Discovery of a pyrimidine compound endowed with antitumor activity.
Antineoplastic Agents
/ chemistry
Apoptosis
Breast Neoplasms
/ drug therapy
Cell Cycle
Cell Line, Tumor
Cell Proliferation
Colonic Neoplasms
/ drug therapy
Drug Discovery
Drug Screening Assays, Antitumor
Female
Glioblastoma
/ drug therapy
Humans
Pyrimidines
/ chemistry
Structure-Activity Relationship
Breast cancer
Colon carcinoma
Glioblastoma multiforme
PJ34
Phenathridinone
Pyrimidine
Journal
Investigational new drugs
ISSN: 1573-0646
Titre abrégé: Invest New Drugs
Pays: United States
ID NLM: 8309330
Informations de publication
Date de publication:
02 2020
02 2020
Historique:
received:
28
01
2019
accepted:
08
03
2019
pubmed:
23
3
2019
medline:
24
10
2020
entrez:
23
3
2019
Statut:
ppublish
Résumé
Recently, some synthetic nitrogen-based heterocyclic molecules, such as PJ34, have shown pronounced antitumor activity. Therefore, we designed and synthesized new derivatives characterized by a nitrogen-containing scaffold and evaluated their antiproliferative properties in tumor cells. We herein report the effects of three newly synthesized compounds on cell lines from three different human cancers: triple-negative breast cancer, colon carcinoma and glioblastoma. We found that two of these compounds did not affect proliferation, while the third significantly inhibited replication of the three cell lines. Moreover, this third molecule at 20 μM led to the upregulation of p21 and p27 and blockage of the cell cycle at G0/G1; in addition, it induced apoptosis in all three cell lines when used at higher concentrations (30-50 μM). The results demonstrate that this compound is a potent inhibitor of replication, an inducer of apoptosis and a negative regulator of cell cycle progression for cancer cells of different histotypes. Our data suggest a potential role for this new molecule as an interesting and powerful tool for new approaches in treating various cancers.
Identifiants
pubmed: 30900116
doi: 10.1007/s10637-019-00762-y
pii: 10.1007/s10637-019-00762-y
doi:
Substances chimiques
Antineoplastic Agents
0
Pyrimidines
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
39-49Références
Jordan MA, Wilson L (2004) Microtubules as a target for anticancer drugs. Nat Rev Cancer 4(4):253–265
doi: 10.1038/nrc1317
Harrison MR, Holen KD, Liu G (2009) Beyond taxanes: a review of novel agents that target mitotic tubulin and microtubules, kinases, and kinesins. Clin Adv Hematol Oncol 7:54–64
pubmed: 19274042
pmcid: 2904974
Tumir LM, Radic Stojkovic M, Plantanida I (2014) Come-back of the phenanthridine and phenanthridinium derivatives in the 21st century. Beilstein J Org Chem 10:2930–2954. https://doi.org/10.3762/bjoc.10.312
doi: 10.3762/bjoc.10.312
pubmed: 25550761
pmcid: 4273281
Visochek L, Castiel A, Mittelman L, Elkin M, Atias D, Golan T, Izraeli S, Peretz T, Cohen-Armon M (2017) Exclusive destruction of mitotic spindles in human cancer cells. Oncotarget 8:20813–20824. https://doi.org/10.18632/oncotarget.15343
doi: 10.18632/oncotarget.15343
pubmed: 28209915
pmcid: 5400547
Inbar-Rozensal D, Castiel A, Visochek L, Castel D, Dantzer F, Izraeli S, Cohen-Armon M (2009) A selective eradication of human nonhereditary breast cancer cells by phenanthridine-derived polyADP-ribose polymerase inhibitors. Breast Cancer Res 11:R78. https://doi.org/10.1186/bcr2445
doi: 10.1186/bcr2445
pubmed: 19891779
pmcid: 2815540
Castiel A, Visochek L, Mittelman L, Dantzer F, Izraeli S, Cohen-Armon M (2011) A phenanthrene derived PARP inhibitor is an extra-centrosomes de-clustering agent exclusively eradicating human cancer cells. BMC Cancer 11:412–419
doi: 10.1186/1471-2407-11-412
Castiel A, Visochek L, Mittelman L, Zilberstein Y, Dantzer F, Izraeli S, Cohen-Armon M (2013) Cell death associated with abnormal mitosis observed by confocal imaging in live cancer cells. J Vis Exp 78:e50568. https://doi.org/10.3791/50568
doi: 10.3791/50568
Li Y, Lu W, Chen D, Boohaker RJ, Zhai L, Padmalayam I, Wennerberg K, Xu B, Zhang W (2015) KIFC1 is a novel potential therapeutic target for breast cancer. Cancer Biol Ther 16:1316–1322. https://doi.org/10.1080/15384047.2015.1070980
doi: 10.1080/15384047.2015.1070980
pubmed: 26177331
pmcid: 4622065
Kleylein-Sohn J, Pollinger B, Ohmer M, Hofmann F, Nigg EA, Hemmings BA, Wartmann M (2012) Acentrosomal spindle organization renders cancer cells dependent on the kinesin HSET. J Cell Sci 125:5391–5402. https://doi.org/10.1242/jcs.107474
doi: 10.1242/jcs.107474
pubmed: 22946058
Xiao YX, Yang WX (2016) KIFC1: a promising chemotherapy target for cancer treatment? Oncotarget 7:48656–48670
pubmed: 27102297
pmcid: 5217046
Vitaku E, Smith DT, Njardarson JT (2014) Analysis of the structural diversity, substitution patterns, and frequency of nitrogen heterocycles among US FDA approved pharmaceuticals. J Med Chem 57:10257–10274. https://doi.org/10.1021/jm501100b
doi: 10.1021/jm501100b
pubmed: 25255204
Martins P, Jesus J, Santos S, Raposo LR, Roma-Rodrigues C, Baptista PV, Fernandes AR (2015) Heterocyclic anticancer compounds: recent advances and the paradigm shift towards the use of nanomedicine’s tool box. Molecules 20:16852–16891. https://doi.org/10.3390/molecules200916852
doi: 10.3390/molecules200916852
pubmed: 26389876
pmcid: 6331900
Hosseinzadeh Z, Ramazani A, Razzaghi-Asl N (2018) Anti-cancer nitrogen-containing heterocyclic compounds. Curr Org Chem 22:1–24. https://doi.org/10.2174/1385272822666181008142138
doi: 10.2174/1385272822666181008142138
Ragab FAF, Abou-Seri SM, Abdel-Aziz SA, Alfayomy AM, Aboelmagd M (2017) Design, synthesis and anticancer activity of new monastrol analogues bearing 1,3,4-oxadiazole moiety. Eur J Med Chem 138:140–151. https://doi.org/10.1016/j.ejmech.2017.06.026
doi: 10.1016/j.ejmech.2017.06.026
pubmed: 28667871
Park HW, Ma Z, Zhu H, Jiang S, Robinson RC, Endow SA (2017) Structural basis of small molecule ATPase inhibition of a human mitotic kinesin motor protein. Sci Rep 7:15121. https://doi.org/10.1038/s41598-017-14754-6
doi: 10.1038/s41598-017-14754-6
pubmed: 29123223
pmcid: 5680195
Saccoliti F, Angiulli G, Pupo G, Pescatori L, Madia VN, Messore A, Colotti G, Fiorillo A, Scipione L, Gramiccia M, Di Muccio T, Di Santo R, Costi R, Ilari A (2017) Inhibition of Leishmania infantum Trypanothione reductase by diaryl sulfide derivatives. J Enzyme Inhib Med Chem 32:304–310. https://doi.org/10.1080/14756366.2016.1250755
doi: 10.1080/14756366.2016.1250755
pubmed: 28098499
pmcid: 6010130
Jain KK (2018) A critical overview of targeted therapies for glioblastoma. Front Oncol 8:419. https://doi.org/10.3389/fonc.2018.00419
doi: 10.3389/fonc.2018.00419
pubmed: 30374421
pmcid: 6196260
Chavez KJ, Garimella SV, Lipkowitz S (2010) Triple negative breast cancer cell lines: one tool in the search for better treatment of triple negative breast cancer. Breast Dis 32:35–48. https://doi.org/10.3233/BD-2010-0307
doi: 10.3233/BD-2010-0307
pubmed: 21778573
pmcid: 3532890
Muthuraja P, Himesh M, Prakash S, Venkatasubramanian U, Manisankar P (2018) Synthesis of N-(1-(6-acetamido-5-phenylpyrimidin-4-yl) piperidin-3-yl) amide derivatives as potential inhibitors for mitotic kinesin spindle protein. Eur J Med Chem 148:106–115. https://doi.org/10.1016/j.ejmech.2018.02.010
doi: 10.1016/j.ejmech.2018.02.010
pubmed: 29454915
Davis PJ, Harris L, Karim A, Thompson AL, Gilpin M, Moloney MG, Pound MJ, Thompson C (2011) Substituted diaryldiazomethanes and diazofluorenes: structure, reactivity and stability. Tetrahedron Lett 52:1553–1556. https://doi.org/10.1016/j.tetlet.2011.01.116
doi: 10.1016/j.tetlet.2011.01.116
Li JH, Kalish VJ, Zhang J, Serdyuk LE, Ferraris DV, Xiao G, Kletzly PW (2001) Sulfonamide and carbamide derivatives of 6(5H) phenanthridinones and their uses. Patent WO2001090077A1.
Taglieri L, Nardo T, Vicinanza R, Ross JM, Scarpa S, Coppotelli G (2017) Thyroid hormone regulates fibronectin expression through the activation of hypoxia inducible factor 1. Biochem Biophys Res Commun 493:1304–1310
doi: 10.1016/j.bbrc.2017.09.169
Gulappa T, Reddy RS, Suman S, Nyakeriga AM, Damodaran C (2013) Molecular interplay between cdk4 and p21 dictates G0/G1 cell cycle arrest in prostate cancer cells. Cancer Lett 337:177–183. https://doi.org/10.1016/j.canlet.2013.05.014
doi: 10.1016/j.canlet.2013.05.014
pubmed: 23684928
pmcid: 3752915
Georgakilas Ag MOA, Bonner WM (2017) P21: a two-faced genome guardian. Trends Mol Med 23:310–319
doi: 10.1016/j.molmed.2017.02.001
Abbas T, Dutta A (2009) P21 in cancer: intricate networks and multiple activities. Nat Rev Cancer 9:400–414
doi: 10.1038/nrc2657
Xia X, Ma Q, Li X, Ji T, Chen P, Xu H, Li K, Fang Y, Weng D, Weng Y, Liao S, Han Z, Liu R, Zhu T, Wang S, Xu G, Meng L, Zhou J, Ma D (2011) Cytoplasmic p21 is a potential predictor for cisplatin sensitivity in ovarian cancer. BMC Cancer 11:399. https://doi.org/10.1186/1471-2407-11-399
doi: 10.1186/1471-2407-11-399
pubmed: 21933447
pmcid: 3184122
Koster R, di Pietro A, Timmer-Bosscha H, Gibcus JH, van den Berg A, Suurmeijer AJ, Bischoff R, Gietema JA, de Jong S (2010) Cytoplasmic p21 expression levels determine cisplatin resistance in human testicular cancer. J Clin Invest 120:3594–3605. https://doi.org/10.1172/JCI41939
doi: 10.1172/JCI41939
pubmed: 20811155
pmcid: 2947220
Xia X, Ma Q, Li X, Ji T, Chen P, Xu H, Li K, Fang Y, Weng D, Weng Y, Liao S, Han Z, Liu R, Zhu T, Wang S, Xu G, Meng L, Zhou J, Ma D (2011) Cytoplasmic p21 is a potential predictor for cisplatin sensitivity in ovarian cancer. BMC Cancer 11:399. https://doi.org/10.1186/1471-2407-11-399
doi: 10.1186/1471-2407-11-399
pubmed: 21933447
pmcid: 3184122
Abukhdeir AM, Park BH (2008) P21 and p27: roles in carcinogenesis and drug resistance. Expert Rev Mol Med 10:e19. https://doi.org/10.1017/S1462399408000744
doi: 10.1017/S1462399408000744
pubmed: 18590585
pmcid: 2678956
Yoon MK, Mitrea DM, Ou L, Kriwacki RW (2012) Cell cycle regulation by the intrinsically disordered proteins p21 and p27. Biochem Soc Trans 40:981–988
doi: 10.1042/BST20120092
Cuadrado M, Gutierrez-Martinez P, Swat A, Nebreda AR, Fernandez-Capetillo O (2009) P27 stabilization is essential fot the mainteinance of cell cycle arrest in response to DNA damage. Cancer Res 69:8726–8732. https://doi.org/10.1158/0008-5472.CAN-09-0729
doi: 10.1158/0008-5472.CAN-09-0729
pubmed: 19843869
pmcid: 3594702
Zhuang Y, Miskimins WK (2008) Cell cycle arrest in metformin treated breast cancer cells involves activation of AMPK, downregulation of cyclin D1 and requires p21 or p27. J Mol Signal 3:18–29. https://doi.org/10.1186/1750-2187-3-18.
doi: 10.1186/1750-2187-3-18.
pubmed: 19046439
pmcid: 2613390
Zohny SF, Al-Malki AL, Zamzami MA, Choundhry H (2018) P21: its paradoxical effect in the regulation of breast cancer. Breast Cancer 26:131–137. https://doi.org/10.1007/s12282-018-0913-1
doi: 10.1007/s12282-018-0913-1
pubmed: 30255294