Antiproliferative Activity of Novel Thiophene and Thienopyrimidine Derivatives

Abstract

A novel series of newly synthesized thiophene derivatives, ethyl-4,5-dimethyl-2-(3-(3,4,5-trimethoxyphenyl)thioureido)thiophene-3-carboxylate 3, ethyl-2-[(2-(dimethylamino)ethoxy)mercapto)methyleneamino)]-4,5-dimethyl-thiophene-3-carboxylate 9, thienopyrimidines 4, 7, 10–20, triazolothienopyrimidines 5, 6 were prepared and tested for their antiproliferative activity. The structures of the synthesized compounds were confirmed on the basis of elemental analysis, IR, ¹H-NMR, ¹³C-NMR and mass spectral data. The results showed that the synthesized compounds were more active on breast cancer than on colon cancer cell lines and the most potent compounds in this study are compounds 3 and 13 which exerted remarkable activity against MDA-MB-231 (breast cancer) and HT-29 (colon cancer) cell lines with IC₅₀ values (40.68, 49.22 μM) for compound 3 and (34.04, 45.62 μM) for compound 13. Also, compounds 4–6, 9 showed a moderate activity against breast cancer cell line, while compounds 15, 19 and 20 showed no activity.

Key words

thiophenes - thienopyrimidines - antiproliferative activity

• References

• 1 Gibbs JB. Mechanism-based target identification and drug discovery in cancer research. Science 2000; 287: 1969-1971
• 2 Unger C. New therapeutic approaches in cancer treatment. Drug Future 1997; 22: 1337-1345
• 3 Partridge AH, Burstein HJ, Winer EP. Side Effects of Chemotherapy and Combined Chemohormonal Therapy in Women With Early-Stage Breast Cancer. J Natl Cancer Inst Monogr 2001; 30: 135-142
• 4 Wakeling AE, Guy SP, Woodburn JR et al. ZD1839 (Iressa): an orally active inhibitor of epidermal growth factor signaling with potential for cancer therapy. Cancer Res 2002; 62: 5749- 5754
• 5 DeAngelo DJ, Stone RM, Heany ML et al. Phase 1 clinical results with tandutinib (MLN518), a novel FLT3 antagonist, in patients with acute myelogenous leukemia or high-risk myelodysplastic syndrome: safety, pharmacokinetics, and pharmacodynamics. Blood 2006; 108: 3674- 3681
• 6 Ibrahim YA, Elwahy AHM. Thienopyrimidines: Synthesis, Reactions, and Biological Activity. Adv Heterocycl Chem 1996; 65: 235-281
• 7 Bhuiyan MH, Rahman KM, Abdur Rahim KH et al. Synthesis and antimicrobial evaluation of some new thienopyrimidine derivatives. Acta Pharm 2006; 56: 441-450
• 8 Hegab MI, Hassan NA, Rashad AE et al. Synthesis, Reactions, and Antimicrobial Activity of Some Fused Thieno[2,3-d]pyrimidine Derivatives. Phosphorus Sulfur Silicon Relat Elem 2007; 182: 1535-1556
• 9 Rashad AE, Ali MA. Synthesis and antiviral screening of some thieno[2,3-d]pyrimidine nucleosides. Nucleosides Nucleotides 2006; 25: 17-28
• 10 Alagarsamy V, Meena S, Ramseshu KV et al. Synthesis, analgesic, anti-inflammatory, ulcerogenic index and antibacterial activities of novel 2-methylthio-3-substituted-5,6,7,8-tetrahydrobenzo (b) thieno[2,3-d]pyrimidin-4(3H)-ones. Eur J Med Chem 2006; 41: 1293-1300
• 11 McClellan WJ, Dai Y, Abad-Zapatero C et al. Discovery of potent and selective thienopyrimidine inhibitors of Aurora kinases. Bioorg Med Chem Lett 2011; 21: 5620-5624
• 12 Pédeboscq S, Gravier D, Casadebaig F et al. Synthesis and evaluation of apoptosis induction of thienopyrimidine compounds on KRAS and BRAF mutated colorectal cancer cell lines. Bioorg Med Chem 2012; 20: 6724-6731
• 13 Li J, Hu H, Lang Q et al. A thienopyrimidine derivative induces growth inhibition and apoptosis in human cancer cell lines via inhibiting Aurora B kinase activity. Eur J Med Chem 2013; 65: 151-157
• 14 Waterson AG, Petrov KG, Hornberger KR et al. Synthesis and evaluation of aniline headgroups for alkynyl thienopyrimidine dual EGFR/ErbB-2 kinase inhibitors. Bioorg Med Chem Lett 2009; 19: 1332-1336
• 15 Phoujdar MS, Kathiravan MK, Bariwal JB et al. Microwave-based synthesis of novel thienopyrimidine bioisosteres of gefitinib. Tetrahedron Lett 2008; 49: 1269-1273
• 16 Kassab AE, Gedawy EM. Synthesis and anticancer activity of novel 2-pyridyl hexahyrocyclooctathieno[2,3-d]pyrimidine derivatives. Eur J Med Chem 2013; 63: 224-230
• 17 Sayed HH, Moustafa AH, Yousif NM et al. Synthesis and Reactions of Some Novel Mercaptopyrimidine Derivatives for Biological Evaluation. Phosphorus, Sulfur Silicon Relat Elem 2008; 183: 2318-2329
• 18 Habib NS, Soliman R, Ismail K et al. Pyrimidines. Part II: Synthesis of novel pyrimidines, 1,2,4-triazolo[4,3-a]pyrimidin-7-ones and pyrimidino[2,1-c][1,2,4]triazin-8-ones for their antimicrobial and anticancer activities. Bull Chim Farm 2003; 142: 396-405
• 19 Heiba HI, Ragab FA, Noaman E et al. Synthesis of Some Novel Sulfur Containing Triazolothienopyrimidines and Biscompounds as Possible Antitumor and Radioprotective Agents. Arzneimittelforschung 2006; 56: 593-599
• 20 Ghorab MM, Ragab FA, Noaman E et al. Synthesis of Certain New Thieno[2,3-d] pyrimidines as Potential Antitumor and Radioprotective Agents. Arzneimittelforschung 2006; 56: 553-560
• 21 Alqasoumi SI, Ragab FA, Alafeefy AM et al. Radioprotective and antitumor activity of some novel amino acids and imisazoles containing thieno[2,3-d]pyrimidine moiety. Phosphorus, Sulfur Silicon Relat Elem 2009; 184: 3241-3257
• 22 Shaaban MA, Ghorab MM, Heiba HI et al. Novel thiophenes, thienopyrimidines, and triazolothienopyrimidines for the evaluation of anticancer and augmentation effects of gamma-radiation. Arch Pharm (Weinheim) 2010; 343: 404-410
• 23 Cheung JW, Rose EE, Paul Santerre J. Perfused culture of gingival fibroblasts in a degradable/polar/hydrophobic/ionic polyurethane (D-PHI) scaffold leads to enhanced proliferation and metabolic activity. Acta Biomater 2013; 9: 6867-6875
• 24 Tsai MD, Chen PR, Tien LT et al. Nuclear condensation and cell cycle arrest induced by telomerase siRNA in neuroblastoma cells. J Neurooncol 2013; 111: 265-272
• 25 Rusovici R, Patel CJ, Chalam KV. Bevacizumab inhibits proliferation of choroidal endothelial cells by regulation of the cell cycle. Clin Ophthalmol 2013; 7: 321-327