Anticancer activities, molecular docking and structure–activity relationship of novel synthesized 4H-chromene, and 5H-chromeno[2,3-d]pyrimidine candidates
In the present study, a series of 4H-chromene and 5H-chromeno[2,3-d]pyrimidine derivatives was synthesized and evaluated as potential cytotoxic agents. The cytotoxic activities of the target compounds were evaluated against four cancer cell lines MCF-7, HCT-116, HepG-2, and A549 in comparison with vinblastine and colchicine as reference drugs. We explored the structure–activity relationship of 4H-chromenes with modification at the 2-,4- or 7-position, and fused pyrimidine ring at 2,3-position. Most of the screened compounds showed marginal antitumor activity against the different cell lines in comparison to the standard drugs. The structure–activity relationship study revealed that the antitumor activity of the synthesized compounds was significantly affected by the lipophilicity of the substituent at the 2-,4- or 7-position for the 4H-chromenes, and 5,8-position or fused pyrimidine ring at 2,3-positions for 5H-chromeno[2,3-d]pyrimidines. Structure–activity relationship was elaborated with the help of molecular docking studies. The structures of the synthesized compounds were established on the basis of the spectral data, infrared, proton nuclear magnetic resonance, 13-Carbon nuclear magnetic resonance and mass spectroscopic data.
Keywords4H-Chromene 5H-Chromeno[2,3-d]pyrimidine Antitumor Lipophilicity SAR Molecular docking
The authors deeply thank the RCMP, Al-Azhar University for carrying out the antitumor study and Elemental analyses.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no competing interests.
- Bingi C, Emmadi NR, Chennapuram M, Poornachandra Y, Kumar CG, Nanubolu JB, Atmakur K (2015) One-pot catalyst free synthesis of novel kojic acid tagged 2-aryl/alkyl substituted-4H-chromenes and evaluation of their antimicrobial and anti-biofilm. Bioorg Med Chem Lett 25:1915–1919CrossRefPubMedGoogle Scholar
- Birch KA, Heath WF, Hermeling RN, Johnston CM, Stramm L, Dell C, Smith C, Williamson JR, Reifel-Miller A (1996) LY290181, an inhibitor of diabetes induced vascular dysfunction, blocks protein kinase C-stimulated transcriptional activation through inhibition of transcription factor binding to a phorbol response element. Diabetes 45:642–650CrossRefPubMedGoogle Scholar
- Doshi JM, Tian D, Xing C (2006) Structure-activity relationship studies of ethyl 2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate (HA 14-1), an antagonist for antiapoptotic Bcl-2 proteins to overcome drug resistance in cancer. J Med Chem 49:7731–7739CrossRefPubMedGoogle Scholar
- El-Agrody AM, Halawa AH, Fouda AM, Al-Dies AM (2016) Anti-proliferative activity of novel 4H-benzo[h]chromenes, 7H-benzo[h]chromeno[2,3-d]pyrimidines and the structure–activity relationships of the 2-, 3-positions and fused rings at the 2, 3-positions. J Saudi Chem Soc. doi: 10.1016/j.jscs.2016.03.002
- Kemnitzer W, Kasibhatla S, Jiang S, Zhang H, Zhao J, Jia S, Xu L, Crogan-Grundy C, Denis R, Barriault N, Vaillancourt L, Charron S, Dodd J, Attardo G, Labrecque D, Lamothe S, Gourdeau H, Tseng B, Drewe J, Cai SX (2005) Discovery of 4-aryl-4H-chromenes as a new series of apoptosis inducers using a cell- and caspase-based high-throughput screening assay. 2. Structure– activity relationships of the 7- and 5-, 6-, 8-positions. Bioorg Med Chem Lett 5:4745–4751CrossRefGoogle Scholar
- Magedov IV, Manpadi M, Evdokimov NM, Elias EM, Rozhkova E, Ogasawara MA, Bettale JD, Przheval’skii NM, Rogelj S, Kornienko A (2007) Antiproliferative and apoptosis inducing properties of pyrano[3,2-c]pyridones accessible by a one-step multicomponent synthesis. Bioorg Med Chem Lett 17:3872–3876CrossRefPubMedPubMedCentralGoogle Scholar
- Rahman AU, Choudhary MI, Thomsen WJ (2001) Bioassay techniquefor drug development. Harwood Academic Publishers; ISBN0-203-34349-2 (Adobe e-Reader Format), ISBN 90-5823-051-1(Print Edition)Google Scholar
- Thomas N, Zachariah SM (2013) In Silico drug design and analysis of 4-Phenyl-4H-chromene derivatives as anticancer and anti-inflammatory agents. Int J Pharm Sci Rev Res 22:50–54Google Scholar