Copyright (c) 2024 Praveen Kumar Bandaru
This work is licensed under a Creative Commons Attribution 4.0 International License.
Novel Pyrrolo-Pyrimidine Derivatives Bearing Amide Functionality as Potential Anticancer Agents: Synthesis and Molecular Docking Studies
Corresponding Author(s) : Praveen Kumar Bandaru
Asian Journal of Chemistry,
Vol. 36 No. 12 (2024): Vol 36 Issue 12, 2024
Abstract
Current investigation presents the synthesis, molecular docking and anticancer evaluation of novel pyrrolo-pyrimidine derivatives designed to target Janus kinase 1 (JAK1), Janus kinase 2 (JAK2) and cyclin-dependent kinase 4 (CDK4). The synthesis route commenced with 2-amino-4,6-dichloropyrimidine-5-carbaldehyde, proceeding through sequential steps involving intermediate formations and coupling reactions to yield a diverse array of pyrrolo-pyrimidine derivatives. Characterization using spectroscopic techniques (1H NMR, 13C NMR and HRMS) confirmed the chemical structures of the synthesized compounds. Molecular docking studies against JAK1, JAK2 and CDK4 demonstrated substantial binding affinities, remarkably compounds 7k, 7l and 7d, which displayed promising interactions within the active sites of the proteins. Anticancer evaluation against breast cancer (MCF-7), chronic myeloid leukemia (SET-2), colorectal carcinoma (HCT-116) and HEK-293 cell lines revealed diverse cytotoxic profiles. Specifically, compounds 7k and 7f exhibited potent activity against breast cancer (MCF-7), 7k and 7f showed efficacy against chronic myeloid leukemia (SET-2) and compounds 7k and 7l demonstrated effectiveness against colorectal carcinoma (HCT-116). These findings underscore the potential of these pyrrolo-pyrimidine derivatives as selective and effective anticancer agents, prompting further exploration for therapeutic development.
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- World Health Organization, Global Cancer Burden Growing, Amidst Mounting Need for Services (2024); https://www.who.int/news/item/01-02-2024-global-cancer-burden-growing--amidst-mounting-need-for-services
- R. Baskar, K.A. Lee, R. Yeo and K.W. Yeoh, Int. J. Med. Sci., 9, 193 (2012); https://doi.org/10.7150/ijms.3635
- D.T. Debela, S.G. Muzazu, K.D. Heraro, M.T. Ndalama, B.W. Mesele, D.C. Haile, S.K. Kitui and T. Manyazewal, SAGE Open Med., 9, 20503121211034366 (2021); https://doi.org/10.1177/20503121211034366
- U. Anand, A. Dey, A.K.S. Chandel, R. Sanyal, A. Mishra, D.K. Pandey, V. De Falco, A. Upadhyay, R. Kandimalla, A. Chaudhary, J.K. Dhanjal, S. Dewanjee, J. Vallamkondu and J.M. Pérez de la Lastra, Genes Dis., 10, 1367 (2023); https://doi.org/10.1016/j.gendis.2022.02.007
- I.A. George, R. Chauhan, R. Dhawale, R. Iyer, S. Limaye, R. Sankaranarayanan, R. Venkataramanan and P. Kumar, Adv. Cancer Biol. Metastasis, 6, 100074 (2022); https://doi.org/10.1016/j.adcanc.2022.100074
- S.L. Groenland, A. Martínez-Chávez, M.G.J. van Dongen, J.H. Beijnen, A.H. Schinkel, A.D.R. Huitema and N. Steeghs, Clin. Pharmacokinet., 59, 1501 (2020); https://doi.org/10.1007/s40262-020-00930-x
- T.Y.J. Appeldoorn, T.H.O. Munnink, L.M. Morsink, M.N.L.D. Hooge and D.J. Touw, Clin. Pharmacokinet., 62, 559 (2023); https://doi.org/10.1007/s40262-023-01225-7
- V. Beljanski, Compr. Pharmacol. Ref., 1, 1 (2007); https://doi.org/10.1016/B978-008055232-3.63731-6
- X. Liang, S. Tang, X. Liu, Y. Liu, Q. Xu, X. Wang, A. Saidahmatov, C. Li, J. Wang, Y. Zhou, Y. Zhang, M. Geng, M. Huang and H. Liu, J. Med. Chem., 65, 1243 (2022); https://doi.org/10.1021/acs.jmedchem.0c02111
- J. Zhang, S. Xing, J. Cui, X. Wei, Z. Cao, B. Shao, N. Jiang and X. Zhai, Arch. Pharm., 357, 2300591 (2024); https://doi.org/10.1002/ardp.202300591
- W. Mao, H. Wu, Q. Guo, X. Zheng, C. Wei, Y. Liao, L. Shen, J. Mi, J. Li, S. Chen and W. Qian, Bioorg. Med. Chem. Lett., 74, 128905 (2022); https://doi.org/10.1016/j.bmcl.2022.128905
- B. Yang, Y. Quan, W. Zhao, Y. Ji, X. Yang, J. Li, Y. Li, X. Liu, Y. Wang and Y. Li, J. Enzyme Inhib. Med. Chem., 38, 2169282 (2023); https://doi.org/10.1080/14756366.2023.2169282
- S.M. Patil, V.A. Patil, K. Asgonkar, V. Randive and I. Mahadik, Curr. Indian Sci., 01, e2210299X258569 (2023); https://doi.org/10.2174/012210299X258569231006094309
- X. Shi, Y. Quan, Y. Wang, Y. Wang and Y. Li, Bioorg. Med. Chem. Lett., 33, 127725 (2021); https://doi.org/10.1016/j.bmcl.2020.127725
- Y. Li, R. Du, Y. Nie, T. Wang, Y. Ma and Y. Fan, Bioorg. Chem., 109, 104717 (2021); https://doi.org/10.1016/j.bioorg.2021.104717
- L.X. Wang, X. Liu, S. Xu, Q. Tang, Y. Duan, Z. Xiao, J. Zhi, L. Jiang, P. Zheng and W. Zhu, Eur. J. Med. Chem., 141, 538 (2017); https://doi.org/10.1016/j.ejmech.2017.10.027
- P. Shirvani and A. Fassihi, Mol. Simul., 46, 1265 (2020); https://doi.org/10.1080/08927022.2020.1810853
- D. Xu, D. Sun, W. Wang, X. Peng, Z. Zhan, Y. Ji, Y. Shen, M. Geng, J. Ai and W. Duan, Eur. J. Med. Chem., 220, 113497 (2021); https://doi.org/10.1016/j.ejmech.2021.113497
- X. Zhao, W. Huang, Y. Wang, M. Xin, Q. Jin, J. Cai, F. Tang, Y. Zhao and H. Xiang, Bioorg. Med. Chem., 23, 891 (2015); https://doi.org/10.1016/j.bmc.2014.10.043
- L. He, H. Pei, C. Zhang, M. Shao, D. Li, M. Tang, T. Wang, X. Chen, M. Xiang and L. Chen, Eur. J. Med. Chem., 145, 96 (2018); https://doi.org/10.1016/j.ejmech.2017.12.079
- Z. Xia, R. Huang, X. Zhou, Y. Chai, H. Chen, L. Ma, Q. Yu, Y. Li, W. Li and Y. He, Eur. J. Med. Chem., 224, 113711 (2021); https://doi.org/10.1016/j.ejmech.2021.113711
- S.J. Kaspersen, J. Han, K.G. Nørsett, L. Rydså, E. Kjøbli, S. Bugge, G. Bjørkøy, E. Sundby and B.H. Hoff, Eur. J. Pharm. Sci., 59, 69 (2014); https://doi.org/10.1016/j.ejps.2014.04.011
- G. Sivaiah, R. Raveesha, S. Benaka Prasad, K. Yogesh Kumar, M. Raghu, F.A. Alharti, M. Prashanth and B.H. Jeon, J. Mol. Struct., 1275, 134728 (2023); https://doi.org/10.1016/j.molstruc.2022.134728
- A.A. Alotaibi, M.M. Alanazi and A.F.M.M. Rahman, Pharmaceuticals, 16, 1324 (2023); https://doi.org/10.3390/ph16091324
- K. Metwally and N.E. Abo-Dya, Curr. Med. Chem., 31, 5918 (2024); https://doi.org/10.2174/0929867331666230815115111
- M. Adel, R.A. Serya, D.S. Lasheen and K.A. Abouzid, Bioorg. Chem., 81, 612 (2018); https://doi.org/10.1016/j.bioorg.2018.09.001
- A.A. Alotaibi, H.H. Asiri, A.M. Rahman and M.M. Alanazi, J. Saudi Chem. Soc., 27, 101712 (2023); https://doi.org/10.1016/j.jscs.2023.101712
- S. Tumkevicius, M. Dailide and A. Kaminskas, J. Heterocycl. Chem., 43, 1629 (2006); https://doi.org/10.1002/jhet.5570430630
- L. Ducry and D.M. Roberge, Org. Process Res. Dev., 12, 163 (2008); https://doi.org/10.1021/op7002002
- D. Webb and T.F. Jamison, Org. Lett., 14, 568 (2012); https://doi.org/10.1021/ol2031872
- B.J. Bender, S. Gahbauer, A. Luttens, J. Lyu, C.M. Webb, R.M. Stein, E.A. Fink, T.E. Balius, J. Carlsson, J.J. Irwin and B.K. Shoichet, Nat. Protoc., 16, 4799 (2021); https://doi.org/10.1038/s41596-021-00597-z
- T.L. Riss, R.A. Moravec, A.L. Niles, S. Duellman, H.A. Benink, T.J. Worzella and L. Minor, Assay Guidance Manual, Eli Lilly & Company and the National Center for Advancing Translational Sciences (2016).
References
World Health Organization, Global Cancer Burden Growing, Amidst Mounting Need for Services (2024); https://www.who.int/news/item/01-02-2024-global-cancer-burden-growing--amidst-mounting-need-for-services
R. Baskar, K.A. Lee, R. Yeo and K.W. Yeoh, Int. J. Med. Sci., 9, 193 (2012); https://doi.org/10.7150/ijms.3635
D.T. Debela, S.G. Muzazu, K.D. Heraro, M.T. Ndalama, B.W. Mesele, D.C. Haile, S.K. Kitui and T. Manyazewal, SAGE Open Med., 9, 20503121211034366 (2021); https://doi.org/10.1177/20503121211034366
U. Anand, A. Dey, A.K.S. Chandel, R. Sanyal, A. Mishra, D.K. Pandey, V. De Falco, A. Upadhyay, R. Kandimalla, A. Chaudhary, J.K. Dhanjal, S. Dewanjee, J. Vallamkondu and J.M. Pérez de la Lastra, Genes Dis., 10, 1367 (2023); https://doi.org/10.1016/j.gendis.2022.02.007
I.A. George, R. Chauhan, R. Dhawale, R. Iyer, S. Limaye, R. Sankaranarayanan, R. Venkataramanan and P. Kumar, Adv. Cancer Biol. Metastasis, 6, 100074 (2022); https://doi.org/10.1016/j.adcanc.2022.100074
S.L. Groenland, A. Martínez-Chávez, M.G.J. van Dongen, J.H. Beijnen, A.H. Schinkel, A.D.R. Huitema and N. Steeghs, Clin. Pharmacokinet., 59, 1501 (2020); https://doi.org/10.1007/s40262-020-00930-x
T.Y.J. Appeldoorn, T.H.O. Munnink, L.M. Morsink, M.N.L.D. Hooge and D.J. Touw, Clin. Pharmacokinet., 62, 559 (2023); https://doi.org/10.1007/s40262-023-01225-7
V. Beljanski, Compr. Pharmacol. Ref., 1, 1 (2007); https://doi.org/10.1016/B978-008055232-3.63731-6
X. Liang, S. Tang, X. Liu, Y. Liu, Q. Xu, X. Wang, A. Saidahmatov, C. Li, J. Wang, Y. Zhou, Y. Zhang, M. Geng, M. Huang and H. Liu, J. Med. Chem., 65, 1243 (2022); https://doi.org/10.1021/acs.jmedchem.0c02111
J. Zhang, S. Xing, J. Cui, X. Wei, Z. Cao, B. Shao, N. Jiang and X. Zhai, Arch. Pharm., 357, 2300591 (2024); https://doi.org/10.1002/ardp.202300591
W. Mao, H. Wu, Q. Guo, X. Zheng, C. Wei, Y. Liao, L. Shen, J. Mi, J. Li, S. Chen and W. Qian, Bioorg. Med. Chem. Lett., 74, 128905 (2022); https://doi.org/10.1016/j.bmcl.2022.128905
B. Yang, Y. Quan, W. Zhao, Y. Ji, X. Yang, J. Li, Y. Li, X. Liu, Y. Wang and Y. Li, J. Enzyme Inhib. Med. Chem., 38, 2169282 (2023); https://doi.org/10.1080/14756366.2023.2169282
S.M. Patil, V.A. Patil, K. Asgonkar, V. Randive and I. Mahadik, Curr. Indian Sci., 01, e2210299X258569 (2023); https://doi.org/10.2174/012210299X258569231006094309
X. Shi, Y. Quan, Y. Wang, Y. Wang and Y. Li, Bioorg. Med. Chem. Lett., 33, 127725 (2021); https://doi.org/10.1016/j.bmcl.2020.127725
Y. Li, R. Du, Y. Nie, T. Wang, Y. Ma and Y. Fan, Bioorg. Chem., 109, 104717 (2021); https://doi.org/10.1016/j.bioorg.2021.104717
L.X. Wang, X. Liu, S. Xu, Q. Tang, Y. Duan, Z. Xiao, J. Zhi, L. Jiang, P. Zheng and W. Zhu, Eur. J. Med. Chem., 141, 538 (2017); https://doi.org/10.1016/j.ejmech.2017.10.027
P. Shirvani and A. Fassihi, Mol. Simul., 46, 1265 (2020); https://doi.org/10.1080/08927022.2020.1810853
D. Xu, D. Sun, W. Wang, X. Peng, Z. Zhan, Y. Ji, Y. Shen, M. Geng, J. Ai and W. Duan, Eur. J. Med. Chem., 220, 113497 (2021); https://doi.org/10.1016/j.ejmech.2021.113497
X. Zhao, W. Huang, Y. Wang, M. Xin, Q. Jin, J. Cai, F. Tang, Y. Zhao and H. Xiang, Bioorg. Med. Chem., 23, 891 (2015); https://doi.org/10.1016/j.bmc.2014.10.043
L. He, H. Pei, C. Zhang, M. Shao, D. Li, M. Tang, T. Wang, X. Chen, M. Xiang and L. Chen, Eur. J. Med. Chem., 145, 96 (2018); https://doi.org/10.1016/j.ejmech.2017.12.079
Z. Xia, R. Huang, X. Zhou, Y. Chai, H. Chen, L. Ma, Q. Yu, Y. Li, W. Li and Y. He, Eur. J. Med. Chem., 224, 113711 (2021); https://doi.org/10.1016/j.ejmech.2021.113711
S.J. Kaspersen, J. Han, K.G. Nørsett, L. Rydså, E. Kjøbli, S. Bugge, G. Bjørkøy, E. Sundby and B.H. Hoff, Eur. J. Pharm. Sci., 59, 69 (2014); https://doi.org/10.1016/j.ejps.2014.04.011
G. Sivaiah, R. Raveesha, S. Benaka Prasad, K. Yogesh Kumar, M. Raghu, F.A. Alharti, M. Prashanth and B.H. Jeon, J. Mol. Struct., 1275, 134728 (2023); https://doi.org/10.1016/j.molstruc.2022.134728
A.A. Alotaibi, M.M. Alanazi and A.F.M.M. Rahman, Pharmaceuticals, 16, 1324 (2023); https://doi.org/10.3390/ph16091324
K. Metwally and N.E. Abo-Dya, Curr. Med. Chem., 31, 5918 (2024); https://doi.org/10.2174/0929867331666230815115111
M. Adel, R.A. Serya, D.S. Lasheen and K.A. Abouzid, Bioorg. Chem., 81, 612 (2018); https://doi.org/10.1016/j.bioorg.2018.09.001
A.A. Alotaibi, H.H. Asiri, A.M. Rahman and M.M. Alanazi, J. Saudi Chem. Soc., 27, 101712 (2023); https://doi.org/10.1016/j.jscs.2023.101712
S. Tumkevicius, M. Dailide and A. Kaminskas, J. Heterocycl. Chem., 43, 1629 (2006); https://doi.org/10.1002/jhet.5570430630
L. Ducry and D.M. Roberge, Org. Process Res. Dev., 12, 163 (2008); https://doi.org/10.1021/op7002002
D. Webb and T.F. Jamison, Org. Lett., 14, 568 (2012); https://doi.org/10.1021/ol2031872
B.J. Bender, S. Gahbauer, A. Luttens, J. Lyu, C.M. Webb, R.M. Stein, E.A. Fink, T.E. Balius, J. Carlsson, J.J. Irwin and B.K. Shoichet, Nat. Protoc., 16, 4799 (2021); https://doi.org/10.1038/s41596-021-00597-z
T.L. Riss, R.A. Moravec, A.L. Niles, S. Duellman, H.A. Benink, T.J. Worzella and L. Minor, Assay Guidance Manual, Eli Lilly & Company and the National Center for Advancing Translational Sciences (2016).