Synthesis and cytotoxic evaluation of some novel quinoxalinedione diarylamide sorafenib analogues

Mojtaba Khandan, Sedighe Sadeghian Rizi, Ghadamali Khodarahmi, Farshid Hassanzadeh

Abstract


A series of novel sorafenib analogues containing a quinoxalinedione ring and amide linker were synthesized. A total of 9 novel compounds in 6 synthetic steps were synthesized. Briefly, the amino group of p-aminophenol was first protected which then followed by O-arylation with 5-chloro-2-nitroaniline to provide compound d. Reduction of the nitro group of compound d and cyclization of the diamine group of compound e with oxalic acid afforded compound f which on deacetylation yeilded compound g. Then compound g was reacted with different acyl halides to afford the target compounds 1h-1p. Chemical structures of synthesized compounds were confirmed by 1H NMR and FT-IR analysis. All compounds were evaluated at 1, 10, 50 and 100 μM concentrations for their cytotoxicity against HeLa and MCF-7 cancer cell lines. Some of the compounds showed good cytotoxic activity, especially compounds 1i and 1k-1n with the IC50 values of 19, 16, 22, 18, and 16 µM against MCF-7 cell line and 20, 18, 25, 20, and 18 µM against HeLa cell line, respectively.


Keywords


Cytotoxicity; Sorafenib; Quinoxalinedione; Amide

Full Text:

PDF

References


Gammal El-Din MM, El-Gamal MI, Abdel-Maksoud MS, Yoo KH, Oh CH. Synthesis and broad-spectrum antiproliferative activity of diarylamides and diarylureas possessing 1,3,4-oxadiazole derivatives. Bioorg Med Chem Lett. 2015;25(8):1692-1699.

Aziz MA, Serya RA, Lasheen DS, Abdel-Aziz AK, Esmat A, Mansour AM, et al. Discovery of potent VEGFR-2 inhibitors based on furopyrimidine and thienopyrimidne scaffolds as cancer targeting agents. Sci Rep. 2016;6:article number:24460.

Diez-Cecilia E, Carson R, Kelly B, van Schaeybroeck S, Murray JT, Rozas I. Probing a 3,4′-bis-guanidinium diaryl derivative as an allosteric inhibitor of the Ras pathway. Bioorg Med Chem Lett. 2015;25(19):4287-4292.

Džolić ZR, Perković I, Pavelić SK, Sedić M, Ilić N, Schols D, et al. Design, synthesis, and cytostatic activity of novel pyrazine sorafenib analogs. Med Chem Res. 2016;25(12):2729-2741.

El-Gamal MI, Khan MA, Tarazi H, Abdel-Maksoud MS, Gamal El-Din MM, Yoo KH, et al. Design and synthesis of new RAF kinase-inhibiting antiproliferative quinoline derivatives. Part 2: Diarylurea derivatives. Eur J Med Chem. 2017;127:413-423.

Wilhelm S, Carter C, Lynch M, Lowinger T, Dumas J, Smith RA, Schwartz B, Simantov R, Kelley S. Discovery and development of sorafenib: a multikinase inhibitor for treating cancer. Nat Rev Drug Discov. 2006;5(10):835-44.

Wang M, Xu S, Wu C, Liu X, Tao H, Huang Y, et al. Design, synthesis and activity of novel sorafenib analogues bearing chalcone unit. Bioorg Med Chem Lett. 2016;26(22):5450-5454.

Wecksler AT, Hwang SH, Liu JY, Wettersten HI, Morisseau C, Wu J, et al. Biological evaluation of a novel sorafenib analogue, t-CUPM. Cancer Chemother Pharmacol. 2015;75(1):161-171.

Chao TI, Tai WT, Hung MH, Tsai MH, Chen MH, Chang MJ, et al. A combination of sorafenib and SC-43 is a synergistic SHP-1 agonist duo to advance hepatocellular carcinoma therapy. Cancer Lett. 2016;371(2):205-213.

Ramalingam P, Ganapaty S, Rao ChB. In vitro antitubercular and antimicrobial activities of 1-substituted quinoxaline-2,3(1H,4H)-diones. Bioorg Med Chem Lett. 2010;20(1):406-408.

Ibáñez-Escribano A, Reviriego F, Nogal-Ruiz JJ, Meneses-Marcel A, Gómez-Barrio A, Escario JA, et al. Synthesis and in vitro and in vivo biological evaluation of substituted nitroquinoxalin-2-ones and 2,3-diones as novel trichomonacidal agents. Eur J Med Chem. 2015;94:276-283.

Shahin MI, El Ella DAA, Ismail NS, Abouzid KA. Design, synthesis and biological evaluation of type-II VEGFR-2 inhibitors based on quinoxaline scaffold. Bioorg Chem. 2014;56:16-26.

Hasegawa M, Nishigaki N, Washio Y, Kano K, Harris PA, Sato H, et al. Discovery of novel benzimidazoles as potent inhibitors of TIE-2 and VEGFR-2 tyrosine kinase receptors. J Med Chem. 2007;50(18):4453-4470.

Zambon A, Ménard D, Suijkerbuijk BMJM, Niculescu-Duvaz I, Whittaker S, Niculescu-Duvaz D, et al. Novel hinge binder improves activity and pharmacokinetic properties of BRAF inhibitors. J Med Chem. 2010;53(15):5639-5655.

Gingrich DE, Reddy DR, Iqbal MA, Singh J, Aimone LD, Angeles TS, et al. A new class of potent vascular endothelial growth factor receptor tyrosine kinase inhibitors: Structure-activity relationships for a series of 9-alkoxymethyl-12-(3-hydroxypropyl) indeno [2,1-a] pyrrolo [3,4-c] carbazole-5-ones and the identification of CEP-5214 and its dimethylglycine ester prodrug clinical candidate CEP-7055. J Med Chem. 2003;46(25):5375-5388.

Sun L, Liang C, Shirazian S, Zhou Y, Miller T, Cui J, et al. Discovery of 5-[5-fluoro-2-oxo-1,2-dihydroindol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicacid(2-diethylaminoethyl) amide, a novel tyrosine kinase inhibitor targeting vascular endothelial and platelet-derived growth factor receptor tyrosine kinase. J Med Chem. 2003;46(7):1116-1119.

Wu C, Xu S, Guo Y, Wu J, Luo R, Wang W, et al. Design, synthesis and biological evaluation of phenylpicolinamide sorafenib derivatives as antitumor agents. Med Chem Res. 2017;26:1-14.

Babić Ž, Crkvenčić M, Rajić Z, Mikecin AM, Kralj M, Balzarini J, et al. New sorafenib derivatives: synthesis, antiproliferative activity against tumour cell lines and antimetabolic evaluation. Molecules. 2012;17(1):1124-1137.

Liu CY, Tseng LM, Su JC, Chang KC, Chu PY, Tai WT, et al. Novel sorafenib analogues induce apoptosis through SHP-1 dependent STAT3 inactivation in human breast cancer cells. Breast Cancer Res. 2013;15(4): 3254-3267.

Zhang ZX, Jin WJ, Yang S, Ji CL. BRAF kinase inhibitor exerts anti-tumor activity against breast cancer cells via inhibition of FGFR2. Am J Cancer Res. 2016;6(5):1040-1052.

Luo W, Xia MY, Ikejima T, Li LH, Guo C. Synthesis and evaluation in vitro of 1-[2-(10-dihydroartemisininoxy) ethyl]-3-phenylurea derivatives as potential agents against cancer. Med Chem Res. 2013;22(7):3170-3176.

Ratnam KSVP, Sannidhi RS, Reddy YRR, Kanala JR. In vitro anticancer activity of Zingiber officinale and Allium sativa towards MCF-7 and K562 cell lines. IJCRR. 2012;4(2):75-82

Wu C, Wang M, Tang Q, Luo R, Chen L, Zheng P, et al. Design, synthesis, activity and docking study of sorafenib analogs bearing sulfonylurea unit. Molecules. 2015;20(10):19361-19371.

Bhat MA, Al-Omar MA, Naglah AM, Abdulla MM, Fun HK. Synthesis and antitumor activity of 4-cyclohexyl/aryl-5-(pyridin-4-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thiones. Med Chem Res. 2015;24:1558-1567.

Mirian M, Behrooeian M, Ghanadian M, Dana N, Sadeghi-Aliabadi H. Cytotoxicity and antiangiogenic effects of Rhus coriaria, Pistacia vera and Pistacia khinjuk oleoresin methanol extracts. Res Pharm Sci. 2015;10(3):233-240.

Noolvi MN, Patel HM, Bhardwaj V, Chauhan A. Synthesis and in vitro antitumor activity of substituted quinazoline and quinoxaline derivatives: search for anticancer agent. Eur J Med Chem. 2011;46(6):2327-2346.

Sanphanya K, Wattanapitayakul SK, Prangsaengtong O, Jo M, Koizumi K, Shibahara N, Priprem A, et al Synthesis and evaluation of 1-(substituted)-3-prop-2-ynylureas as antiangiogenic agents. Bioorg Med Chem Lett. 2012;22(8):3001-3005.

Sadeghian-Rizi S, Khodarahmi G, Sakhteman A, Jahanian-Najafabadi A, Rostami M, Mirzaei M, et al. Synthesis and characterization of some novel diaryl urea derivatives bearing quinoxalindione moiety. Res. Pharm.Sci. 2018;13(1):82-92.


Refbacks

  • There are currently no refbacks.


Creative Commons Attribution-NonCommercial 3.0

This work is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License which allows users to read, copy, distribute and make derivative works for non-commercial purposes from the material, as long as the author of the original work is cited properly.