Leukemia is a tumor of the primary blood-forming cells. leukemia is not only a cancer of the white blood cells but also it originates in other blood cell types. Types of leukemia are categorized based on the rate of growth to acute (fastgrowing) or chronic (slower growing), and whether it arises in myeloid cells or lymphoid cells. Different types of leukemia have a different line of treatment and prognosis.
Nucleoside drugs have high clinical efficacy in alleviating cancer. Currently, different drugs are prescribed in the treatment of Leukemia [1-4]. For examples, Fludarabine, Cladribine, Clofarabine, Troxacitabine, and Pentostatin (Figure 1). Pentostatin is a deoxy sugar of imidazolodiazepine architecture. Pentostatin is an antimetabolite drug used in hairy cell leukemia. Cytarabine is an antimetabolite drug which arrests cell in the S phase. It should be activated intracellular to the nucleotide metabolite ara-CTP. It is used in different types of Leukemia such as acute or chronic in addition to non- Hodgkin lymphoma. Liposomal cytarabine is prescribed in the cancer of the lymph system that has spread to the brain. Nucleosides, as small molecule drug candidates especially N-ribosylation and N-mannosylation compounds have a great role in anticancer activity.
|Compound||IC5 a (μM) cellules L-1210
Table 1: Patient characteristics.
Our research interest focused on design and synthesize new small heterocyclic nucleosides targeting cancer especially leukemia . The elaboration of rhodanine derivatives linked with ribofuranose and mannopyranose sugars (Figure 1) to form the target nucleosides was our task . Judging from drugs chemical structure, we can conclude that these drugs contain two moieties: a) glycoside part either sugar, deoxy sugar or dioxane. the second moiety is the aglycone part which complement different varieties of the heterocyclic core. In this regard, our compounds were designed and synthesized to target Leukemia. All compounds were synthesized and confirmed by different analyses methods and were screened against leukaemia 1210. These compounds were found to be considerably less potent (Ic50% 1.4-10.6 μM) than doxorubicin (Ic50% 0.02 μM). Compounds Id and IIb, with ribose moiety, have better activity than those with mannose sugar. DFT calculations with B3LYP/6-31+G (d) level were used to analyze the electronic and geometric characteristics deduced from the stable structure of the compounds. The principal quantum chemical descriptors showed a good correlation with the experimental observations. Rapid Overlay Chemical Similarity (ROCS) study was operated to explain the similarity of the compounds and to figure out the most important pharmacophoric features. Glycosides of structurally similar heterocyclic systems have been reported before [7-15].
The electronic and geometric structures [16-25] were deduced from DFT calculations with B3LYP/6-31 + G (d) level to analyze the stable structure of the compounds. The quantum chemical parameters obtained from the calculations showed a good correlation with the experimental observations. ROCS analysis [26-28] showed that the sugar part is an important molecular descriptor. 3D-QSAR showed ribose (furanose skeleton) has better inactivity than mannose (hexoses). The aryl part has EDG capability to form HB with receptors. The antiviral and the antitumor activities of the newly prepared compounds are under investigation and will be reported in the due time. The nucleoside bases I, II and III can be utilized as starting materials for the synthesis of other carbohydrate derivatives as deoxy, amino and azido nucleosides.
2. Mikhailopulo IA, Miroshnikov AI. New trends in nucleoside biotechnology. Acta Naturae 2010;2(2):36-59.
3. Mikhailopulo IA, Miroshnikov AI. Biologically important nucleosides: modern trends in biotechnology and application. Mendeleev Communications. 2011 Mar 1;21(2):57-114.
4. Lewkowicz ES, Iribarren AM. Nucleoside phosphorylases. Current Organic Chemistry. 2006 Jul 1;10(11):1197-215.
5. Khodair AI, Gesson JP. A new approach for the N-and S-galactosylation of 5-arylidene-2-thioxo-4- thiazolidinones. Carbohydrate Research. 2011 Dec 27;346(18):2831-7.
6. Khodair AI, Awad MK, Gesson JP, Elshaier YA. New N-ribosides and N-mannosides of rhodanine derivatives with anticancer activity on leukemia cell line: Design, synthesis, DFT and molecular modelling studies. Carbohydrate Research. 2020 Jan 1;487:107894.
7. El-Barbary AA, Khodair AI, Pedersen EB, Nielsen C. S-Glucosylated hydantoins as new antiviral agents. Journal of Medicinal Chemistry. 1994 Jan;37(1):73-7.
8. Khodair AI, El-Subbagh HI, El-Emam AA. Synthesis of certain 5-substituted 2-thiohydantoin derivatives as potential cytotoxic and antiviral agents. Bollettino Chimico Farmaceutico. 1997 Sep;136(8):561-567.
9. Al-Obaid AM, El-Subbagh HI, Khodair A, Elmazar MM. 5-substituted-2-thiohydantoin analogs as a novel class of antitumor agents. Anti-Cancer Drugs. 1996 Nov 1;7(8):873-80.
10. Khodair AI. Glycosylation of 2-thiohydantoin derivatives. Synthesis of some novel S-alkylated and S-glucosylated hydantoins. Carbohydrate Research. 2001 Apr 23;331(4):445-53.
11. Khodair AI. Synthesis of 2-thiohydantoins and their S-glucosylated derivatives as potential antiviral and antitumor agents. Nucleosides, Nucleotides and Nucleic Acids. 2001 Sep 30;20(9):1735-50.
12. Khodair AI, Attia AM, Gendy EA, Elshaier YA, El-Magd MA. Discovery of New S-Glycosides and N-Glycosides of Pyridine-biphenyl System with Antiviral Activity and Induction of Apoptosis in MCF 7 Cells. Journal of Heterocyclic Chemistry. 2019 Jun;56(6):1733-47.
13. Attia AM, Khodair AI, Gendy EA, El-Magd MA, Elshaier YA. New 2-oxopyridine/2-thiopyridine derivatives tethered to a benzotriazole with cytotoxicity on MCF7 cell lines and with antiviral activities. Letters in Drug Design & Discovery. 2020 Feb 1;17(2):124-37.
14. Khodair AI. A convenient synthesis of 2-Arylidene-5Hthiazolo [2, 3-b] quinazo-line-3, 5 [2H]-diones and their benzoquinazoline derivatives. Journal of Heterocyclic Chemistry. 2002 Nov;39(6):1153-60.
15. Ahmed A, Khodair AI, Pedersen EB, Nielsen C. Synthesis of Uridine with Methylene-2-thiohydantoin as 5-Substituent. Liebigs Annalen der Chemie. 1994 Jun 13;1994(6):619-21.
16. Becke AD. Density-functional thermochemistry. II. The effect of the Perdew–Wang generalized-gradient correlation correction. The Journal of Chemical Physics. 1992 Dec 15;97(12):9173-7.
17. Becke AD. A new mixing of Hartree–Fock and local density-functional theories. The Journal of Chemical Physics. 1993 Jan 15;98(2):1372-7.
18. Lee C, Yang W, Parr RG. Development of the Colle- Salvetti correlation-energy formula into a functional of the electron density. Physical Review B. 1988 Jan 15;37(2):785-789.
19. Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, et al. Gaussian 09, Revision d. 01, Gaussian. Inc., Wallingford CT. 2009;201.
20. Senet P. Chemical hardnesses of atoms and molecules from frontier orbitals. Chemical Physics Letters. 1997 Sep 5;275(5-6):527-32.
21. Langenaeker W, Geerlings P, De Proft F. Theory, conceptual density functional. Chem. Reviews. 2003;103:1793-874.
22. Pu LS. Observing High Second Harmonic Generation and Control of Molecular Alignment in One Dimension: Cyclobutenediones as a Promising New Acceptor for Nonlinear Optical Materials. ACS Symposium Series. 1991;455, 331–342.
23. E. Scrocco E, Tomasi J. Interpretation by means of electrostatic molecular potentials. Advances in Quantum Chemistry. 1979 Feb 12;11:115-20.
24. Awad MK, Masoud MS, Shaker MA, Ali AE, El- Tahawy MM. MP2 and DFT theoretical studies of the geometry, vibrational and electronic absorption spectra of 2-aminopyrimidine. Research on Chemical Intermediates. 2013 Jul 1;39(6):2741-61.
25. Atlam FM, Awad MK, El-Bastawissy EA. Computational simulation of the effect of quantum chemical parameters on the molecular docking of HMG-CoA reductase drugs. Journal of Molecular Structure. 2014 Oct 5;1075:311-26.
26. http://www.openey.com. ROCS, version 22.214.171.124; OpenEye.
27. VIDA, version 4.1.2; OpenEye Scientific software, santa Fe, NM (USA). http://www.eyesopen.com
28. Abdellatif KR, Fadaly WA, Kamel GM, Elshaier YA, El-Magd MA. Design, synthesis, modeling studies and biological evaluation of thiazolidine derivatives containing pyrazole core as potential anti-diabetic PPAR-γ agonists and anti-inflammatory COX-2 selective inhibitors. Bioorganic chemistry. 2019 Feb 1;82:86-99.