Y, Yang X, Fang H. Design, synthesis and biological evaluation of 3-aryl-rhodanine benzoic acids as anti-apoptotic protein Bcl-2 Inhibitors. Bioorg Med Chem Lett. 2015; 25(22): 5265-5269.
PubMed, CrossRef - Liu W, Bulgaru A, Haigentz M, Stein CA, Perez-Soler R, Mani S. The Bcl2-family of protein ligands as cancer drugs: the next generation of therapeutics. Curr Med Chem. Anticancer Agents. 2003; 3(3): 217-223. PubMed, CrossRef
- Lugovskoy AA, Degterev AI, Fahmy AF, Zhou P, Gross JD, Yuan J, Wagner GA. A novel approach for characterizing protein ligand complexes: molecular basis for specificity of small-molecule Bcl-2 inhibitors. J Am Chem Soc. 2002; 124(7): 1234-1240. PubMed, CrossRef
- Xing C, Wang L, Tang X, Sham YY. Development of selective inhibitors for anti-apoptotic Bcl-2 proteins from BHI-1. Bioorg Med Chem. 2007; 15(5): 2167-2176. PubMed, PubMedCentral, CrossRef
- Shiau CW, Yang CC, Kulp SK, Chen KF, Chen CS, Huang JW, Chen CS. Thiazolidenediones mediate apoptosis in prostate cancer cells in part through inhibition of Bcl-xL/Bcl-2 functions independently of PPARγ. Cancer Res. 2005; 65(4): 1561-1569. PubMed, PubMedCentral, CrossRef
- Tomašic T, Peterlin Mašic LP. Rhodanine as a scaffold in drug discovery: a critical review of its biological activities and mechanisms of target modulation. Expert Opin Drug Discov. 2012; 7(7): 549-560. PubMed, CrossRef
- Mendgen T, Steuer C, Klein CD. Privileged scaffolds or promiscuous binders: a comparative study on rhodanines and related heterocycles in medicinal chemistry. J Med Chem. 2012; 55(2): 743-753. PubMed, CrossRef
- Baell JB, Holloway GA. New substructure filters for removal of pan assay interference compounds (PAINS) from screening libraries and for their exclusion in bioassays. J Med Chem. 2010; 53(7): 2719-2740. PubMed, CrossRef
- Pinson JA, Schmidt-Kittler O, Frazzetto M, Zheng Z, Jennings IG, Kinzler KW, Vogelstein B, Chalmers DK, Thompson E. Synthesis and pharmacological evaluation of 4-iminothiazolidinones for inhibition of PI3 kinase. Aust J Chem. 2012; 65(10): 1396-1404. PubMed, PubMedCentral, CrossRef
- Zhou H, Wu S, Zhai S, Liu A, Sun Y, Li R, Zhang Y, Ekins S, Swaan PW, Fang B, Zhang B, Yan B. Design, synthesis, cytoselective toxicity, structure activity relationships, and pharmacophore of thiazolidinone derivatives targeting drug-resistant lung cancer cells. J Med Chem. 2008; 51(5): 1242-1251. PubMed, CrossRef
- Smelcerovic Z, Veljkovic A, Kocic G, Yancheva D, Petronijevic Z, Anderluh M, Smelcerovic A. Xanthine oxidase inhibitory properties and anti-inflammatory activity of 2-amino-5-alkylidene-thiazol-4-ones. Chem Biol Interact. 2015; 229: 73-81. PubMed, CrossRef
- Morphy R, Rankovic Z. Designed multiple ligands. An emerging drug discovery paradigm. J Med Chem. 2005; 48(21): 6523-6543. PubMed, CrossRef
- Ge X, Wakim B, Sem DS. Chemical proteomics-based drug design: target and antitarget fishing with a catechol − rhodanine privileged scaffold for NAD(P)(H) binding proteins. J Med Chem. 2008; 51(15): 4571-4580. PubMed, CrossRef
- Kryshchyshyn AP, Atamanyuk DV, Kaminskyy DV, Grellier Ph, Lesyk RB. Investigation of anticancer and anti-parasitic activity of thiopyrano[2,3-d]thiazoles bearing norbornane moiety. Biopolym Cell. 2017; 33(3): 183-205. CrossRef
- Kryshchyshyn A, Roman O, Lozynskyi A, Lesyk R. Thiopyrano[2,3-d]thiazoles as new efficient scaffolds in medicinal chemistry. Sci Pharm. 2018; 86(2): 26. PubMed, PubMedCentral, CrossRef
- Kavitha CV, Chandrappa S, Narasimhamurthy KH, Rangappa KS. Synthesis and evaluation of 5-((5-(4-methoxyphenyl)furan-2-yl) methylene)thiazolidine-2,4-diones as a new class of cytotoxic agents for leukemia treatment. Asian J Biochem Pharm Res. 2014; 4: 309-323.
- Kaminskyy D, Subtel’na I, Zimenkovsky B, Karpenko O, Gzella A, Lesyk R. Synthesis and evaluation of anticancer activity of 5-ylidene-4-aminothiazol-2(5H)-one derivatives. Med Chem. 2015; 11(6): 517-530. PubMed, CrossRef
- Liu X, Zu YG, Fu YJ, Yao LP, Gu CB, Wang W, Efferth T. Antimicrobial activity and cytotoxicity towards cancer cells of Melaleuca alternifolia (teatree) oil. Eur Food Res Technol. 2009; 229(2): 247-253. CrossRef
- Litchfield JT, Wilcoxon F. A simplified method of evaluating dose-effect experiments. J Pharmacol Exp Ther. 1949; 96(2): 99-113. PubMed
- Andersson LC, Nilsson K, Gahmberg CG. K562—a human erythroleukemic cell line. Int J Cancer. 1979; 23(2): 143-147.
PubMed, CrossRef - Greenberg SM, Rosenthal DS, Greeley TA, Tantravahi R, Handin RI. Characterization of a new megakaryocytic cell line: the Dami cell. Blood. 1988; 72(6): 1968-1977. PubMed, CrossRef
- Saito H. 3 Megakaryocytic cell lines. Baillieres Clin Haematol. 1997; 10(1): 47-63. PubMed, CrossRef
- Collins SJ. The HL-60 promyelocytic leukemia cell line: proliferation, differentiation, and cellular oncogene expression. Blood. 1987; 70(5): 1233-1244. PubMed, CrossRef
- Abraham RT, Weiss A. Jurkat T cells and development of the T-cell receptor signalling paradigm. Nat Rev Immunol. 2004; 4(4): 301-308. PubMed, CrossRef
- Smith WG. 1 Pharmacological Screening Tests. Eds. Ellis GP, West GB. Progress in Medicinal Chemistry. 1961; 1: 1-33. CrossRef
