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Table 1. Comparative study toward the synthesis of sugar hydrazones 2-5. Sugar hydrazones can exist in an equilibrium between the acyclic Schi ff’s bases and the cyclic N-glycosyl hydrazine derivatives, which can adapt either a pyranose or furanose ring with different anomeric configurations (a or 6). The nature of the acyclic-cyclic equilibrium mixture that exists in solution is highly influenced by the effect of the so vent, of the sugar, and the basicity of the reacted hydrazine [65-68]. Structure eluc the synthesized products (2-5) was deduced from their spectral analyses: 'H-, 'H-'H DOF COSY and 'H-'8C HMQC experiments. These products s characterization of 2 in a solution of DMSO-d¢ showed its existence in an eq mixture of acyclic hydrazones 2A and the cyclic pyranosyl hydrazine analog 2B in a 3: ratio (Scheme 2). This investigation was based on the presence of a doublet signal resonated at 54; 7.49 ppm with 0.75 proton intensity corresponding to the azomethine proton (CH=N); howed different behavior in solution of DMSO-d¢ depending on the nature of the sugar. Thus, the spectra he nature idation of 13C_NMR, uilibrium this signal was correlated with its carbon resonated at 5c 148.6 ppm. On the other hand, the
Table 1. Comparative study toward the synthesis of sugar hydrazones 2-5. Sugar hydrazones can exist in an equilibrium between the acyclic Schi ff’s bases and the cyclic N-glycosyl hydrazine derivatives, which can adapt either a pyranose or furanose ring with different anomeric configurations (a or 6). The nature of the acyclic-cyclic equilibrium mixture that exists in solution is highly influenced by the effect of the so vent, of the sugar, and the basicity of the reacted hydrazine [65-68]. Structure eluc the synthesized products (2-5) was deduced from their spectral analyses: 'H-, 'H-'H DOF COSY and 'H-'8C HMQC experiments. These products s characterization of 2 in a solution of DMSO-d¢ showed its existence in an eq mixture of acyclic hydrazones 2A and the cyclic pyranosyl hydrazine analog 2B in a 3: ratio (Scheme 2). This investigation was based on the presence of a doublet signal resonated at 54; 7.49 ppm with 0.75 proton intensity corresponding to the azomethine proton (CH=N); howed different behavior in solution of DMSO-d¢ depending on the nature of the sugar. Thus, the spectra he nature idation of 13C_NMR, uilibrium this signal was correlated with its carbon resonated at 5c 148.6 ppm. On the other hand, the
Scheme 1. Reaction of the hydrazine derivative 1 with sugar aldoses. Condensation of aldoses with amino compounds can be attempted under mild con- ditions with deprotected hydroxyl groups or through activation of the anomeric carbon. Thus, condensation of 2-hydrazinyl-6-methylpyrimidin-4-one 1 with different aldoses [64] (D-xylose, D-glucose, D-mannose, and D-galactose) in ethanol under reflux for 7-10 h afforded the corresponding hydrazones 2-5, respectively. However, when the reaction was established using ultrasound irradiation, better yields within a shorter time were observed (Scheme 1). The ultrasound irradiation at 75 °C reduces the reaction time to 45-120 min compared to the conventional methods (Table 1).
Scheme 1. Reaction of the hydrazine derivative 1 with sugar aldoses. Condensation of aldoses with amino compounds can be attempted under mild con- ditions with deprotected hydroxyl groups or through activation of the anomeric carbon. Thus, condensation of 2-hydrazinyl-6-methylpyrimidin-4-one 1 with different aldoses [64] (D-xylose, D-glucose, D-mannose, and D-galactose) in ethanol under reflux for 7-10 h afforded the corresponding hydrazones 2-5, respectively. However, when the reaction was established using ultrasound irradiation, better yields within a shorter time were observed (Scheme 1). The ultrasound irradiation at 75 °C reduces the reaction time to 45-120 min compared to the conventional methods (Table 1).
Scheme 2. Equilibration of the acyclic and cyclic nature of sugar hydrazones 2-5. cyclic B-D-xylopyranosyl hydrazinyl derivative 2B was deduced from the doublet signal corresponding to the anomeric H-1' which resonated at 5y 3.76 ppm (J,2" = 8.8 Hz) (after addition of D2O to overcome the overlap of the signals of NH and OH). This large Jy) 9 value confirmed the antiparallel relationship between H-1' and H-2’. The later signal was correlated to C-1' signal assigned at 5¢ 92.2 ppm in 'C-NMR spectrum. Moreover, the pyranose structure was deduced from the signal corresponding to C-4’ observed at 5c 70.0 ppm and agreed with that reported in the literature [69,70]. Moreover, other carbons and protons were fully assigned (Experimental Section).
Scheme 2. Equilibration of the acyclic and cyclic nature of sugar hydrazones 2-5. cyclic B-D-xylopyranosyl hydrazinyl derivative 2B was deduced from the doublet signal corresponding to the anomeric H-1' which resonated at 5y 3.76 ppm (J,2" = 8.8 Hz) (after addition of D2O to overcome the overlap of the signals of NH and OH). This large Jy) 9 value confirmed the antiparallel relationship between H-1' and H-2’. The later signal was correlated to C-1' signal assigned at 5¢ 92.2 ppm in 'C-NMR spectrum. Moreover, the pyranose structure was deduced from the signal corresponding to C-4’ observed at 5c 70.0 ppm and agreed with that reported in the literature [69,70]. Moreover, other carbons and protons were fully assigned (Experimental Section).
Scheme 3. Annulation of sugar hydrazones 2 and 5 to 1,2,4-triazolo[4,3-a]pyrimidinone acyclo C-nucleosides 6 and 7.
Scheme 3. Annulation of sugar hydrazones 2 and 5 to 1,2,4-triazolo[4,3-a]pyrimidinone acyclo C-nucleosides 6 and 7.
Scheme 4. Annulation of sugar hydrazones 3 and 4 to 1,2,4-triazolo[4,3-a]pyrimidinone acyclc C-nucleosides 8-9. showed another extra signal corresponding to the 7-methy]-5-oxo-1,2,4 triazolopyrimidine regioisomer 9B. Signals corresponding to H-6 and H-3 of isomer 9B were observed at 54 5.31 and 6.49 ppm, respectively, and their carbons were assigned at 5c 98.0 and 72.1 ppm, respectively. In addition, new signals for the alditolyl chain of 9B were recorded. Therefore, possible Dimroth rearrangement has taken place under the effect of light, affording the thermodynamically 7-methyl-5-oxo-1,2,4 triazolopyrimidine isomer 9B.
Scheme 4. Annulation of sugar hydrazones 3 and 4 to 1,2,4-triazolo[4,3-a]pyrimidinone acyclc C-nucleosides 8-9. showed another extra signal corresponding to the 7-methy]-5-oxo-1,2,4 triazolopyrimidine regioisomer 9B. Signals corresponding to H-6 and H-3 of isomer 9B were observed at 54 5.31 and 6.49 ppm, respectively, and their carbons were assigned at 5c 98.0 and 72.1 ppm, respectively. In addition, new signals for the alditolyl chain of 9B were recorded. Therefore, possible Dimroth rearrangement has taken place under the effect of light, affording the thermodynamically 7-methyl-5-oxo-1,2,4 triazolopyrimidine isomer 9B.
Similarly, the D-manno acyclo C-nucleoside 9A existed in the more stable extended zigzag conformational structure VIII which resulted from the rotation around the C-4’-C- 5’ bond to verify the intermediate magnitude of Js, = 4.4 Hz. The coupling constants (experimental) of the other protons verify their dispositions.
Similarly, the D-manno acyclo C-nucleoside 9A existed in the more stable extended zigzag conformational structure VIII which resulted from the rotation around the C-4’-C- 5’ bond to verify the intermediate magnitude of Js, = 4.4 Hz. The coupling constants (experimental) of the other protons verify their dispositions.
Table 2. Cytotoxicity and anticancer selectivity profiles of the pyrimidine sugar hydrazones 2-5 and 1,2,4-triazolo[4,3-a]pyrimidinone acyclo C-nucleosides 6-9.
Table 2. Cytotoxicity and anticancer selectivity profiles of the pyrimidine sugar hydrazones 2-5 and 1,2,4-triazolo[4,3-a]pyrimidinone acyclo C-nucleosides 6-9.
Figure 3. Morphological alteration of 8- and 9-treated Wi-38 cells (at 30 nM), MDA-MB231, Caco-2 and HepG-2 (at 1 nM) compared to Dox-treated and control cells. All values are expressed as mean + SEM. ® SI: selectivity index equals the ratio between the compounds ICs9 on normal cells and its ICs59 on cancer cells.
Figure 3. Morphological alteration of 8- and 9-treated Wi-38 cells (at 30 nM), MDA-MB231, Caco-2 and HepG-2 (at 1 nM) compared to Dox-treated and control cells. All values are expressed as mean + SEM. ® SI: selectivity index equals the ratio between the compounds ICs9 on normal cells and its ICs59 on cancer cells.
* pICso: -logICso, > LE: ligand efficiency [89], © LLE: lipophilic ligand efficiency [90], 4 LELP: ligand efficiency- dependent lipophilicity index [88]. Table 3. In vitro VEGFR-2 inhibitory activities of 8 and 9 and their ligand efficiency metrics.
* pICso: -logICso, > LE: ligand efficiency [89], © LLE: lipophilic ligand efficiency [90], 4 LELP: ligand efficiency- dependent lipophilicity index [88]. Table 3. In vitro VEGFR-2 inhibitory activities of 8 and 9 and their ligand efficiency metrics.
Table 4. In vitro MMP-2 inhibitory activities of 8 and 9 and their ligand efficiency metrics. 2.2.4. CA II Inhibitory Activity
Table 4. In vitro MMP-2 inhibitory activities of 8 and 9 and their ligand efficiency metrics. 2.2.4. CA II Inhibitory Activity
Table 5. In vitro CAII inhibitory activities of 8 and 9 and their ligand efficiency metrics. 3. Structure-Activity Relationship (SAR) and Molecular Modeling Studies 3.1. SAR
Table 5. In vitro CAII inhibitory activities of 8 and 9 and their ligand efficiency metrics. 3. Structure-Activity Relationship (SAR) and Molecular Modeling Studies 3.1. SAR
all On the other hand, 9A and its minor regioisomer 9B missed most of the previously mentioned interactions. Only one hydrogen bond was displayed by the acetylated sugar part of 9A with the receptor’s Cys1024, whereas two hydrogen bonds were predicted involving the acetylated sugar part anomeric CH and the key amino acid Asp1046 as well as Leu1049 and N!-acetyl group in the case of 9B. These observations postulated that both 8 and 9 may be type-II inhibitors. In addition, the docking simulations results are generally consistent with the in vitro enzymatic activities where 8 was 2 folds more active than 9.
all On the other hand, 9A and its minor regioisomer 9B missed most of the previously mentioned interactions. Only one hydrogen bond was displayed by the acetylated sugar part of 9A with the receptor’s Cys1024, whereas two hydrogen bonds were predicted involving the acetylated sugar part anomeric CH and the key amino acid Asp1046 as well as Leu1049 and N!-acetyl group in the case of 9B. These observations postulated that both 8 and 9 may be type-II inhibitors. In addition, the docking simulations results are generally consistent with the in vitro enzymatic activities where 8 was 2 folds more active than 9.
Figure 4. (A) The 3D binding mode of 8A (yellow sticks), (B) 2D binding mode of 8A, (C) 3D binding mode of 8B (green sticks), (D) 2D binding mode of 8B, (E) 3D binding mode of 9A (pink sticks), (F) 2D binding mode of 9A, (G) 3D binding mode of 9B (cyan sticks), (H) 2D binding mode of 9B, (I) 3D binding mode of sorafenib (magenta sticks), and (J) 2D binding mode of sorafenib in the active site of VEGFR-2 (PDB ID: 4ASD [95]).
Figure 4. (A) The 3D binding mode of 8A (yellow sticks), (B) 2D binding mode of 8A, (C) 3D binding mode of 8B (green sticks), (D) 2D binding mode of 8B, (E) 3D binding mode of 9A (pink sticks), (F) 2D binding mode of 9A, (G) 3D binding mode of 9B (cyan sticks), (H) 2D binding mode of 9B, (I) 3D binding mode of sorafenib (magenta sticks), and (J) 2D binding mode of sorafenib in the active site of VEGFR-2 (PDB ID: 4ASD [95]).
Figure 5. (A) The 3D binding mode of 8A (yellow sticks), (B) 2D binding mode of 8A, (C) 3D binding mode of 8B (green sticks), (D) 2D binding mode of 8B, (E) 3D binding mode of 9A (pink sticks), (F) 2D binding mode of 9A, (G) 3D binding mode of 9B (cyan sticks), (H) 2D binding mode of 9B, (I) 3D binding mode of the co-crystallized the hydroxamic acid inhibitor SC-74020 (magenta sticks), and (J) 2D binding mode of SC-74020 in the active site of MMP-2 (PDB ID: 1HOV [101]).
Figure 5. (A) The 3D binding mode of 8A (yellow sticks), (B) 2D binding mode of 8A, (C) 3D binding mode of 8B (green sticks), (D) 2D binding mode of 8B, (E) 3D binding mode of 9A (pink sticks), (F) 2D binding mode of 9A, (G) 3D binding mode of 9B (cyan sticks), (H) 2D binding mode of 9B, (I) 3D binding mode of the co-crystallized the hydroxamic acid inhibitor SC-74020 (magenta sticks), and (J) 2D binding mode of SC-74020 in the active site of MMP-2 (PDB ID: 1HOV [101]).
Figure 6. (A) The 3D binding mode of 8A (yellow sticks), (B) 2D binding mode of 8A, (C) 3D binding mode of 8B (green sticks), (D) 2D binding mode of 8B, (E) 3D binding mode of 9A (pink sticks), (F) 2D binding mode of 9A, (G) 3D binding mode of 9B (cyan sticks), (H) 2D binding mode of 9B, (I) 3D binding mode of the co-crystallized CA II inhibitor AL5 (magenta sticks), and (J) 2D binding mode of ALS in the active site of CA II (PDB ID:1BN1 [102]).
Figure 6. (A) The 3D binding mode of 8A (yellow sticks), (B) 2D binding mode of 8A, (C) 3D binding mode of 8B (green sticks), (D) 2D binding mode of 8B, (E) 3D binding mode of 9A (pink sticks), (F) 2D binding mode of 9A, (G) 3D binding mode of 9B (cyan sticks), (H) 2D binding mode of 9B, (I) 3D binding mode of the co-crystallized CA II inhibitor AL5 (magenta sticks), and (J) 2D binding mode of ALS in the active site of CA II (PDB ID:1BN1 [102]).
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