1. bookVolume 71 (2021): Edizione 4 (December 2021)
Dettagli della rivista
Prima pubblicazione
28 Feb 2007
Frequenza di pubblicazione
4 volte all'anno
access type Accesso libero

New derivatives of sulfonylhydrazone as potential antitumor agents: Design, synthesis and cheminformatics evaluation

Pubblicato online: 03 Apr 2021
Volume & Edizione: Volume 71 (2021) - Edizione 4 (December 2021)
Pagine: 545 - 565
Accettato: 08 Dec 2020
Dettagli della rivista
Prima pubblicazione
28 Feb 2007
Frequenza di pubblicazione
4 volte all'anno

Phosphoinositide 3-kinase α (PI3Kα) is a propitious target for designing anticancer drugs. A series of new N’-(diphenylmethylene)benzenesulfonohydrazide was synthesized and characterized using FT-IR, NMR (1H and 13C), HRMS, and elemental analysis. Target compounds exhibited an antiproliferative effect against the human colon carcinoma (HCT-116) cell line. Our cheminformatics analysis indicated that the para-tailored derivatives [p-NO2 (3) and p-CF3 (7)] have better ionization potentials based on calculated Moran autocorrelations and ionization potentials. Subsequent in vitro cell proliferation assays validated our cheminformatics results by providing experimental evidence that both derivatives 3 and 7 exhibited improved antiproliferative activities against HCT-116. Hence, our results emphasized the importance of electron-withdrawing groups and hydrogen bond-acceptors in the rational design of small-molecule chemical ligands targeting PI3Kα. These results agreed with the induced-fit docking against PI3Kα, highlighting the role of p-substituted aromatic rings in guiding the ligand-PI3Kα complex formation, by targeting a hydrophobic pocket in the ligand-binding site and forming π-stacking interactions with a nearby tryptophan residue.


1. B. Vanhaesebroeck, L. Stephens and P. Hawkins, PI3K signalling: the path to discovery and understanding, Nat. Rev. Mol. Cell Biol.13 (2012) 195–203; https://doi.org/10.1038/nrm329010.1038/nrm329022358332Search in Google Scholar

2. I. Vivanco and C. L. Sawyers, The phosphatidylinositol 3-kinase-AKT pathway in human cancer, Nat. Rev. Cancer2 (2002) 489–501; https://doi.org/10.1038/mrc839Search in Google Scholar

3. B. Vanhaesebroeck and M. D. Waterfield, Signaling by distinct classes of phosphoinositide 3-kinases, Exp. Cell Res.253 (1999) 239–254; https://doi.org/10.1006/excr.1999.470110.1006/excr.1999.470110579926Search in Google Scholar

4. L. C. Cantley, The phosphoinositide 3-kinase pathway, Science296 (2002) 1655–1657; https://doi.org/10.1126/science.296.5573.165510.1126/science.296.5573.165512040186Search in Google Scholar

5. C.-H. Huang, D. Mandelker, O. Schmidt-Kittler, Y. Samuels, V. E. Velculescu, K. W. Kinzler, B. Vogelstein, S. B. Gabelli and L. M. Amzel, The structure of a human p110 alpha/p85 alpha complex elucidates the effects of oncogenic PI3K alpha mutations, Science318 (2007) 1744–1748; https://doi.org/10.1126/science.115079910.1126/science.115079918079394Search in Google Scholar

6. N. Miled, Y. Yan, W.-C. Hon, O. Perisic, M. Zvelebil, Y. Inbar, D. Schneidman-Duhovny, H. J. Wolf-son, J. M. Backer and R. L. Williams, Mechanism of two classes of cancer mutations in the phosphoinositide 3-kinase catalytic subunit, Science317 (2007) 239–242; https://doi.org/10.1126/science.113539410.1126/science.113539417626883Search in Google Scholar

7. L. Zhao and P. K. Vogt, Helical domain and kinase domain mutations in p110 alpha of phosphatidylinositol 3-kinase induce gain of function by different mechanisms, Proc. Natl. Acad. Sci. USA.105 (2008) 2652–2657; https://doi.org/10.1073/pnas.071216910510.1073/pnas.0712169105226819118268322Search in Google Scholar

8. Y. Samuels and V. E. Velculescu, Oncogenic mutations of PIK3CA in human cancers, Cell Cycle3 (2004) 1221–1224; https://doi.org/10.4161/cc.3. https://doi.org/10.1164Search in Google Scholar

9. Y. Samuels, L. A. Diaz, O. Schmidt-Kittler, J. M. Cummins, L. DeLong, I. Cheong, C. Rago, D. L. Huso, C. Lengauer, K. W. Kinzler, B. Vogelstein and V. E. Velculescu, Mutant PIK3CA promotes cell growth and invasion of human cancer cells, Cancer Cell7 (2005) 561–573; https://doi.org/10.1016/j.ccr.2005. in Google Scholar

10. P. Liu, H. Cheng, S. Santiago, M. Raeder, F. Zhang, A. Isabella, J. Yang, D. J. Semaan, C. Chen, E. A. Fox, N. S. Gray, J. Monahan, R. Schlegel, R. Beroukhim, G. B. Mills and J. J. Zhao, Oncogenic PIK3CA-driven mammary tumors frequently recur via PI3K pathway-dependent and PI3K pathway-independent mechanisms, Nat. Med.17 (2011) 1116–1120; https://doi.org/10.1038/nm.240210.1038/nm.2402316972421822287Search in Google Scholar

11. L. Zhao and P. K. Vogt, Hot-spot mutations in p110α of phosphatidylinositol 3-kinase (PI3K): differential interactions with the regulatory subunit p85 and with RAS, Cell Cycle9 (2010) 596–600; https://doi.org/10.4161/cc.9.3.1059910.4161/cc.9.3.10599283581520009532Search in Google Scholar

12. P. Liu, H. Cheng, T. M. Roberts and J. J. Zhao, Targeting the phosphoinositide 3-kinase pathway in cancer, Nat. Rev. Drug Discov.8 (2009) 627–644; https://doi.org/10.1038/nrd292610.1038/nrd2926314256419644473Search in Google Scholar

13. T. M. Bauer, M. R. Patel and J. R. Infante, Targeting PI3 kinase in cancer, Pharmacol. Ther.146 (2015) 53–60; https://doi.org/10.1016/j.pharmthera.2014.09.00610.1016/j.pharmthera.2014.09.00625240910Search in Google Scholar

14. M. Cully, H. You, A. J. Levine and T. W. Mak, Beyond PTEN mutations: the PI3K pathway as an integrator of multiple inputs during tumorigenesis, Nat. Rev. Cancer6 (2006) 184–192; https://doi.org/10.1038/nrc181910.1038/nrc181916453012Search in Google Scholar

15. A. Carracedo and P. P. Pandolfi, The PTEN-PI3K pathway: of feedbacks and cross-talks, Oncogene27 (2008) 5527–5541; https://doi.org/10.1038/onc.2008.24710.1038/onc.2008.24718794886Search in Google Scholar

16. M. Hayakawa, H. Kaizawa, H. Moritomo, T. Koizumi, T. Ohishi, M. Okada, M. Ohta, S.-I. Tsukamoto, P. Parker, P. Workman and M. Waterfield, Synthesis and biological evaluation of 4-morpholino-2-phenylquinazolines and related derivatives as novel PI3 kinase p110 alpha inhibitors, Bioorg. Med. Chem.14 (2006) 6847–6858; https://doi.org/10.1016/j.bmc.2006.06.04610.1016/j.bmc.2006.06.04616837202Search in Google Scholar

17. M. Hayakawa, H. Kaizawa, K.-I. Kawaguchi, N. Ishikawa, T. Koizumi, T. Ohishi, M. Yamano, M. Okada, M. Ohta, S.-I. Tsukamoto, F. I. Raynaud, M. D. Waterfield, P. Parker and P. Workman, Synthesis and biological evaluation of imidazo[1,2-a]pyridine derivatives as novel PI3 kinase p110 alpha inhibitors, Bioorg. Med. Chem.15 (2007) 403–412; https://doi.org/10.1016/j.bmc.2006.09.04710.1016/j.bmc.2006.09.04717049248Search in Google Scholar

18. M. Hayakawa, H. Kaizawa, H. Moritomo, T. Koizumi, T. Ohishi, M. Yamano, M. Okada, M. Ohta, S. Tsukamoto, F. I. Raynaud, P. Workman, M. D. Waterfield and P. Parker, Synthesis and biological evaluation of pyrido[3’,2’:4,5]furo[3,2-d]pyrimidine derivatives as novel PI3 kinase p110alpha inhibitors, Bioorg. Med. Chem. Lett.17 (2007) 2438–2442; https://doi.org/10.1016/j.bmcl.2007.02.03210.1016/j.bmcl.2007.02.03217339109Search in Google Scholar

19. D. A. Sabbah, N. A. Simms, W. Wang, Y. Dong, E. L. Ezell, M. G. Brattain, J. L. Vennerstrom and H. A. Zhong, N-phenyl-4-hydroxy-2-quinolone-3-carboxamides as selective inhibitors of mutant H1047R phosphoinositide-3-kinase (PI3Kα), Bioorg. Med. Chem.20 (2012) 7175–7183; https://doi.org/10.1016/j.bmc.2012.09.05910.1016/j.bmc.2012.09.05923121722Search in Google Scholar

20. D. A. Sabbah, B. Hishmah, K. Sweidan, S. Bardaweel, M. AlDamen, H. A. Zhong, R. Abu Khalaf, I. Hasan, T. Al-Qirim and G. Abu Sheikha, Structure-based design: Synthesis, X-ray crystallography, and biological evaluation of N-substituted-4-hydroxy-2-quinolone-3-carboxamides as potential cytotoxic agents, Anticancer Agents Med. Chem.18 (2018) 263–276; https://doi.org/10.2174/187152061766617091117115210.2174/187152061766617091117115228901259Search in Google Scholar

21. D. A. Sabbah, F. Al-Tarawneh, W. H. Talib, K. Sweidan, S. K. Bardaweel, E. Al-Shalabi, H. A. Zhong, G. Abu Sheikha, R. Abu Khalaf and M. S. Mubarak, Benzoin Schiff bases: Design, synthesis, and biological evaluation as potential antitumor agents, Med. Chem.14 (2018) 695–708; https://doi.org/10.2174/157340641466618041216014210.2174/157340641466618041216014229651943Search in Google Scholar

22. D. A. Sabbah, A. H. Ibrahim, W. H. Talib, K. M. Alqaisi, K. Sweidan, S. K. Bardaweel, G. A. Sheikha, H. A. Zhong, E. Al-Shalabi and R. A. Khalaf, Ligand-based drug design: Synthesis and biological evaluation of substituted benzoin derivatives as potential antitumor agents, Med. Chem.15 (2019) 417–429; https://doi.org/10.2174/157340641466618091211184610.2174/157340641466618091211184630207238Search in Google Scholar

23. D. Kong and T. Yamori, Advances in development of phosphatidylinositol 3-kinase inhibitors, Curr. Top. Med. Chem.16 (2009) 2839–2854; https://doi.org/10.2174/09298670978880322210.2174/09298670978880322219689267Search in Google Scholar

24. D. A. Sabbah, M. G. Brattain and H. A. Zhong, Dual inhibitors of PI3K/mTOR or mTOR-selective inhibitors: Which way shall we go?, Curr. Med. Chem.18 (2011) 5528–5544; https://doi.org/10.2174/09298671179834729810.2174/09298671179834729822172063Search in Google Scholar

25. D. A. Sabbah, J. Hu and H. A. Zhong, Advances in the development of class I phosphoinositide 3-kinase (PI3K), Curr. Top. Med. Chem.16 (2016) 1413–1426; https://doi.org/10.2174/156802661566615091511582310.2174/156802661566615091511582326369826Search in Google Scholar

26. National Institutes of Health, National Cancer Institute, NCI Open Database Compounds, Release 4, NCI, Bethesda (MD) 2012; http://cactus.nci.nih.gov/download/nci, last access date June 15, 2017Search in Google Scholar

27. D. A. Sabbah, N. A. Simms, M. G. Brattain, J. L. Vennerstrom and H. Zhong, Biological evaluation and docking studies of recently identified inhibitors of phosphoinositide-3-kinases, Bioorg. Med. Chem. Lett.22 (2012) 876–880; https://doi.org/10.1016/j.bmcl.2011.12.04410.1016/j.bmcl.2011.12.044447244622212721Search in Google Scholar

28. D. A. Sabbah, M. Saada, R. A. Khalaf, S. Bardaweel, K. Sweidan, T. Al-Qirim, A. Al-Zughier, H. A. Halim and G. A. Sheikha, Molecular modeling based approach, synthesis, and cytotoxic activity of novel benzoin derivatives targeting phosphoinostide 3-kinase (PI3Kα), Bioorg. Med. Chem. Lett.25 (2015) 3120–3124; http://dx.doi.org/https://doi.org/10.1016/j.bmcl.2015.06.01110.1016/j.bmcl.2015.06.01126099539Search in Google Scholar

29. H. A. Younus, A. Hameed, A. Mahmood, M. S. Khan, M. Saeed, F. Batool, A. Asari, H. Mohamad, J. Pelletier, J. Sévigny, J. Iqbal and M. al-Rashida, Sulfonylhydrazones: Design, synthesis and investigation of ectonucleotidase (ALP & e5′NT) inhibition activities, Bioorg. Chem.100 (2020) Article ID 103827; https://doi.org/https://doi.org/10.1016/j.bioorg.2020.10382710.1016/j.bioorg.2020.10382732402802Search in Google Scholar

30. W. H. Talib and A. M. Mahasneh, Antiproliferative activity of plant extracts used against cancer in traditional medicine, Sci. Pharm.78 (2010) 33–46; https://doi.org/10.3797/scipharm.0912-1110.3797/scipharm.0912-11300282621179373Search in Google Scholar

31. W. H. Talib, Consumption of garlic and lemon aqueous extracts combination reduces tumor burden by angiogenesis inhibition, apoptosis induction, and immune system modulation, Nutr. J.4344 (2017) 89–97; https://doi.org/https://doi.org/10.1016/j.nut.2017.06.01510.1016/j.nut.2017.06.01528935151Search in Google Scholar

32. W. H. Talib, Regressions of breast carcinoma syngraft following treatment with piperine in combination with thymoquinone, Sci. Pharm.85 (2017) 27–38; https://doi.org/10.3390/scipharm8503002710.3390/scipharm85030027562051528671634Search in Google Scholar

33. W. H. Talib and L. T. Al Kury, Parthenolide inhibits tumor-promoting effects of nicotine in lung cancer by inducing P53 – dependent apoptosis and inhibiting VEGF expression, Biomed. Pharmacother.107 (2018) 1488–1495; https://doi.org/10.1016/j.biopha.2018.08.13910.1016/j.biopha.2018.08.13930257366Search in Google Scholar

34. D. A. Sabbah, J. L. Vennerstrom and H. Zhong, Docking studies on isoform-specific inhibition of phosphoinositide-3-kinases, J. Chem. Inf. Model.50 (2010) 1887–1898; https://doi.org/https://doi.org/10.1021/ci100267910.1021/ci1002679448077220866085Search in Google Scholar

35. D. Mandelker, S. B. Gabelli, O. Schmidt-Kittler, J. Zhu, I. Cheong, C.-H. Huang, K. W. Kinzler, B. Vogelstein and L. M. Amzel, A frequent kinase domain mutation that changes the interaction between PI3K alpha and the membrane, Proc. Natl. Acad. Sci. USA106 (2009) 16996–7001; https://doi.org/10.1073/pnas.090844410610.1073/pnas.0908444106276133419805105Search in Google Scholar

36. Protein Preparation Wizard, Maestro, Macromodel, and QPLD-dock, Schrödinger, LLC, Portland, (OR), 2016Search in Google Scholar

37. R. Hajjo, C. M. Grulke, A. Golbraikh, V. Setola, X.-P. Huang, B. L. Roth and A. Tropsha, Development, Validation, and use of quantitative structure-activity relationship models of 5-hydroxytryptamine (2B) receptor ligands to identify novel receptor binders and putative valvulopathic compounds among common drugs, J. Med. Chem.53 (2010) 7573–7586; https://doi.org/10.1021/jm100600y10.1021/jm100600y343829220958049Search in Google Scholar

38. Alvascience, alvaDesc (software for molecular descriptors calculation) version 1.0.18, 2020, Lecco, Italy; https://www.alvascience.comSearch in Google Scholar

39. D. Szklarczyk, J. H. Morris, H. Cook, M. Kuhn, S. Wyder, M. Simonovic, A. Santos, N. T. Doncheva, A. Roth, P. Bork, L. J. Jensen and C. von Mering, The STRING database in 2017: quality-controlled protein–protein association networks, made broadly accessible, Nucleic Acids Res.45 (2016) D362– D368; https://doi.org/10.1093/nar/gkw93710.1093/nar/gkw937521063727924014Search in Google Scholar

40. M. Kanehisa, M. Araki, S. Goto, M. Hattori, M. Hirakawa, M. Itoh, T. Katayama, S. Kawashima, S. Okuda, T. Tokimatsu and Y. Yamanishi, KEGG for linking genomes to life and the environment, Nucleic Acids Res.36 (2007) D480–D484; https://doi.org/10.1093/nar/gkm88210.1093/nar/gkm882223887918077471Search in Google Scholar

41. M. G. Brattain, A. E. Levine, S. Chakrabarty, L. C. Yeoman, J. K. V. Willson and B. Long, Heterogeneity of human colon carcinoma, Cancer Metastasis Rev.3 (1984) 177–191; https://doi.org/10.1007/bf0004838410.1007/BF000483846437669Search in Google Scholar

42. J. Karar and A. Maity, PI3K/AKT/mTOR pathway in angiogenesis, Front. Mol. Neurosci.4 (2011) Article ID 51; https://doi.org/10.3389/fnmol.2011.0005110.3389/fnmol.2011.00051322899622144946Search in Google Scholar

43. W. H. Talib, S. A. Al-Hadid, M. B. W. Ali, I. H. Al-Yasari and M. R. A. Ali, Role of curcumin in regulating p53 in breast cancer: an overview of the mechanism of action, Breast Cancer (Dove Med Press)10 (2018) 207–217; https://doi.org/10.2147/bctt.s16781210.2147/BCTT.S167812627663730568488Search in Google Scholar

44. R. A. Friesner, J. L. Banks, R. B. Murphy, T. A. Halgren, J. J. Klicic, D. T. Mainz, M. P. Repasky, E. H. Knoll, M. Shelley, J. K. Perry, D. E. Shaw, P. Francis, P. S. Shenkin, Glide: A new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy, J. Med. Chem.47 (2004) 1739–1749; https://doi.org/10.1021/jm030643010.1021/jm030643015027865Search in Google Scholar

45. R. A. Friesner, R. B. Murphy, M. P. Repasky, L. L. Frye, J. R. Greenwood, T. A. Halgren, P. C. Sanschagrin, D. T. Mainz, Extra precision glide:  Docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes, J. Med. Chem.49 (2006) 6177–6196; https://doi.org/10.1021/jm051256o10.1021/jm051256o17034125Search in Google Scholar

46. K. Sweidan, D. A. Sabbah, S. Bardaweel, K. A. Dush, G. A. Sheikha, M. S. Mubarak, Computer-aided design, synthesis, and biological evaluation of new indole-2-carboxamide derivatives as PI3Kα/EGFR inhibitors, Bioorg. Med. Chem. Lett.26 (2016) 2685–2690; https://doi.org/10.1016/j.bmcl.2016.04.01110.1016/j.bmcl.2016.04.01127084677Search in Google Scholar

47. Y. Zhao, X. Zhang, Y. Chen, S. Lu, Y. Peng, X. Wang, C. Guo, A. Zhou, J. Zhang, Y. Luo, Q. Shen, J. Ding, L. Meng and J. Zhang, Crystal structures of PI3Kα complexed with PI103 and its derivatives: new directions for inhibitors design, ACS Med. Chem. Lett.5 (2014) 138–142; https://doi.org/10.1021/ml400378e10.1021/ml400378e402762824900786Search in Google Scholar

48. D. J. Adams and L. R. Morgan, Tumor physiology and charge dynamics of anticancer drugs: implications for camptothecin-based drug development, Curr. Med. Chem.18 (2011) 1367–1372; https://doi.org/10.2174/09298671179502960910.2174/092986711795029609308683721366528Search in Google Scholar

49. J. W. Godden, L. Xue and J. Bajorath, Combinatorial preferences affect molecular similarity/diversity calculations using binary fingerprints and Tanimoto coefficients, J. Chem. Inf. Comput. Sci.40 (2000) 163–166; https://doi.org/10.1021/ci990316u10.1021/ci990316u10661563Search in Google Scholar

50. A. Kamal, S. Azeeza, E. V. Bharathi, M. S. Malik and R. V. Shetti, Search for new and novel chemotherapeutics for the treatment of human malignancies, Mini Rev. Med. Chem.10 (2010) 405–435; https://doi.org/10.2174/13895571079133091810.2174/13895571079133091820370699Search in Google Scholar

51. A. Kamal, Y. V. V. Srikanth, M. Ashraf, M. N. A. Khan, T. B. Shaik, S. V. Kalivendi, N. Suri and A. K. Saxena, Synthesis and anticancer activities of new benzothiadiazinyl hydrazinecarboxamides and anilino[1,2,4]triazolo[1,5-b][1,2,4]thiadiazine 5,5-diones, Med. Chem.7 (2011) 165–172; https://doi.org/10.2174/15734061179556425910.2174/15734061179556425921486211Search in Google Scholar

52. A. Martinez, C. Gil, A. Castro, A. M. Bruno, C. Pérez, C. Prieto and J. Otero, Benzothiadiazine dioxide human cytomegalovirus inhibitors: synthesis and antiviral evaluation of main hetero-cycle modified derivatives, Antivir. Chem. Chemother.14 (2003) 107–114; https://doi.org/10.1177/09563202030140020610.1177/09563202030140020612856922Search in Google Scholar

53. E. Goffin, T. Drapier, A. P. Larsen, P. Geubelle, C. P. Ptak, S. Laulumaa, K. Rovinskaja, J. Gilissen, P. de Tullio, L. Olsen, K. Frydenvang, B. Pirotte, J. Hanson, R. E. Oswald, J. S. Kastrup and P. Fran-cotte, 7-Phenoxy-substituted 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides as positive allosteric modulators of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors with nanomolar potency, J. Med. Chem.61 (2018) 251–264; https://doi.org/10.1021/acs.jmedchem.7b0132310.1021/acs.jmedchem.7b01323605235629256599Search in Google Scholar

54. The Molecular Operating, Environment Chemical Computing Group, Inc., Montreal (Quebec) Canada, 2016Search in Google Scholar

Articoli consigliati da Trend MD

Pianifica la tua conferenza remota con Sciendo