A Review On Pyrimidine Derivatives As A Potential Anticancer Agents
Abstract
Cancer affects people's quality of life, poses a threat to world health, and has a number of negative side effects when treated. The search for new anticancer agents has been prompted by the resistance of cancer cells to the available medications. A favored scaffold called pyrimidine is found in living things and is essential for many biological processes, including the development of cancer. It is regarded as an important molecule in the therapy of cancer because of its structural similarities to the nucleotide base pair of DNA and RNA.
In the past several years, a large number of brand-new pyrimidine derivatives have been created and studied for their anticancer activities. Focusing on the structure-activity relationship (SAR) of pyrimidine derivatives as an anticancer agent throughout the past ten years is the main goal of the current review.
This review aims to aid in the creation of pyrimidine-based anticancer medications that are stronger and more effective.
References
Miller KD, Nogueira L, Mariotto AB, Rowland JH, Yabroff KR, Alfano CM et al. Cancer treatment and survivorship statistics, 2019. CA Cancer J Clin. 2019;69(5):363-85. doi: 10.3322/caac.21565, PMID 31184787.
MohanaRoopan S, Sompalle R. Synthetic chemistry of pyrimidines and fused pyrimidines: a review. Synth Commun. 2016;46(8):645-72. doi: 10.1080/00397911.2016.1165254.
Prachayasittikul S, Pingaew R, Worachartcheewan A, Sinthupoom N, Prachayasittikul V, Ruchirawat S et al. Roles of pyridine and pyrimidine derivatives as privileged scaffolds in anticancer agents. Mini Rev Med Chem. 2017;17(10):869-901. doi: 10.2174/1389557516666160923125801. PMID 27670581.
Selvam TP, James CR, Dniandev PV, Valzita SK. A mini review of pyrimidine and fused pyrimidine marketed drugs. Res Pharm. 2012;2(4):01-9.
Xu Y, Hao SY, Zhang XJ, Li WB, Qiao XP, Wang ZX et al. Discovery of novel 2, 4-disubstituted pyrimidines as aurora kinase inhibitors. Bioorg Med Chem Lett. 2020;30(3):126885. doi: 10.1016/j.bmcl.2019.126885. PMID 31862411.
Hu G, Wang C, Xin X, Li S, Li Z, Zhao Y et al. Design, synthesis and biological evaluation of novel 2, 4-diaminopyrimidine derivatives as potent antitumor agents. New J Chem. 2019;43(25):10190-202. doi: 10.1039/C9NJ02154J.
Kamal A, Dastagiri D, Ramaiah MJ, Reddy JS, Bharathi EV, Reddy MK et al. Synthesis and apoptosis inducing ability of new anilino substituted pyrimidine sulfonamides as potential anticancer agents. Eur J Med Chem. 2011;46(12):5817-24. doi: 10.1016/j.ejmech.2011.09.039, PMID 22000207.
Reddy OS, Suryanarayana CV, Narayana KJP, Anuradha V, Babu BH. Synthesis and cytotoxic evaluation for some new 2, 5-disubstituted pyrimidine derivatives for anticancer activity. Med Chem Res. 2015;24(5):1777-88. doi: 10.1007/s00044-014-1276-6.
Mule SNR, Nurbhasha S, Kolla JN, Jadav SS, Jayaprakash V, Bhavanam LR et al. Synthesis, biological screening and molecular docking studies of novel 4, 6-pyrimidine derivatives as EGFR-TK inhibitors. Med Chem Res. 2016;25(11):2534-46. doi: 10.1007/s00044-016-1668-x.
Qin WW, Sang CY, Zhang LL, Wei W, Tian HZ, Liu HX et al. Synthesis and biological evaluation of 2, 4-diaminopyrimidines as selective aurora A kinase inhibitors. Eur J Med Chem. 2015;95:174-84. doi: 10.1016/j.ejmech.2015.03.044, PMID 25812967.
Kraljević TG, Klika M, Kralj M, Martin-Kleiner I, Jurmanović S, Milić A et al. Synthesis, cytostatic activity and ADME properties of C5 substituted and N-acyclic pyrimidine derivatives. Bioorg Med Chem Lett. 2012;22(1):308-12. doi: 10.1016/j.bmcl.2011.11.009, PMID 22130132.
Weinberg LR, Albom MS, Angeles TS, Husten J, Lisko JG, McHugh RJ et al. Fused bicyclic derivatives of 2, 4-diaminopyrimidine as c-Met inhibitors. Bioorg Med Chem Lett. 2011;21(1):164-7. doi: 10.1016/j.bmcl.2010.11.045, PMID 21123062.
Kahriman N, Serdaroğlu V, Peker K, Aydın A, Usta A, Fandaklı S et al. Synthesis and biological evaluation of new 2, 4, 6-trisubstituted pyrimidines and their N-alkyl derivatives. Bioorg Chem. 2019;83:580-94 https:. doi: 10.1016/j.bioorg.2018.10.068, PMID 30471580.
Cheremnykh KP, Savelyev VA, Pokrovskii MA, Baev DS, Tolstikova TG, Pokrovskii AG et al. Design, synthesis, cytotoxicity, and molecular modeling study of 2, 4, 6-trisubstituted pyrimidines with anthranilate ester moiety. Med Chem Res. 2019;28(4):545-58. doi: 10.1007/s00044-019-02314-8.
Omar AM, Abd El Razik HA, Hazzaa AA, El-Attar MA, El Demellawy MA, Abdel Wahab AE et al. New pyrimidines and triazolopyrimidines as antiproliferative and antioxidants with cyclooxygenase-1/2 inhibitory potential. Future Med Chem. 2019;11(13):1583-603. doi: 10.4155/fmc-2018-0285, PMID 31469327.
Kumar B, Sharma P, Gupta VP, Khullar M, Singh S, Dogra N et al. Synthesis and biological evaluation of pyrimidine bridged combretastatin derivatives as potential anticancer agents and mechanistic studies. Bioorg Chem. 2018;78:130-40. doi: 10.1016/j.bioorg.2018.02.027, PMID 29554587.
Long L, Luo Y, Hou ZJ, Ma HJ, Long ZJ, Tu ZC et al. Synthesis and biological evaluation of aurora kinases inhibitors based on Ntrisubstituted pyrimidine scaffold. Eur J Med Chem. 2018;145:805-12. doi: 10.1016/j.ejmech.2017.12.082, PMID 29358147.
Shao KP, Zhang XY, Chen PJ, Xue DQ, He P, Ma LY et al. Synthesis and biological evaluation of novel pyrimidine– benzimidazol hybrids as potential anticancer agents. Bioorg Med Chem Lett. 2014;24(16):3877-81. doi: 10.1016/j.bmcl.2014.06.050, PMID 25001482.
Shao H, Shi S, Huang S, Hole AJ, Abbas AY, Baumli S et al. Substituted 4-(thiazol-5-yl)-2-(phenylamino) pyrimidines are highly active CDK9 inhibitors: synthesis, X-ray crystal structures, structure–activity relationship, and anticancer activities. J Med Chem. 2013;56(3):640-59. doi: 10.1021/jm301475f, PMID 23301767.
Khanage SG, Raju SA, Mohite PB, Pandhare RB. Synthesis and pharmacological evaluation of some new pyrimidine derivatives containing 1, 2, 4-triazole. Adv Pharm Bull. 2012;2(2):213-22.https://dx.doi.org/10.5681%2Fapb.2 012.033–222. doi: 10.5681/apb.2012.033, PMID 24312796.
Sridhar S, Prasad YR, Dinda SC. Synthesis and anticancer activity of some novel pyrimidine derivatives. Int J Pharm Sci Res. 2011;2(10):2562-5.
Rashid M, Husain A, Shaharyar M, Mishra R, Hussain A, Afzal O. Design and synthesis of pyrimidine molecules endowed with thiazolidin-4-one as new anticancer agents. Eur J Med Chem. 2014;83:630-45. doi: 10.1016/j.ejmech.2014.06.033, PMID 25010935.
Luo G, Tang Z, Lao K, Li X, You Q, Xiang H. Structure–activity relationships of 2, 4-disubstituted pyrimidines as dual ERα/VEGFR-2 ligands with anti-breast cancer activity. Eur J Med Chem. 2018;150:783-95. doi: 10.1016/j.ejmech.2018.03.018, PMID 29587221.
Abdel HT, Mohsen GAS, Mahmoud AE, Ali MM, El Diwani HI. New 2, 4-disubstituted-2-thiopyrimidines as VEGFR-2 inhibitors: design, synthesis, and biological evaluation. Arch Pharm. 2019;352(11):1900089.
El-Sayed WA, Mohamed AM, Khalaf HS, EL-Kady DS, Al-Manawaty M. Synthesis, docking studies and anticancer activity of new substituted pyrimidine and triazolopyrimidine glycosides. J App Pharm Sci. 2017;7(09):001-11. doi: 10.7324/JAPS.2017.70901.
Hassan AY, Saleh NM, Kadh MS, Abou-Amra ES. New fused pyrazolopyrimidine derivatives; heterocyclic styling, synthesis, molecular docking and anticancer evaluation. J Heterocycl Chem. 2020;57(7):2704-21. doi: 10.1002/jhet.3979.
Hassan AS, Mady MF, Awad HM, Hafez TS. Synthesis and antitumor activity of some new pyrazolo [1, 5-a] pyrimidines. Chin Chem Lett. 2017;28(2):388-93. doi: 10.1016/j.cclet.2016.10.022.
Hassan AS, Moustafa GO, Awad HM. Synthesis and in vitro anticancer activity of pyrazolo [1, 5-a] pyrimidines and pyrazolo [3, 4-d][1, 2, 3] triazines. Synth Commun. 2017;47(21):1963-72. doi: 10.1080/00397911.2017.13 58368.
Ajeesh Kumar AK, Bodke YD, Lakra PS, Sambasivam G, Bhat KG. Design, synthesis and anti-cancer evaluation of a novel series of pyrazolo [1, 5-a] pyrimidine substituted diamide derivatives. Med Chem Res. 2017;26(4):714-44. doi: 10.1007/s00044-016-1770-0.
Bagul C, Rao GK, Makani VKK, Tamboli JR, Pal-Bhadra M, Kamal A. Synthesis andbiological evaluation of chalcone-linked pyrazolo. Med ChemCommun. 2017;8(9):1810-6. doi: 10.1039/C7MD00193B.
Zhao M, Ren H, Chang J, Zhang D, Yang Y, He Y et al. Design and synthesis of novel pyrazolo [1, 5-a] pyrimidine derivatives bearing nitrogen mustard moiety and evaluation of their antitumor activity in vitro and in vivo. Eur J Med Chem. 2016;119:183-96. doi: 10.1016/j, PMID 27162123. ejmech.2016.04.068.
Kaping S, Kalita U, Sunn M, Singha LI, Vishwakarma JN. A facile, regioselective synthesis of pyrazolo [1, 5-a] pyrimidine analogs in the presence of KHSO 4 in aqueous media assisted by ultrasound and their anti-inflammatory and anti-cancer activities. Monatsh Chem. 2016;147(7):1257-76. doi: 10.1007/s00706-015-1638-x.
Hassan AS, Hafez TS, Osman SAM, Ali MM. Synthesis and in vitro cytotoxic activity of novel pyrazolo [1, 5- a] pyrimidines and related Schiff bases. Turk J Chem. 2015;39(5):1102-13. doi: 10.3906/kim-1504-12.
Phillipson LJ, Segal DH, Nero TL, Parker MW, Wan SS, de Silva M et al. Discovery and SAR of novel pyrazolo [1, 5-a] pyrimidines as inhibitors of CDK9. Bioorg Med Chem. 2015;23(19):6280-96. doi: 10.1016/j.bmc.2015.08.035, PMID 26349627.
Gaonkar S, Savanur MA, Nadaf AA, Najare MS, Mantur S, Garbhagudi M et al. KIA Novel pyrazolo. 2020 [3, 4-d] pyrimidine derivatives inhibit human cancer cellproliferation and induce apoptosis by ROS generation. Arch Pharm 353(4):1900296. doi: 10.1002/ardp.201900296.
Cherukupalli S, Chandrasekaran B, Aleti RR, Sayyad N, Hampannavar GA, Merugu SR et al. Synthesis of 4, 6-disubstituted pyrazolo[3, 4-d] pyrimidine analogues: cyclin-dependent kinase 2 (CDK2) inhibition, molecular docking and anticancer evaluation. J Mol Struct. 2019;1176:538-51. doi: 10.1016/j.molstruc.2018.08.104.
Cherukupalli S, Chandrasekaran B, Kryštof V, Aleti RR, Sayyad N, Merugu SR et al. Synthesis, anticancer evaluation, and molecular docking studies of some novel 4, 6-disubstituted pyrazolo [3, 4-d] pyrimidines as cyclin-dependent kinase 2 (CDK2) inhibitors. Bioorg Chem. 2018;79:46-59. doi: 10.1016/j.bioorg.2018.02.030, PMID 29753773.
Santhosh Kumar G, Jitender Dev G, Ravi Kumar N, Krishna Swaroop D, Poorna Chandra Y, Ganesh Kumar C et al. Synthesis of novel pyrido [1, 2-a] pyrimidine-3-carboxamide derivatives and their anticancer activity. Chem Pharm Bull (Tokyo). 2015;63(8):584-90. doi: 10.1248/cpb.c15-00219, PMID 26235166.
Naresh Kumar R, Poornachandra Y, Nagender P, Mallareddy G, Ravi Kumar N, Ranjithreddy P et al. Synthesis of novel trifluoromethyl substituted furo [2, 3-b] pyridine and pyrido [3′, 2′: 4, 5] furo [3, 2-d] pyrimidine derivatives as potential anticancer agents. Eur J Med Chem. 2016;108:68-78. doi: 10.1016/j.ejmech.2015.11.007, PMID 26629861.
AbedelRehim EM, AbdEllatif M. Synthesis of some novel pyrido [2, 3- d] pyrimidine and pyrido [3, 2-e][1, 3, 4] triazolo and tetrazolo [1, 5-c] pyrimidine derivatives as potential antimicrobial and anticancer agents. J Heterocycl Chem. 2018;55(2):419-30. doi: 10.1002/jhet.3058.
Fares M, Abou-Seri SM, Abdel-Aziz HA, Abbas SE, Youssef MM, Eladwy RA. Synthesis and antitumor activity of pyrido [2, 3-d] pyrimidine and pyrido [2, 3-d][1, 2, 4] triazolo [4, 3-a] pyrimidine derivatives that induce apoptosis through G1 cell-cycle arrest. Eur J Med Chem. 2014;83:155-66 https:. doi: 10.1016/j.ejmech.2014.06.027, PMID 24956552.
