Potencial anticancerígeno das bases de Mannich em neoplasias hematológicas - uma revisão de escopo

José Armando Leite Neto; Gabriele Gomes Fenício; Diogo Teixeira Carvalho; Raquel Tognon-Ribeiro

doi:10.18593/evid.36114

Authors

José Armando Leite Neto Graduando em Farmácia pela Faculdade de Ciências Farmacêuticas da Universidade Federal de Alfenas, Alfenas, Minas Gerais, Brasil.
Gabriele Gomes Fenício Graduanda em Farmácia pela Faculdade de Ciências Farmacêuticas da Universidade Federal de Alfenas, Alfenas, Minas Gerais, Brasil. https://orcid.org/0000-0002-1646-6644
Diogo Teixeira Carvalho Universidade Federal de Alfenas (UNIFAL) https://orcid.org/0000-0002-6362-2822
Raquel Tognon-Ribeiro UNIFAL-MG

DOI:

https://doi.org/10.18593/evid.36114

Keywords:

Antineoplastic Agents, Hematologic Neoplasms, Mannich Bases

Abstract

Oncological diseases are a global public health problem. Hematological neoplasms are clonal diseases of the hematopoietic stem cell, which compromise the production of normal blood cells, and are among the 15 types of cancer with the highest incidence in the world. Mannich bases are molecules that can act as important pharmacophores, recognized by studies in medicinal chemistry for potential biological activities, including anticancer potential. This scoping review aims to identify and map the data available in the literature regarding the cytotoxic activity of molecules classified as Mannich bases, aminomethylated compounds derived from the Mannich reaction, against hematologic neoplasms. For the selection of the articles, the MEDLINE and Science Direct databases were searched without time limitation, and 163 articles were obtained. Inclusion criteria were original articles using cell lines, animal models or patients with hematological neoplasms and investigating the anticancer potential of Mannich bases using cellular, preclinical or clinical assays. We excluded review articles, articles written in languages other than Portuguese or English, articles that did not have an abstract available, and articles that were not available on open access or through Periódicos Capes. Two researchers, blinded, performed the selection and conflicts were resolved through discussion. Twenty articles were included in this review and the data were extracted into a spreadsheet. For the discussion, the papers were grouped according to the type of precursor molecule used for the synthesis of each Mannich base. It was noteworthy that in most cases, the Mannich bases were more cytotoxic than their precursor analogues, especially when the latter were cyclic amines and bis-Mannich bases. In general, the mechanism of action was related to their interaction with intracellular thiols and induction of apoptosis.

Downloads

Download data is not yet available.

Author Biography

Diogo Teixeira Carvalho, Universidade Federal de Alfenas (UNIFAL)

Departamento de Alimentos e Medicamentos, Faculdade de Ciências Farmacêuticas da Universidade Federal de Alfenas (UNIFAL) — Alfenas, MG, Brasil.

References

Bala, S., Sharma, N., Kajal, A., Kamboj, S., & Saini, V. (2014). Mannich bases: an important pharmacophore in present scenario. International journal of medicinal chemistry, 2014, 191072. DOI: https://doi.org/10.1155/2014/191072

Bhilare, N. V., Marulkar, V. S., Shirote, P. J., Dombe, S. A., Pise, V. J., Salve, P. L., Biradar, S. M., Yadav, V. D., Jadhav, P. D., Bodhe, A. A., Borkar, S. P., Ghadge, P. M ., Shelar, P. A., Jadhav, A. V., & Godse, K. C. (2022). Mannich Bases: Centrality in Cytotoxic Drug Design. Medicinal Chemistry, 18(7), 735-756. DOI: https://doi.org/10.2174/1573406418666211220124119

Bray, F., Laversanne, M., Sung, H., Ferlay, J., Siegel, R. L., Soerjomataram, I., & Jemal, A. (2024). Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: a cancer journal for clinicians, 74(3), 229–263. DOI: https://doi.org/10.3322/caac.21834

Chen, J., Lou, J., Liu, T., Wu, R., Dong, X., He, Q., Yang, B., & Hu, Y. (2009). Synthesis and In‐Vitro Antitumor Activities of Some Mannich Bases of 9‐Alkyl‐1, 2, 3, 4‐ tetrahydrocarbazole‐1‐ones. Archiv der Pharmazie: An International Journal Pharmaceutical and Medicinal Chemistry, 342(3), 165-172. DOI: 10.1002/ardp.200800179. DOI: https://doi.org/10.1002/ardp.200800179

Chereda, B., & Melo, J. V. (2015). Natural course and biology of CML. Annals of hematology, 94 Suppl 2, S107–S121. DOI: https://doi.org/10.1007/s00277-015-2325-z

Choi, H.S., Kim, B.S., Yoon, S., Oh, S.O., Lee, D. (2024). Leukemic Stem Cells and Hematological Malignancies. Int J Mol Sci, 25(12):6639. DOI: 10.3390/ijms25126639. DOI: https://doi.org/10.3390/ijms25126639

Collins, S. J., Gallo, R. C., & Gallagher, R. E. (1977). Continuous growth and differentiation of human myeloid leukaemic cells in suspension culture. Nature, 270(5635), 347-349. DOI: 10.1038/270347a0. DOI: https://doi.org/10.1038/270347a0

Crowley, L. C., Marfell, B. J., Scott, A. P., & Waterhouse, N. J. (2016). Quantitation of Apoptosis and Necrosis by Annexin V Binding, Propidium Iodide Uptake, and Flow Cytometry. Cold Spring Harbor protocols, 2016(11), 10.1101/pdb.prot087288. DOI: https://doi.org/10.1101/pdb.prot087288

Crowley, L. C., Marfell, B. J., & Waterhouse, N. J. (2016). Analyzing Cell Death by Nuclear Staining with Hoechst 33342. Cold Spring Harbor protocols, 2016(9), 10.1101/pdb.prot087205. DOI: https://doi.org/10.1101/pdb.prot087205

Dimmock, J. R., Padmanilayam, M. P., Das, U., Zello, G. A., Sharma, R. K., Shrivastav, A., Selvakumar, P., Pasha, M. K., Nienaber, K. H., Lee, J. S., Allen, T. M., Santos, C. L., Balzarini, J., & De Clercq, E. (2003). Cytotoxic Mannich bases of 1-arylidene-2-tetralones. Journal of Enzyme Inhibition and Medicinal Chemistry, 18(4), 313-324. DOI: 10.1080/1475636031000121929 DOI: https://doi.org/10.1080/1475636031000121929

Dimmock, J. R, Erciyas, E., Kumar, P., Hetherington, M., Quail, J. W, Pugazhenthi, U., Arpin, S. A., Hayes, S. J., Allen, T. M., Halleran., De Clercq, E., Balzarini, J., & Stables, J. P (1997). Mannich bases of phenolic azobenzenes possessing cytotoxic activity. European Journal of Medicinal Chemistry, 32(7-8), 583-594. DOI: 10.1016/S0223-5234(97)83284-9 DOI: https://doi.org/10.1016/S0223-5234(97)83284-9

Dimmock, J. R., Vashishtha, S. C., Quail, J. W., Pugazhenthi, U., Zimpel, Z., Sudom, A. M, Allen, T. M., Kao, G. Y., Balzarini, J., & De Clercq, E. (1998). 4-(β-Arylvinyl)-3-(β- arylvinylketo)-1-ethyl-4-piperidinols and Related Compounds: A Novel Class of Cytotoxic and Anticancer Agents. Journal of Medicinal Chemistry, 41(21), 4012-4020. DOI: 10.1021/jm980145 DOI: https://doi.org/10.1021/jm9801455

Dimmock, J. R.., Jha, A., Kumar, P., Zello, G. A., Quail, J. W., Oloo, E. O., Oucharek, J. J., Pasha, M. K., Seitz, D., Sharma, R. K., Allen, T. M., Santos, C. L., Manavathu, E. K., De Clercq, E., Balzarini, J., & Stables, J. P (2002). Cytotoxic 1, 4-bis (2-oxo-1- cycloalkylmethylene) benzenes and related compounds. European Journal of Medicinal Chemistry, 37(1), 35-44. DOI: 10.1016/S0223-5234(01)01294-6 DOI: https://doi.org/10.1016/S0223-5234(01)01294-6

Dimmock, J. R., Kumar, P., Nazarali, A. J., Motaganahalli, N. L., Kowalchuk, T. P., Beazely, M. A., Quail, J. W., Oloo, E. O., Allen, T. M., Szydlowski, J., De Clercq, E., & Balzarini, J. (2000). Cytotoxic 2, 6-bis (arylidene) cyclohexanones and related compounds. European journal of medicinal chemistry, 35(11), 967-977. DOI: 10.1016/S0223-5234(00)01173-9 DOI: https://doi.org/10.1016/S0223-5234(00)01173-9

Dimmock, J. R., Kandepu, N. M., Hetherington, M., Quail, J. W., Pugazhenthi, U., Sudom, A. M., Chamankhah, M., Rosa, P., Pass, E., Allen, T. M., Halleran, S., Szydlowski, J. Mutus, B., Tannous, M., Manavathu, E. K., Myers, T. G., De Clercq, E., & Balzarini, J. (1998). Cytotoxic activities of Mannich bases of chalcones and related compounds. Journal of Medicinal Chemistry, 41(7), 1014-1026. DOI: 10.1021/jm970432t DOI: https://doi.org/10.1021/jm970432t

Filho, J. F. A., Fiorot, R. G., Delarmelina, M., Lacerda, Jr, V., Dos Santos, R. B., & Greco, S. J. (2013). Reação de Mannich: Metodologia Clássica na Formação de Ligação Carbono- Carbono. Orbital: The Electronic Journal of Chemistry, 5(2), 96-142.

Fillion, H., Porte, M., Bartoli, M. H., Bouaziz, Z., Berlion, M., & Villard, J. (1991). Synthesis of Mannich bases of 5-hydroxynaphthalene-1, 8-carbolactone as potential antifungal or antitumor agents. Chemical and Pharmaceutical Bulletin, 39(2), 493-495. DOI: 10.1248/cpb.39.493 DOI: https://doi.org/10.1248/cpb.39.493

Foley, G. E., Lazarus, H., Farber, S., Uzman, B. G., Boone, B. A., & McCarthy, R. E. (1965). Continuous culture of human lymphoblasts from peripheral blood of a child with acute leukemia. Cancer, 18(4), 522-529. DOI: 10.1002/1097-0142(196504)18:4<522::aid- cncr2820180418>3.0.co;2-j. DOI: https://doi.org/10.1002/1097-0142(196504)18:4<522::AID-CNCR2820180418>3.0.CO;2-J

Gottlieb, E., Armour, S. M., Harris, M. H., & Thompson, C. B. (2003). Mitochondrial membrane potential regulates matrix configuration and cytochrome c release during apoptosis. Cell death and differentiation, 10(6), 709–717. DOI: https://doi.org/10.1038/sj.cdd.4401231

Gul, H. I., Vepsalainen, J., Gul, M., Erciyas, E., & Hanninen, O. (2000). Cytotoxic activities of mono and bis Mannich bases derived from acetophenone against Renca and Jurkat cells. Pharmaceutica Acta Helvetiae, 74(4), 393-398. DOI:10.1016/S0031-6865(00)00022-4 DOI: https://doi.org/10.1016/S0031-6865(00)00022-4

Hassan, A. Y., Abou-Amra, E. S., & El-Sebaey, S. A (2023). Design and synthesis of new series of chiral pyrimidine and purine analogs as COX-2 inhibitors: Anticancer screening, molecular modeling, and in silico studies. Journal of Molecular Structure, 1278, 134930. DOI: 10.1016/j.molstruc.2023.134930 DOI: https://doi.org/10.1016/j.molstruc.2023.134930

Holla, B. S., Veerendra, B., Shivananda, M. K., & Poojary, B. (2003). Synthesis characterization and anticancer activity studies on some Mannich bases derived from 1, 2, 4- triazoles. European Journal of Medicinal Chemistry, 38(7-8), 759-767. DOI: 10.1016/S0223- 5234(03)00128-4 DOI: https://doi.org/10.1016/S0223-5234(03)00128-4

Hu, G., Wang, G., Duan, N., Wen, X., Cao, T., Xie, S., & Huang, W. (2012). Design, synthesis and antitumor activities of fluoroquinolone C-3 heterocycles (IV): s-triazole Schiff–Mannich bases derived from ofloxacin. Acta Pharmaceutica Sinica B, 2(3), 312-317. DOI: 10.1016/j.apsb.2011.11.003 DOI: https://doi.org/10.1016/j.apsb.2011.11.003

Instituto Nacional De Câncer José Alencar Gomes Da Silva (2022). Leucemias: taxas brutas. https://www.gov.br/inca/ptbr/assuntos/cancer/numeros/estimativa/por-neoplasia-taxas- brutas/leucemias.

Instituto Nacional De Câncer José Alencar Gomes Da Silva (2023). Estimativa de 2023: Incidência de Câncer no Brasil. https://www.inca.gov.br/sites/ufu.sti.inca.local/files/media/document/estimativa-2023.pdf.

Ivanova, Y., Momekov, G., Petrov, O., Karaivanova, M., & Kalcheva, V. (2007). Cytotoxic Mannich bases of 6-(3-aryl-2-propenoyl)-2 (3H)-benzoxazolones. European Journal of Medicinal Chemistry, 42(11-12), 1382-1387. DOI: 10.1016/j.ejmech.2007.02.019 DOI: https://doi.org/10.1016/j.ejmech.2007.02.019

Jadus, M. R., Natividad, J., Mai, A., Ouyang, Y., Lambrecht, N., Szabo, S., Ge, L., Hoa, N., & Dacosta-Iyer, M. G (2012). Lung Cancer: a classic example of tumor escape and progression while providing opportunities for immunological intervention. Clinical And Developmental Immunology, 2012, 1-21. DOI: https://doi.org/10.1155/2012/160724

Klein, E., Vánky, F., Ben‐Bassat, H., Neumann, H., Ralph, P., Zeuthen, J., & Polliack, A. (1976). Properties of the K562 cell line, derived from a patient with chronic myeloid leukemia. International Journal of Cancer, 18(4), 421-431. DOI:10.1002/ijc.2910180405 DOI: https://doi.org/10.1002/ijc.2910180405

Kumar, S., Pathania, A. S., Satti, N. K., Dutt, P., Sharma, N., Mallik, F. A., & Ali, A. (2015). Synthetic modification of hydroxychavicol by Mannich reaction and alkyne–azide cycloaddition derivatives depicting cytotoxic potential. European Journal of Medicinal Chemistry, 92, 236-245. DOI: 10.1016/j.ejmech.2014.12.047 DOI: https://doi.org/10.1016/j.ejmech.2014.12.047

López-López, J., Omaña-Cepeda, C., & Jané-Salas, E. (2015). Pré câncer e câncer bucal. Medicina Clínica, 145(9), 404-408. DOI: https://doi.org/10.1016/j.medcli.2014.11.014

Lozzio C.B. and Lozzio B.B. (1975) Human chronic myelogenous leukemia cell-line with positive Philadelphia chromosome. Blood, 45(3): 321-334 DOI: https://doi.org/10.1182/blood.V45.3.321.321

Minowada J., Onuma T. and Moore G.E. (1972) Rosette-forming human lymphoid cell lines. I. Establishment and evidence for origin of thymus-derived lymphocytes. Journal of the National Cancer Institute 49(3): 891-895.

Moore, G. E., Sandberg, A. A., & Ulrich, K. (1966). Suspension cell culture and in vivo and in vitro chromosome constitution of mouse leukemia L1210. Journal of the National Cancer Institute, 36(3), 405-421.

Moore, G. E., & Kitamura, H. (1968). Cell line derived from a patient with myeloma. The New York Medical Journal, 68(15), 2054-2060.

Nagy, L. I., Fehér, L. Z., Szebeni, G. J., Gyuris, M., Sipos, P., Alföldi, R., Hackler, L., Balázs, A., Batár, P., Kanizsai, I., & Puskás, L. G. (2015). Curcumin and its analogue induce apoptosis in leukemia cells and have additive effects with bortezomib in cellular and xenograft models. BioMed Research International, 2015. DOI: 10.1155/2015/968981 DOI: https://doi.org/10.1155/2015/968981

Ouzzani, M., Hammady, H., Fedorowicz, Z., & Elmagarmid, A. (2016). Rayyan – a web and mobile app for systematic reviews. Systematic Reviews, 5, 1-10. DOI: 10.1186/s13643-016- 0384-4. DOI: https://doi.org/10.1186/s13643-016-0384-4

Paiva, B. K. R.; Sarandini, Y. M.; Silva, A. E. da. (2021). Sintomas de Fadiga e Força Muscular Respiratória de Pacientes Onco-hematológicos em Quimioterapia. Revista Brasileira de Cancerologia, 67(3), e–12130. DOI: 10.32635/2176-9745.RBC.2021v67n3.1309. DOI: https://doi.org/10.32635/2176-9745.RBC.2021v67n3.1309

Pakjoo, M., Ahmadi, S. E., Zahedi, M., Jaafari, N., Khademi, R., Amini, A., & Safa, M. (2024). Interplay between proteasome inhibitors and NF-κB pathway in leukemia and lymphoma: a comprehensive review on challenges ahead of proteasome inhibitors. Cell communication and signaling : CCS, 22(1), 105. DOI: https://doi.org/10.1186/s12964-023-01433-5

Pegoraro L., Matera L., Ritz J., Levis A., Palumbo A. and Biagini G. (1983) Establishment of a Ph1-positive human cell line (BV173). Journal of the National Cancer Institute, 70(3), 447-453.

PRISMA for Scoping Reviews (PRISMA-ScR). https://www.prisma-statement.org/scoping. Acesso em 10 de abril de 2025. Acesso em 10 de abril de 2025.

Shchekotikhin, A. E., Shtil, A. A., Luzikov, Y. N., Bobrysheva, T. V., Buyanov, V. N., & Preobrazhenskaya, M. N. (2005). 3-Aminomethyl derivatives of 4, 11-dihydroxynaphtho [2, 3- f] indole-5, 10-dione for circumvention of anticancer drug resistance. Bioorganic & Medicinal Chemistry, 13(6), 2285-2291. DOI: 10.1016/j.bmc.2004.12.044 DOI: https://doi.org/10.1016/j.bmc.2004.12.044

Silva, J. L. S., Contrera, L., Campos, E. V., & Carvalho, A. M. A. (2021). Perfil das notificações de câncer relacionado ao trabalho em um hospital referência em oncologia no estado de Mato Grosso do Sul, Brasil. Multitemas, 137-157. DOI: https://doi.org/10.20435/multi.v26i62.3050

Sun, B., Liu, J., Gao, Y., Zheng, H. B., Li, L., Hu, Q. W., Yuan, H., & Lou, H. X. (2017). Design, synthesis and biological evaluation of nitrogen-containing macrocyclic bisbibenzyl derivatives as potent anticancer agents by targeting the lysosome. European Journal of Medicinal Chemistry, 136, 603-618. DOI: 10.1016/j.ejmech.2017.05.050 DOI: https://doi.org/10.1016/j.ejmech.2017.05.050

Tricco, A. C., Lillie, E., Zarin, W., O'Brien, K. K., Colquhoun, H., Levac, D., Moher, D., Peters, M. D. J., Horsley, T., Semanas, L., Hempel, S., Elie, A., Chang, C., McGowan, J., Stewart, L., Hartling, L., Aldcroft, A. B. A., Wilson, M. G., Garritty, C., et al. (2018). PRISMA extension for scoping reviews (PRISMA-ScR): checklist and explanation. Annals of Internal Medicine, 169(7), 467-473. DOI: 10.7326/M18-0850. DOI: https://doi.org/10.7326/M18-0850

Vashishtha, S. C., Zello, G. A., Nienaber, K. H., Balzarini, J., De Clercq, E., Stables, J. P., & Dimmock, J. R. (2004). Cytotoxic and anticonvulsant aryloxyaryl Mannich bases and related compounds. European Journal of Medicinal Chemistry, 39 (1), 27-35. DOI: 10.1016/j.ejmech.2003.09.011 DOI: https://doi.org/10.1016/j.ejmech.2003.09.011

Venturini, F. E., Antoniazi, M. K., Ferreira, R. Q., dos Santos, G. F., Pessoa, C., Guimarães, C. J., Neto, J. B. V., Silva, A. M. S., & Greco, S. J. (2022). A Green Multicomponent Domino Mannich‐Michael Reaction to Synthesize Novel Naphthoquinone‐Polyphenols with Antiproliferative and Antioxidant Activities. European Journal of Organic Chemistry, 2022(39), e202200442. DOI: doi.org/10.1002/ejoc.202200442 DOI: https://doi.org/10.1002/ejoc.202200442

Zhu, T., Wang, S.-H., Li, D., Wang, S.-Y., Liu, X., Song, J., Wang, Y.-T., & Zhang, S.-Y. (2021). Progress of tubulin polymerization activity detection methods. Bioorganic & Medicinal Chemistry Letters, 37, 127698. DOI: https://doi.org/10.1016/j.bmcl.2020.127698

Yang, J., Liu, Y., Xue, C., Yu, W., Zhang, J., & Qiao, C. (2014). Synthesis and biological evaluation of glaucocalyxin A derivatives as potential anticancer agents. European Journal of Medicinal Chemistry, 86, 235-241. DOI: 10.1016/j.ejmech.2014.08.061 DOI: https://doi.org/10.1016/j.ejmech.2014.08.061