Abstract
Some 4H-benzo[h]chromene and 7H-benzo[h]chromeno[2,3-d]pyrimidine derivatives were prepared as potential cytotoxic agents. The in vitro cytotoxic activity of the synthesized compounds was investigated in comparison with the well-known anticancer standard drugs Vinblastine, Colchicine, and Doxorubicin using MTT colorimetric assay. It was found that compounds 23, 15, 20, and 21 showed the highest anticancer activity against the three tumor cell lines MCF-7, HCT, and HepG-2, compared with Vinblastine and Colchicine, while compound 23 was the most active against HepG-2 as compared with Doxorubicin. We explored the SAR of 4H-benzo[h]chromenes with modification at the 2-,3- positions and 7H-benzo[h]chromeno[2,3-d]pyrimidine at 2,3-positions. The structure–activity relationship (SAR) study revealed that the antitumor activity on 4H-benzo[h]chromene and 7H-benzo[h]chromeno[2,3-d]pyrimidine derivatives were significantly affected by the lipophilicity (hydrophobic or hydrophilic), of the substituent at 2-,3- and 2,3-positions. Structures of these compounds were established on the basis of spectral data, IR, 1H NMR, 13C NMR, 13C NMR-DEPT, and MS data.
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References
Abd-El-Aziz AS, El-Agrody AM, Bedair AH, Christopher Corkery T, Ata A (2004) Synthesis of hydroxyquinoline derivatives, aminohydroxychromene, aminocoumarin and their antimicrobial activities. Heterocycles 63:1793–1812
Abd-El-Aziz AS, Mohamed HM, Mohammed S, Zahid S, Ata A, Bedair AH, El-Agrody AM, Harvey PD (2007) Synthesis of novel coumarin and benzocoumarin derivatives and their biological and photophysical studies. J Heterocycl Chem 44:1287–1300
Al-Ghamdi AM, Abd EL-Wahab AHF, Mohamed HM, El-Agrody AM (2012) Synthesis and antitumor activities of 4H-pyrano[3,2-h]quinoline-3-carbonitrile, 7H-pyrimido [4′,5′:6,5]pyrano[3,2-h]quinoline, and 14H-pyrimido[4′,5′:6,5]pyrano[3,2-h][1,2,4]triazolo[1,5-c]quinoline derivatives. Lett Drug Des Discov 9:459–470
Al-Sehemi AG, Irfan A, El-Agrody AM (2012) Synthesis, characterization and DFT study of 4H-benzo[h]chromene derivatives. J Mol Struct 1018:171–175
Alvey L, Prado S, Saint-Joanis B, Michel S, Koch M, Cole ST, Tillequin F, Janin YL (2009) Diversity-oriented synthesis of furo[3,2-f]chromanes with antimycobacterial activity. Eur J Med Chem 44:2497–2505
Bruhlmann C, Ooms F, Carrupt P, Testa B, Catto M, Leonetti F, Altomare C, Cartti A (2001) Coumarins derivatives as dual inhibitors of acetylcholinesterase and monoamine oxidase. J Med Chem 44:3195–3198
Cingolant GM, Pigini M (1969) Researches in the field of antiviral compounds. Mannich bases of 3-hydroxycoumarin. J Med Chem 12:531–532
El-Agrody AM, Al-Ghamdi AM (2011) Synthesis of certain novel 4H-pyrano[3,2-h]quinoline derivatives. Arkivoc xi:134–146
El-Agrody AM, Sabry NM, Motlaq SS (2011) Synthesis of some new 2-substituted 12H-chromeno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine, 3-ethoxycarbonyl-12H-chromeno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine-2-one, ethyl 2-formylamino\acetylamino-4H-chromene-3-carboxylate and some of their antimicrobial activities. J Chem Res 35:77–83
El-Agrody AM, Khattab ESAEH, Fouda AM, Al-Ghamdi AM (2012) Synthesis, antimicrobial and antitumor activities of certain novel 2-amino-9-(4-halostyryl)-4H-pyrano[3,2-h]-quinoline derivatives. Med Chem Res. doi:10.1007/s00044-011-9965-x
El-Agrody AM, Abd-Rabboh HSM, Al-Ghamdi AM (2013) Synthesis, antitumoractivity, and structure–activity relationship of some 4H-pyrano[3,2-h]quinoline and 7H-pyrimido-[4′,5′:6,5]pyrano[3,2-h]quinoline derivatives. Med Chem Res 22:1339–1355
El-Agrody AM, Al-Anood MA, Fouda AM (2014) Microwave assisted synthesis of 2-amino-6-methoxy-4H-benzo[h]chromene derivatives. Eur J Med Chem 5:133–137
El-Sayed AT, Ibrahim MA (2010) Synthesis and antimicrobial activity of chromone-linked-2-pyridone fused with 1,2,4-triazoles, 1,2,4-triazines and 1,2,4-triazepines ring systems. J Braz Chem 21:1007–1016
Endo S, Matsunaga T, Kuwata K, Zhao H-T, El-Kabbani O, Kitade Y, Hara A (2010) Chromene-3-carboxamide derivatives discovered from virtual screening as potent inhibitors of the tumour maker, AKR1B10. Bioorg Med Chem 18:2485–2490
Gourdeau H, Leblond L, Hamelin B, Desputeau C, Dong K, Kianicka I, Custeau D, Boudreau C, Geerts L, Cai SX, Drewe J, Labreque D, Kasibhatla S, Tseng B (2004) Antivascular and antitumor evaluation of 2-amino-4-(3-bromo-4,5-dimethoxy-phenyl)-3-cyano-4H-chromenes, a novel series of anticancer agents. Mol Cancer Ther 3:1375–1383
Hiramoto K, Nasuhara A, Michiloshi K, KatoT Kikugawa K (1997) DNA strand-breaking activity and mutagenicity of 2,3-dihydro-3,5-dihydroxy-6-methyl-4H-pyran-4-one (DDMP), a Maillard reaction product of glucose and glycine. Mutat Res 395:47–56
Kasibhatla S, Gourdeau H, Meerovitch K, Drewe J, Reddy S, Qiu L, Zhang H, Bergeron F, Bouffard D, Yang Q, Herich J, Lamothe S, Cai SX, Tseng B (2004) Discovery and mechanism of action of a novel series of apoptosis inducers with potential vascular targeting activity. Mol Cancer Ther 3:1365–1373
Kemnitzer W, Drewe J, Jiang S, Zhang H, Zhao J, Wang Y, Zhao J, Jia S, Herich J, Labreque D, Storer R, Meerovitch K, Bouffard D, Rej R, Denis R, Blais R, Lamothe S, Attardo G, Gourdeau H, Tseng B, Kasibhatla S, Cai SX (2004) Discovery of 4-aryl-4H-chromenes as a new series of apoptosis inducers using a cell- and caspase-based high-throughput Screening Assay. 4. Structure–activity Relationships of the 4-aryl group. J Med Chem 47:6299–6310
Kemnitzer W, Drewe J, Jiang S, Zhang H, Zhao J, Crogan-Grundy C, Xu L, Lamothe S, Gourdeau H, Denis R, Tseng B, Kasibhatla S, Cai SX (2007) Discovery of 4-aryl-4H-chromenes as a new series of apoptosis inducers using a cell- and caspase-based high-throughput screening assay. 3. Structure–activity relationships of fused rings at the 7,8-positions. J Med Chem 50:2858–2864
Kemnitzer W, Drewe J, Jiang S, Zhang H, Zhao J, Crogan-Grundy C, Labreque D, Dubenick M, Attardo G, Denis R, Lamothe S, Gourdeau H, Tseng B, Kasibhatla S, Cai SX (2008) Discovery of 4-aryl-4H-chromenes as a new series of apoptosis inducers using a cell- and caspase-based high-throughput screening assay. 4. Structure–activity relationships of N-alkyl substituted pyrrole fused at the 7,8-positions. J Med Chem 51:417–423
Keri RS, Hosamani KM, Shingalapur RV, Hugar MH (2010) Analgesic, anti-pyretic and DNA cleavage studies of novel pyrimidine derivatives of coumarin moiety. Eur J Med Chem 45:2597–2605
Kesten SR, Heffner TG, Johnson SJ, Pugsley TA, Wright JL, Wise DL (1999) Design, synthesis, and evaluation of chromen-2-ones as potent and selective human dopamine D4 antagonists. J Med Chem 42:3718–3725
Khafagy MM, Abd El-Wahab AHF, Eid FA, El-Agrody AM (2002) Synthesis of halogen derivatives of benzo[h]cheromene and benzo[a]anthracene with promising antimicrobial activities. IL Farmaco 57:715–722
Kidwai M, Poddar R, Bhardwaj S, Singh S, Mehta LP (2010) Aqua mediated synthesis of 2-amino-6-benzothiazol-2-ylsulfanyl-chromenes and its in vitro study, explanation of the structure–activity relationships (SARs) as antibacterial agent. Eur J Med Chem 45:5031–5038
Lee K-S, Khil L-Y, Chae S-H, Kim D, Lee B-H, Hwang G-S, Moon C-H, Chang T-S, Moon C-K (2006) Effects of DK-002, a synthesized (6aS, cis)-9,10-dimethoxy-7,11b-dihydro-indeno[2,1-c]chromene-3,6a-diol, on platelet activity. Life Sci 78:1091–1097
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 17:3872–3876
Mahmoodi M, Aliabadi A, Emami S, Safavi M, Rajabalian S, Mohagheghi MA, Khoshzaban A, Samzadeh-Kermani A, Lamei N, Shafiee A, Foroumadi A (2010) Synthesis and in vitro cytotoxicity of poly-functionalized 4-(2-arylthiazol-4-yl)-4H-chromenes. Arch Pharm Chem 343:411–416
Mossman T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65:55–63
Rahman AU, Choudhary MI, Thomsen WJ (2001) Bioassay technique for drug development. Harwood Academic Publishers, Chur
Sabry NM, Mohamed HM, Khattab Essam Shawky AEH, Motlaq SS, El-Agrody AM (2011) Synthesis of 4H-chromene, coumarin, 12H-chromeno[2,3-d]pyrimidine derivatives and some of their antimicrobial and cytotoxicity activities. Eur J Med Chem 46:765–772
Sashidhara KV, Kumar M, Modukuri RK, Srivastava A, Puri A (2011) Discovery and synthesis of novel substituted benzocoumarins as orally active lipid modulating agents. Bioorg Med Chem Lett 21:6709–6713
Singh OM, Devi NS, Thokchom DS, Sharma GJ (2010) Novel 3-alkanoyl/aroyl/-heteroaroyl-2H-chromene-2-thiones: synthesis and evaluation of their antioxidant activities. Eur J Med Chem 45:2250–2257
Snedecor GM, Cochran WG (1982) Statistical methods, 7th edn. lowa state University Press, Ames, pp 325–330
Tanaka JCA, Da Silva CC, Ferreira ICP, Machado GMC, Leon LL, De Oliveira AJB (2007) Antileishmanial activity of indole alkaloids from Aspidosperma ramiflorum. Phytomedicine 14:377–380
Tseng T-H, Chuang S-K, Hu C–C, Chang C-F, Huang Y-C, Lin C-W, Lee Y-J (2010) The synthesis of morusin as a potent antitumor agent. Tetrahedron 66:1335–1340
Vosooghi M, Rajabalian S, Sorkhi M, Badinloo M, Nakhjiri M, Negahbani AS, Asadipour A, Mahdavi M, Shafiee A, Foroumadi A (2010) Synthesis and cytotoxic activity of some 2-amino-4-aryl-3-cyano-7-(dimethylamino)-4H-chromenes. RPS 5:13–18
Vukovic N, Sukdolak S, Solujic S, Niciforovic N (2010) Substituted imino and amino derivatives of 4-hydroxycoumarins as novel antioxidant, antibacterial and antifungal agents: synthesis and in vitro assessments. Food Chem 120:1011–1018
Acknowledgments
This research was supported by a program to support research and researchers at King Khalid University, Abha, Saudi Arabia and No. KKU-SCI-11-028. The authors deeply thank the Regional Center for Mycology & Biotechnology (RCMP), Al-Azhar University for carrying out the antitumor study, and Mr. Ali Y. A. Alshahrani for making the 1H NMR and 13C NMR spectra.
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El-Agrody, A.M., Fouda, A.M. & Al-Dies, AA.M. Studies on the synthesis, in vitro antitumor activity of 4H-benzo[h]chromene, 7H-benzo[h]chromene[2,3-d]pyrimidine derivatives and structure–activity relationships of the 2-,3- and 2,3-positions. Med Chem Res 23, 3187–3199 (2014). https://doi.org/10.1007/s00044-013-0904-x
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DOI: https://doi.org/10.1007/s00044-013-0904-x