Design, synthesis and molecular docking study of new pyrimidine-based hydrazones with selective anti-proliferative activity against MCF-7 and MDA-MB-231 human breast cancer cell lines

被引:13
作者
Badawi, Waleed A. [1 ]
Samir, Mohamed [2 ]
Fathy, Hazem M. [2 ]
Okda, Tarek M. [3 ]
Noureldin, Mohamed H. [4 ]
Atwa, Gamal M. K. [5 ]
AboulWafa, Omaima M. [6 ]
机构
[1] Univ Damanhour, Fac Pharm, Dept Pharmaceut Chem, Damanhour 22511, Egypt
[2] Al Azhar Univ, Fac Pharm, Dept Pharmaceut Organ Chem, Assiut Branch, Assiut 71524, Egypt
[3] Damanhour Univ, Fac Pharm, Dept Biochem, Damanhour 22511, Egypt
[4] Arab Acad Sci, Coll Pharm Technol & Maritime Transport, Dept Biochem, Div Clin & Biol Sci, POB 1029, Alexandria, Egypt
[5] Port Said Univ, Fac Pharm, Dept Biochem, Port Said 42515, Egypt
[6] Alexandria Univ, Fac Pharm, Dept Pharmaceut Chem, Alexandria 21215, Egypt
关键词
Hydrazinylpyrimidines; Breast cancer antiproliferation activity; Enzymes inhibition; Apoptosis; Cell cycle arrest; RAPID COLORIMETRIC ASSAY; BIOLOGICAL EVALUATION; AROMATASE INHIBITORS; CDK4/6; INHIBITOR; RECEPTOR; GROWTH; CHALLENGES; RESISTANCE; SURVIVAL;
D O I
10.1016/j.bioorg.2023.106610
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Efforts were directed on the design, synthesis and evaluation of the anticancer activity of some pyrimidine-based hydrazones against two breast cancer cell lines, MCF-7 and MDA-MB-231. Preliminary screening results revealed that some candidates scrutinized for their antiproliferative activities exhibited IC50 values of 0.87 mu M-12.91 mu M in MCF-7 and 1.75 mu M-9.46 mu M in MDA-MB-231 cells, indicating almost equal activities on both cell lines and better growth inhibition activities than those of the positive control 5-fluorouracil (5-FU) which displayed IC50 values of 17.02 mu M and 11.73 mu M respectively. Selectivity of the significantly active compounds was estimated against MCF-10A normal breast cells when compounds 7c, 8b, 9a and 10b exhibited superior activity for cancerous cells than for normal cells when compound 10b presented the best selectivity Index (SI) with respect to both MCF-7 and MDA-MB-231 cancer cells in comparison to the reference drug 5-FU. Mechanisms of their actions were explored by inspecting activation of caspase-9, annexin V staining and cell cycle analysis. It was noticed that compounds 7c, 8b, 8c 9a-c and 10b produced an increase in caspase-9 levels in MCF-7 treated cells with 10b inducing the highest elevation (27.13 +/- 0.54 ng/mL) attaining 8.26-fold when compared to control MCF-7 which was higher than that of staurosporine (19.011 +/- 0.40 ng/mL). The same compounds boosted caspase-9 levels in MDA-MB-231 treated cells when an increase in caspase-9 concentration reaching 20.40 +/- 0.46 ng/mL (4.11-fold increase) was observed for compound 9a. We also investigated the role of these compounds for their increasing apoptosis ability against the 2 cell lines. Compounds 7c, 8b and 10b tested on MCF-7 cells displayed pre-G1 apoptosis and arrested cell cycle in particular at the S and G1 phases. Further clarification of their effects was made by modulating their related activities as inhibitors of ARO and EGFR enzymes when 8c and 9b showed 52.4% and 58.9% inhibition activity relative to letrozole respectively and 9b and 10b showed 36% and 39% inhibition activity of erlotinib. Also, the inhibition activity was verified by docking into the chosen enzymes.
引用
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页数:19
相关论文
共 69 条
[1]   New functionalized 6-thienylpyrimidine-5-carbonitriles as antiproliferative agents against human breast cancer cells [J].
AboulWafa, Omaima M. ;
Daabees, Hoda M. G. ;
Hammad, Ali ;
Badawi, Waleed A. .
ARCHIV DER PHARMAZIE, 2021, 354 (11)
[2]   2-Anilinopyrimidine derivatives: Design, synthesis, in vitro anti-proliferative activity, EGFR and ARO inhibitory activity, cell cycle analysis and molecular docking study [J].
AboulWafa, Omaima M. ;
Daabees, Hoda M. G. ;
Badawi, Waleed A. .
BIOORGANIC CHEMISTRY, 2020, 99
[3]   Advances and challenges in targeting FGFR signalling in cancer [J].
Babina, Irina S. ;
Turner, Nicholas C. .
NATURE REVIEWS CANCER, 2017, 17 (05) :318-332
[4]   Treating triple negative breast cancer cells with erlotinib plus a select antioxidant overcomes drug resistance by targeting cancer cell heterogeneity [J].
Bao, Bin ;
Mitrea, Cristina ;
Wijesinghe, Priyanga ;
Marchetti, Luca ;
Girsch, Emily ;
Farr, Rebecca L. ;
Boerner, Julie L. ;
Mohammad, Ramzi ;
Dyson, Greg ;
Terlecky, Stanley R. ;
Bollig-Fischer, Aliccia .
SCIENTIFIC REPORTS, 2017, 7
[5]   Phase II and tumor pharmacodynamic study of gefitinib in patients with advanced breast cancer [J].
Baselga, J ;
Albanell, J ;
Ruiz, A ;
Lluch, A ;
Gascón, P ;
Guillém, V ;
González, S ;
Sauleda, S ;
Marimón, I ;
Tabernero, JM ;
Koehler, MT ;
Rojo, F .
JOURNAL OF CLINICAL ONCOLOGY, 2005, 23 (23) :5323-5333
[6]   Triple-negative breast cancer: challenges and opportunities of a heterogeneous disease [J].
Bianchini, Giampaolo ;
Balko, Justin M. ;
Mayer, Ingrid A. ;
Sanders, Melinda E. ;
Gianni, Luca .
NATURE REVIEWS CLINICAL ONCOLOGY, 2016, 13 (11) :674-690
[7]   Update on Mammography Trends Comparisons of Rates in 2000, 2005, and 2008 [J].
Breen, Nancy ;
Gentleman, Jane F. ;
Schiller, Jeannine S. .
CANCER, 2011, 117 (10) :2209-2218
[8]   Abemaciclib: a CDK4/6 inhibitor for the treatment of HR+/HER2-advanced breast cancer [J].
Corona, Silvia Paola ;
Generali, Daniele .
DRUG DESIGN DEVELOPMENT AND THERAPY, 2018, 12 :321-330
[9]  
Davison C., NPJ BREAST CANCER
[10]   Interaction of letrozole and its degradation products with aromatase: chemometric assessment of kinetics and structure-based binding validation [J].
De Luca, Michele ;
Occhiuzzi, Maria Antonietta ;
Rizzuti, Bruno ;
Ioele, Giuseppina ;
Ragno, Gaetano ;
Garofalo, Antonio ;
Grande, Fedora .
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY, 2022, 37 (01) :1600-1609