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. 2022 Jan 24;27(3):756.
doi: 10.3390/molecules27030756.

Investigation of the Anticancer Effect of α-Aminophosphonates and Arylidine Derivatives of 3-Acetyl-1-aminoquinolin-2(1H)-one on the DMBA Model of Breast Cancer in Albino Rats with In Silico Prediction of Their Thymidylate Synthase Inhibitory Effect

Mohamed A Nassan  1 , Adil Aldhahrani  1 , Hamada H Amer  2 , Ahmed Elhenawy  3 , Ayman A Swelum  4   5 , Omar M Ali  2 , Yasser H Zaki  6   7
Affiliations

Investigation of the Anticancer Effect of α-Aminophosphonates and Arylidine Derivatives of 3-Acetyl-1-aminoquinolin-2(1H)-one on the DMBA Model of Breast Cancer in Albino Rats with In Silico Prediction of Their Thymidylate Synthase Inhibitory Effect

Mohamed A Nassan et al. Molecules. .

Abstract

Breast cancer is a major cause of death in women worldwide. In this study, 60 female rats were classified into 6 groups; negative control, α-aminophosphonates, arylidine derivatives of 3-acetyl-1-aminoquinolin-2(1H)-one, DMBA, DMBA & α-aminophosphonates, and DMBA & arylidine derivatives of 3-acetyl-1-aminoquinolin-2(1H)-one. New α-aminophosphonates and arylidine derivatives of 3-acetyl-1-aminoquinolin-2(1H)-one were synthesized and elucidated by different spectroscopic and elemental analysis. Histopathological examination showed marked proliferation of cancer cells in the DMBA group. Treatment with α-aminophosphonates mainly decreased tumor mass. Bcl2 expression increased in DMBA-administered rats and then declined in the treated groups, mostly with α-aminophosphonates. The level of CA15-3 markedly declined in DMBA groups treated with α-aminophosphonates and arylidine derivatives of 3-acetyl-1-aminoquinolin-2(1H)-one. Gene expression of GST-P, PCNA, PDK, and PIK3CA decreased in the DMBA group treated with α-aminophosphonates and arylidine derivatives of 3-acetyl-1-aminoquinolin-2(1H)-one, whereas PIK3R1 and BAX increased in the DMBA group treated with α-aminophosphonates and arylidine derivatives of 3-acetyl-1-aminoquinolin-2(1H)-one. The molecular docking postulated that the investigated compounds can inhibt the Thymidylate synthase TM due to high hydrophobicity charachter.

Keywords: 3-acetyl-1-aminoquinolin-2(1H)-one; DMBA; breast cancer; thymidylate synthase; α-aminophosphonates.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Scheme 1
Scheme 1
Reagent condition: (i) NaOH, EtOH, reflux, for 3: 90%. (ii) HCOOH, NH2NH2.H2O, reflux for 4: 80%. (iii) RNH2 (5a, b), (PhO)3P (6), H3PO4, CH3CN, reflux for 7a: 90%; for 7b: 92%.
Scheme 2
Scheme 2
Reagent conditions: (i) Pip., EtOH, reflux, for 10: 80%. (ii) EtOH, NH2NH2. H2O, reflux, for 11:80%. (iii) 4-Chlorobenzaldehyde (12), EtOH, AcOH, reflux, for 13: 93%. (iv) RCHO (14a, b), Pip., EtOH, reflux, for 15a: 95%; for 15b: 97%.
Figure 1
Figure 1
Effect of 7b and 15b compounds on changes in gene expression induced by DMBA in breast. Values are means ± SE of 10 rats. * p < 0.05 vs. control group; # p < 0.05 vs. DMBA group. (A) Upper panels are mRNA expression of examined gene. (B) Lower columns are densitometric analysis of gene expression.
Figure 2
Figure 2
Effect of 7b and 15b compounds on changes in gene expression induced by DMBA in breast. Values are means ± SE of 10 rats. * p < 0.05 vs. control group; # p < 0.05 vs. DMBA group. (A) Upper panels are mRNA expression of examined gene. (B) Lower columns are densitometric analysis of gene expression.
Figure 3
Figure 3
Effect of 7b and 15b compounds on changes in gene expression induced by DMBA in breast. Values are means ± SE of 10 rats. * p < 0.05 vs. control group; # p < 0.05 vs. DMBA group. (A) Upper panels are mRNA expression of examined gene. (B) Lower columns are densitometric analysis of gene expression.
Figure 4
Figure 4
Results of histopathological assessment. (A) Negative control group shows the normal structure of the acini (arrow) with adipose tissue inbetween (*). (B) 7b group showing normal acini (arrow) and adipocytes (*). (C) The 15b group showed normal lobules (arrow) and adipose tissue (*). (D) Breast tissue from the DMBA group showed extensive proliferation of cancer cells (arrows). (E) Adult female rats administered DMBA and treated with 7b showed marked regression of tumor mass (arrow). (F) breast tissue of DMBA-treated rats with 15b revealed moderate regression of tumor mass (arrow). H & E. Scale bar = 50 μm.
Figure 5
Figure 5
Results of Immunohistochemical Assessment of Bcl2. (A) Breast tissue of negative control group showed over-expression of Bcl2. The (B) 7b group showed increased acinar Bcl2 expression. (C) 15b group showed marked Bcl2 expression in the lobular tissue. (D) Breast tissue of DMBA-dosed rats revealed over-expression of Bcl2 in the tumor mass. (E) Breast tissue of DMBA dosed rats treated with 7b revealed faint Bcl2 expression. (F) Moderate Bcl2 expression was detected in the DMBA group treated with 15b. Scale bar = 50 μm.
Figure 6
Figure 6
Molecular docking of the active compounds (A) for 7a, (B) for 7b, (C) for 15a, and (D) for 15b against Thimidylate synthase protein (6w63).
Figure 7
Figure 7
(A) PLIF histogram plotted, (B) statistical key interaction, (C) interaction key for (7a, 7b, 15a, and 15b) with active site.
See this image and copyright information in PMC

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