Biopolym. Cell. 2010; 26(2):136-145.
Bioorganic Chemistry
Structure–anticancer activity relationships among 4-azolidinone-3-carboxylic acids derivatives
1Kaminskyy D. V., 1Lesyk R. B.
  1. Danylo Halytsky Lviv National Medical University
    69, Pekarska Str., Lviv, Ukraine, 79010


The aim of present research was investigation of anticancer activity of 4-azolidinone-3-carboxylic acids derivatives, and studies of structure–activity relationships (SAR) aspects. Methods. Organic synthesis; spectral methods; anticancer screening was performed according to the US NCI protocol (Developmental Therapeutic Program). Results. The data of new 4-thiazolidinone-3-alkanecarboxylic acids derivatives in vitro anticancer activity were described. The most active compounds which belong to 5-arylidene-2,4- thia(imida)zolidinone-3-alkanecarboxylic acids; 5-aryl(heteryl)idenerhodanine-3-succinic acids derivatives were selected. Determination of some SAR aspects which allowed to determine directions in lead-compounds structure optimization, as well as desirable molecular fragments for design of potential anticancer agents based on 4-azolidinone scaffold were performed. 5-Arylidenehydantoin-3-acetic acids amides were identified as a new class of significant selective antileukemic agents. Possible pharmacophore scaffold of 5-ylidenerhodanine-3-succinic acids derivatives was suggested. Conclusions. The series of active compounds with high anticancer activity and/or selectivity levels were selected. Some SAR aspects were determined and structure design directions were proposed.
Keywords: 4-azolidinone-3-carboxylic acids, anticancer activity, SAR


[1] Lesyk R. B., Zimenkovsky B. S. 4-Thiazolidones: Centenarian history, current status and perspectives for modern organic and medicinal chemistry Curr. Org. Chem 2004 8, N 16 P. 1547–1577.
[2] Prabhakar Y. S., Solomon V. R., Gupta M. K., Katti S. B. QSAR studies on thiazolidines: biologically privileged scaffold Top. Heterocycl. Chem 2006 4 P. 161–249.
[3] Ottana R., Carotti S., Maccari R., Landini I., Chiricosta G., Caciagli B., Vigorita M. G., Mini E. In vitro antiproliferative activity against human colon cancer cell lines of representative 4-thiazolidinones. Part I Bioorg. Med. Chem. Lett 2005 15, N 17 P. 3930–3933.
[4] Shih M. H., Ke F. Y. Synthesis and evaluation of antioxidant activity of sydnonyl substituted thiazolidinone and thiazoline derivatives Bioorg. Med. Chem 2004 12, N 17 P. 4633– 4643.
[5] Kesel A. S., Sonnenbicher I., Polborn K., Gurtler L., Klinkert W. E. F., Modolell M., Nussler A. K., Oberthur W. A new antioxidative vitamine B6-analogue modulates pathophysiological cell proliferation and demage Bioorg. Med. Chem 1999 7, N 2 P. 359–367.
[6] Avendano C., Menendez J. C. Medicinal chemistry of anticancer drugs Amsterdam: Elsevier, 2008 400 p.
[7] Liu W. J., Bulgaru A., Haigentz M., Stein C. A., Perez-Soler R., Mani S. The BCL2-family of protein ligands as cancer drugs: the next generation of therapeutics Curr. Med. Chem. Anti Cancer Agents 2003 3, N 3 P. 217–223.
[8] Degterev A., Lugovskoy A., Cardone M., Mulley B., Wagner G., Mitchison T., Yuan J. Identification of small-molecule inhibitors of interaction between the BH3 domain and Bcl-xl Nat. Cell Biol 2001 3, N 2 P. 173–182.
[9] Lugovskoy A. A., Degterev A. I., Fahmy A. F., Zhou P., Gross J. D., Yuan J., Wagner G. A Novel approach for characterizing protein ligand complexes: molecular basis for specificity of small-molecule Bcl-2 inhibitors J. Am. Chem. Soc 2002 124, N 7 P. 1234–1240.
[10] Xing C., Wang L., Tang X. H., Sham Y.Y. Development of selective inhibitors for anti-apoptotic Bcl-2 proteins from BHI1 Bioorg. Med. Chem 2007 15, N 5 P. 2167–2176.
[11] Cutshall N. S., O'Day C., Prezhdo M. Rhodanine derivatives as inhibitors of JSP-1 Bioorg. Med. Chem. Lett 2005 15, N 14 P. 3374–3379.
[12] Look G. C., Shuilck J. R., Holmes Ch. P., Chinn J. P., Gordon E. M., Gallop M. A. The identification of cyclooxygenase-1 inhibitors from 4-thiazolidinone combinatorial library Bioorg. Med. Chem. Lett 1996 6, N 6 P. 707–712.
[13] Lee J., Kim J., Koh J. S., Chung H. H., Kim K. H. Hydantoin derivatives as non-peptidic inhibitors of Ras farnesyl transferase Bioorg. Med. Chem. Lett 2006 16, N 7 P. 1954– 1956.
[14] Mazieres J., Pradines A., Favre G. Perspectives on farnesyl transferase inhibitors in cancer therapy Cancer Lett 2004 206, N 2 P. 159–164.
[15] Zhao L., Huang W., Liu H., Wang L., Zhong W., Xiao J., Hu Y., Li S. FK506-binding protein ligands: structure-based design, synthesis, and neurotrophic/neuroprotective properties of substituted 5,5-dimethyl-2-(4-thiazolidine) carboxylates J. Med. Chem 2006 49, N 14 P. 4059–4071.
[16] Liuqing W., Gan X., Zhong J., Alliston K. R., Groutas W. C. Noncovalent inhibitors of human leukocyte elastase based on the 4-imidazolidinone scaffold Bioorg. Med. Chem 2003 11, N 23 P. 5149–5153.
[17] Carmi C., Cavazzoni A., Zuliani V., Lodola A., Bordi F., Plazzi P. V., Alfieri R. R., Petronini P. G., Mor M. 5-Benzylidene-hydantoins as new EGFR inhibitors with antiproliferative activity Bioorg. Med. Chem. Lett 2006 16, N 15 P. 4021–4025.
[18] Rajic Z., Zorc B., Raic-Malic S., Ester K., Kralj M., Pavelic K., Balzarini J., Clercq E. D., Mintas M. Hydantoin derivatives of Land D-amino acids: synthesis and evaluation of their antiviral and antitumoral activity Molecules 2006 11, N 11 P. 837–848.
[19] Gibbs J. B., Oliff A. The potential of farnesyltransferase inhibitors as cancer chemotherapeutics Ann. Rev. Pharmacol. Toxicol 1997 37 P. 143–166.
[20] Haluska P., Dy G. K., Adjei A. A. Farnesyl transferase inhibitors as anticancer agents Eur. J. Cancer 2002 38, N 13 P. 1685–1700.
[21] Lv P. C., Zhou C. F., Chen J., Liu P. G., Wang K. R., Mao W. J., Li H. Q., Yang Y., Xiong J., Zhu H. L. Design, synthesis and biological evaluation of thiazolidinone derivatives as potential EGFR and HER-2 kinase inhibitors Bioorg. Med. Chem 2010 18, N 1 P. 314–319.
[22] Pevarello P., Brasca M. G., Orsini P., Traquandi G., Longo A., Nesi M., Orzi F., Piutti C., Sansonna P., Varasi M., Cameron A., Vulpetti A., Roletto F., Alzani R., Ciomei M., Albanese C., Pastori W., Marsiglio A., Pesenti E., Fiorentini F., Bischoff J. R., Mercurio C. 3-Aminopyrazole inhibitors of CDK2/cyclin A as antitumor agents. 2. Lead optimization J. Med. Chem 2005 48, N 8 P. 2944–2956.
[23] Dayam R., Aiello F., Deng J., Wu Y., Garofalo A., Chen X., Neamati N. Discovery of small molecule integrin v3 antagonists as novel anticancer agents J. Med. Chem 2006 49, N 15 P. 4526–4534.
[24] Pat. US2003/0119894, IPC A 61K31/404, N 09/9106291. Methods for treatment of cancer or neoplastic disease and for inhibiting growth of cancer cells and neoplastic cellsmurthy. M. S. R. Murthy, G. C. Shore, J. Bajorath, F. L. Stahura Publ. 26.06.2003.
[25] Teng X., Degterev A., Jagtap P., Xing X., Choi S., Denu R., Yuan J., Cuny G. D. Structure-activity relationship study of novel necroptosis inhibitors Bioorg. Med. Chem. Lett 2005 15, N 22 P. 5039–5044.
[26] Lesyk R., Zimenkovsky B., Lukyanchuk V., Atamanyuk D., Vovk O. Chemistry and pharmacology of 4-thiazolidone derivatives Ann. Polish Chem. Soc 2003 2:293–298.
[27] Zimenkovsky B. S., Lesyk R. B. Purposeful synthesis of biological active compound base on 4-azolidinone J. Org. Pharm. Chem 2003 1, N 1–2 P. 24–30.
[28] 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, N 9 P. 3627–3636.
[29] Kaminskyy D. V., Roman O. M., Atamanyuk D. V., Lesyk R. B. 5-Ylidene-2-thioxo-4-thiazolidinone-3-succinic acids and their derivatives: synthesis, anticancer activity, QSAR-analysis J. Org. Pharm. Chem. 2006; 4, N 1(13):41–48.
[30] Kaminskyy D. V., Lesyk R. B. Synthesis and biological activity of 4-thiazolidinone-3-acetic acids derivatives. Farmacevt. Zhur. (Kyiv). 2008;3:70–78.
[31] Monks A., Scudiero D., Skehan P., Shoemaker R., Paull K., Vistica D., Hose C., Langley J., Cronise P., Vaigro-Wolff A., Gray-Goodrich M., Campbell H., Mayo J., Boyd M. Feasibility of a high-flux anticancer drug screen using a diverse panel of cultured human tumor cell lines J. Nat. Cancer Inst 1991 83, N 11 P. 757–766.
[32] Boyd M. R., Paull K. D. Some practical considerations and applications of the national cancer institute in vitro anticancer drug discovery screen Drug Develop. Res 1995 34, N 2 P. 91–109.
[33] Boyd M. R. Anticancer drug development guide: preclinical screening, clinical trials, and approval in: cancer drug discovery and development. Ed. A. Teicher Totowa: Humana Press, 1997 P. 23–43.
[34] Shoemaker R. H. The NCI60 human tumour cell line anticancer drug screen Nat. Rev. Cancer 2006 6, N 10 P. 813– 823.
[35] Gududuru V., Hurh E., Dalton J. T., Miller D. D. Synthesis and antiproliferative activity of 2-aryl-4-oxo-thiazolidin-3yl-amides for prostate cancer Bioorg. Med. Chem. Lett 2004 14, N 21 P. 5289–5293.