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Int J Mol Sci
2020 Apr 26;219:. doi: 10.3390/ijms21093049.
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Effects of Ferrocenyl 4-(Imino)-1,4-Dihydro-quinolines on Xenopus laevis Prophase I - Arrested Oocytes: Survival and Hormonal-Induced M-Phase Entry.
Marchand G, Wambang N, Pellegrini S, Molinaro C, Martoriati A, Bousquet T, Markey A, Lescuyer-Rousseau A, Bodart JF, Cailliau K, Pelinski L, Marin M.
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Xenopus oocytes were used as cellular and molecular sentinels to assess the effects of a new class of organometallic compounds called ferrocenyl dihydroquinolines that have been developed as potential anti-cancer agents. One ferrocenyl dihydroquinoline compound exerted deleterious effects on oocyte survival after 48 h of incubation at 100 μM. Two ferrocenyl dihydroquinoline compounds had an inhibitory effect on the resumption of progesterone induced oocyte meiosis, compared to controls without ferrocenyl groups. In these inhibited oocytes, no MPF (Cdk1/cyclin B) activity was detected by western blot analysis as shown by the lack of phosphorylation of histone H3. The dephosphorylation of the inhibitory Y15 residue of Cdk1 occurred but cyclin B was degraded. Moreover, two apoptotic death markers, the active caspase 3 and the phosphorylated histone H2, were detected. Only 7-chloro-1-ferrocenylmethyl-4-(phenylylimino)-1,4-dihydroquinoline (8) did not show any toxicity and allowed the assembly of a histologically normal metaphase II meiotic spindle while inhibiting the proliferation of cancer cell lines with a low IC50, suggesting that this compound appears suitable as an antimitotic agent.
Figure 1. Structure and synthesis of 4-(imino)-1,4-dihydroquinoline derivatives. A. Structures of ferrocifen, hydroxyferrocifen and ferroquine; B. Synthesis of ferrocenyl 4-(imino)-1,4-dihydroquinolines 6-8. C. Synthesis of benzyl 4-(imino)-1,4-dihydroquinolines 9 and 10: (a) benzyl chloride, NaI, acetone, reflux, 12 h; (b) RNH2, EtOH, relux, 1 h. Synthesis of benzyl 4-(imino)-1,4-dihydroquinolines 11: (c) aniline, microwaves, 100 °C, 10 min; (d) benzyl chloride, microwaves, 80 °C, 40 min.
Figure 2. Effect of ferrocenyl 4-(amino)-1,4-dihydroquinolines exposures on oocytes survival. Oocytes were exposed up to 48 h to 100 µM of each compound (9 in dark blue, 6 in light blue, 10 in red, 7 in pink, 11 in dark green and 8 in light green). After 24 h and 48 h of exposure, oocytes survival was assessed by phenotypical approach. As depicted, healthy oocytes (named as prophase I) presented a brown homogenous pigmentation compared to unhealthy one. All the results were compiled and compared to control (ND96, in grey) conditions. Statistical significance was assessed by a two-way ANOVA followed by Dunnett’s test, *** P < 0.001. N refers to the number of females and n to the number of oocytes (N = 3 and n = 60).
Figure 3. Western blot analysis of oocytes treated by 4-(imino)-1,4-dihydroquinolines. Oocytes untreated (C) or treated with progesterone (PG) were submitted to 4-(imino)-1,4-dihydroquinolines 6, 7, 8, 9, 10, 11 for 24 h. After electrophoresis, antibodies were used to reveal total and phosphorylated forms of Erk2 and P-Erk2 on Y202/Y204, Rsk and P-Rsk on S380, Cdk1 and P-Cdk1 on Y15, and phosphorylated form of P-H3 on S10, P-H2B on S14, or cleaved caspase 3, cyclin B2, Mos and actin. The membranes were revealed using an Advanced ECL chemiluminescence technology. Staurosporine 20 mM was used as apoptosis control. Erk2, Rsk, Cdk1 and actin serve as internal loading controls.
Figure 5. Observed abnormalities in white spot oocytes after ferrocenyl 4-(alkyl-amino)-1,4-dihydroquinolines exposures. Oocytes were exposed to compound 8 and 11 (100 µM) during meiosis resumption. Typical pictures of the observed structures are shown (black arrows) and summarized in the table. N refers to the number of females and n to the number of oocytes.
Figure 6. Determination of metaphase II entry in oocytes pre-exposed to ferrocenyl 4-(alkylamino)-1,4-dihydroquinolines. After incubation or not with compounds 9, 6, 10, 7, 11, 8 for 24 h, oocytes were rinsed four times in ND96 for 30 min, before progesterone stimulation. White spot appearance was scored after 15 h. N refers to the number of females and n to the number of oocytes (N = 2 and n = 60).
Figure 7. Partenogennetic activation of metaphase II oocytes treated by ferrocenyl 4-(alkylamino)-1,4-dihydroquinolines. Oocytes were incubated or not with compounds 8 or 11 before they were transfered to a 5×-diluted ND96 solution added with A23187 calcium ionophore (50 μM). The numbers of cortical retraction were scored. N refers to the number of females and n to the number of oocytes (N = 2 and n = 40).
Figure 8. Effect of ferrocenyl 4-(imino)-1,4-dihydroquinolines on oocytes arrested in prophase I (PI) and oocytes induced to progress in metaphase II (MII). Progesterone activates PKA, Mos synthesis and the MAPKK/MAPK/Rsk cascade. The two pathways further activate phosphatase Cdc25, inhibit kinase Myt1 and converge to activate the Cdk1/cyclin B complex. Rsk, Mos and the activated Cdk1/cyclin B complex inhibit Myt1. The activated Cdk1/cyclin B complex also activates Cdc25 and phosphorylates histone H3. The germinal vesicle (GV) of prophase I oocytes is disrupted (GVBD) upon progesterone addition and the oocytes progress into metaphase I and metaphase II. The nuclear spindle (microtubules-green and chromosomes-red) is formed in metaphase I, is attached to the plasma membrane in metaphase II and accompanied by the emission of a polar body. Ferrocenyl 4-(imino)-1,4-dihydroquinolines 6, 7 (in yellow/orange) induce Cdk1 dephosphorylation, cyclin B degradation, caspase 3 cleavage and histone H2B phosphorylation leading to oocytes apoptosis after meiosis resumption has been triggered by progesterone addition (grey rectangle). Compound 7 produces the same effect on prophase I arrested oocytes. Compound 8 (in yellow/orange) did not affect oocyte progression into metaphase II.
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