A Novel Tri-Coordination Zinc Complex Functionalized Silicotungstate with ROS Catalytic Ability and Anti-Tumor Cells Activity

Round 1

Reviewer 1 Report

This manuscript reports on the synthesis, structural analysis and ROS-generating ability of a binuclear complex  [Zn₂(4,4’-bpy)(Phen)₂][SiW₁₂O₄₀] along with its special antitumor activity against anti-ROS-sensitive PC12 tumor cells. The experiments were desribed appropriatelly, however the interpretation of the results is not convincing.

My first concern is the lack of a plausible interpretation of the mechanism of electron-transfer involving the metal clusters of which synergizing effect was stated by the authors. 

The second one is associated with the orbital hybridisation-based the structural and electronic description of the cationic zinc complex and the vague reasoning of "valence-state deviation" from +2, as put by the authors. I think that this part should be clarified with exact and theoretically (DFT) supported statement about the mode of the actual electron-transfer. At least a DFT analysis of the cationic part should be carried out with special regard to the frontier MO's. Otherwise, one can expect that having an exceptionally stable +2 valence state, zinc can be hardly implicated in any redox process under bioligical conditions. 

 

 

Author Response

Reviewer: #1

Thank you for your positive comments. We have revised our manuscript according to the suggestions.

 

Comment (C) 1: My first concern is the lack of a plausible interpretation of the mechanism of electron-transfer involving the metal clusters of which synergizing effect was stated by the authors. The second one is associated with the orbital hybridisation-based the structural and electronic description of the cationic zinc complex and the vague reasoning of "valence-state deviation" from +2, as put by the authors. I think that this part should be clarified with exact and theoretically (DFT) supported statement about the mode of the actual electron-transfer. At least a DFT analysis of the cationic part should be carried out with special regard to the frontier MO's. Otherwise, one can expect that having an exceptionally stable +2 valence state, zinc can be hardly implicated in any redox process under bioligical conditions.

A2: Thanks for your good question and suggestion. Gaussian 09 package was used to perform the optimization and frequency computational calculations at the DFT B3LYP/Lanl2dz level [1]. The frontier molecular orbital is an invaluable method to analyzing the electric characteristics of coordination compound. The selected electron occupied (HOMO) and unoccupied (LUMO) MOs with energy values of [Zn₂(4,4’-bpy)(Phen)₂]⁴⁺ and the Keggin-type [SiW₁₂O₄₀]^4– cluster were shown in the following Figures A and B, respectively. For [Zn₂(4,4’-bpy)(Phen)₂]⁴⁺, the electron clouds of HOMO are distributed on the molecular skeleton of aromatic ring at both ends. Those of LUMO are homogeneous distributed on the well molecular skeleton. As for [SiW₁₂O₄₀]^4– cluster, the electron clouds in HOMO were mainly accumulated in the molecular center, however, in case of LUMO, the function groups on the molecular outed layer contribute to the electron cloud of LUMO. As also shown in Figure 6, the values of ΔE (ELUMO–EHOMO) of [Zn₂(4,4’-bpy)(Phen)₂]⁴⁺ (A) and [SiW₁₂O₄₀]^4– cluster (B) were 0.01164 and 0.20083 a.u., respectively.

In addition, the chemical potential (μ), the chemical harness (η), and the fraction number of electrons (ΔN) of electronic transmission between A and B were also analyzed by using DFT calculation based on literature [2, 3]. Eqs 1–3 were used to calculate above parameters:

(1)

(2)

(3)

where μ_A, μ_B and η_A, η_B are the chemical potentials and chemical harnesses of system [Zn₂(4,4’-bpy)(Phen)₂]⁴⁺ and [SiW₁₂O₄₀]^4– cluster, respectively. Calculated by Eqs 1-3, the μ and η for [Zn₂(4,4’-bpy)(Phen)₂]⁴⁺ were –0.09856 a.u. and 0.00582 a.u., respectively. As for [SiW₁₂O₄₀]^4–, the μ and η were –0.17613 a.u. and 0.10041 a.u., respectively. In addition, ΔN between [Zn₂(4,4’-bpy)(Phen)₂]⁴⁺ and [SiW₁₂O₄₀]^4– cluster were –0.12242. The negative values illustrated that [SiW₁₂O₄₀]^4– acted as electron acceptor and [Zn₂(4,4’-bpy)(Phen)₂]⁴⁺ acted as electron donor during the [Zn₂(4,4’-bpy)(Phen)₂]⁴⁺ and [SiW₁₂O₄₀]^4– cluster systems. Therefore, it is likely that, as well as avoiding disturbance of the catalytic centers, the POM fragment in concert with the Zn complexes may also facilitate synergistic production of ROS.

These calculations have been added to the text.

 

Figure R1. The selected surfaces of the molecular orbital plots (HOMO and LUMO) of [Zn₂(4,4’-bpy)(Phen)₂]⁴⁺ (A) and [SiW₁₂O₄₀]^4– cluster (B).

• Frisch,J.; Trucks, G.W.; Schlegel, H.B.; Scuseria, G.E.; Robb, M.A.; Cheeseman, J.R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G.A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H.P.; Izmaylov, A.F.; Bloino, J.; Zheng, G.; Sonnenberg, J.L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Normand, J.; Montgomery, Jr., A.; Peralta, J.E.; Ogliaro, F.; Bearpark, M.; Heyd, J.J.; Brothers, E.; Kudin, K.N.; Staroverov, V.N.; Keith, T.; Kobayashi, R.; Raghavachari, J.K.; Rendell, A.; Burant, J.C.; Iyengar, S.S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, J.M.; Klene, M.;  Knox, J.E.; Cross, J.B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R.E.; Yazyev, O.; Austin, A.J.; Cammi, R.; Pomelli, C.; Ochterski, J.W.; Martin, R.L.; Morokuma, K.;  Zakrzewski,V.G.; Voth, G.A.; Salvador, P.; Dannenberg, J.J.; Dapprich, S.;  Daniels, A.D.; Farkas, O.; Foresman, J.B.; Ortiz, J.V.; Cioslowski, J.; Fox, D.J.  Gaussian 09 Revision D.
• Padmanabhan,; Parthasarathi, R.; Subramanian, V.; Chattaraj, P.K. Group philicity and electrophilicity as possible descriptors for modeling ecotoxicity applied to chlorophenols. Chem. Res. Toxicol. 2006, 19 356–364.

         Wang, Y.Q.; Han, Q.Q.; Zhang, H.M.; Yan, Y.Y. Evaluation of the binding interactions of p-acetylaminophenol, aspirin, ibuprofen and aminopyrine with norfloxacin from the view of antipyretic and anti-inflammatory. J. Mol. Liq. 2020, 312, 113397.

Author Response File: Author Response.pdf

Reviewer 2 Report

I think the manuscript can be published in its form and I recommend it for publication.

 

Author Response

Reviewer: #2

Thank you for your careful reviews and positive comments.

Reviewer 3 Report

The manuscript of Jiai Hua et al. is devoted to the study of a new organo-inorganic catalyst based on zinc-phenanthroline cation silicotungstate. The work is of particular interest and after completion can be published.

1. *.Cif crystal structure file must be given in SI
2. Page 1 Line 37 “In such materials, the activity of zinc complexes is the most potent”.   Due to the lack of the possibility for Zn2+ ions to participate in redox reactions, this phrase is not entirely correct. Under certain conditions, in a certain environment, among structurally similar complexes, a zinc compound may outperform compounds of copper and other cations, but this statement cannot be replicated as a universal conclusion.
3. It is necessary to bring the experimenthal and calculated from CIF PXRD data of the powder to prove that the structure of one crystal coincides with the bulk of the substance
4. What role does oxalic acid play in the synthesis?
5. The Shape program can be used to analyze the Zn2+ coordination environment. This requirement is not mandatory, but a recommendation. See  http://www.ee.ub.edu/index.php?option=com_content&view=article&id=575:shape-available&catid=80:news&Itemid=466
6. Page 4 line 148 "in coordination chemistry, metal ions always have a tetra-, penta-, and hexa- coordination configuration"  This statement is completely incorrect, for example, the Fe3+ complex with EDTA has CN = 7, lanthanide compounds show CN on average from 7 to 10, and Ag+, Au+, Cu+ compounds prefer CN = 2, 3. If we are talking about zinc compounds, then this should be clarified.
7. P5 Line 177 and further ( Page 8 Table 2) - the values of the valence sums must be given with an error
8. The bands in the IR spectra (Page 7 Fig 4) are superimposed on each other, which makes the figure unsatisfactory. The numbers "881" can only be seen with good eyesight
9. For a journal dedicated to catalysis, catalytic properties are not well researched. Is it even possible to study the reaction kinetics in the presence of a catalyst?

Author Response

Reviewer: #3

Thank you for your careful reviews and positive comments. We have revised our manuscript detailedly according to the suggestions and discussed the details.

 

Comment (C) 1: *.Cif crystal structure file must be given in SI.

Answer (A) 1: Thank you for your suggestion. The crystal structure file has been uploaded to ESI as ZSW.Cif.

 

C2: Page 1 Line 37 “In such materials, the activity of zinc complexes is the most potent”.   Due to the lack of the possibility for Zn2+ ions to participate in redox reactions, this phrase is not entirely correct. Under certain conditions, in a certain environment, among structurally similar complexes, a zinc compound may outperform compounds of copper and other cations, but this statement cannot be replicated as a universal conclusion.

A2: Thanks for your correction and suggestion. The paragraph was revised as “In such researches, the study of copper complex occupies a dominant position, however the research on another essential bio-metal ions, such as zinc ions, is relatively lagged.”

 

C3: It is necessary to bring the experimenthal and calculated from CIF PXRD data of the powder to prove that the structure of one crystal coincides with the bulk of the substance.

A3: Thanks for your good suggestion. The PXRD patterns of ZSW have been added to the text as Figure 4B.

 

C4: What role does oxalic acid play in the synthesis?

A4: Thank you for your good question. The oxalic acid plays an important role in the synthesis process. The addition of oxalic acid affects the yield and crystal quality of ZSW. Without the addition of oxalic acid, the crystals generated by the reaction are mostly powder crystals, which which cannot be used for X-ray single crystal diffraction test. After adding oxalic acid, the crystal quality is improved, but the reaction yield is decreased.

 

C5: The Shape program can be used to analyze the Zn2+ coordination environment. This requirement is not mandatory, but a recommendation. See  http://www.ee.ub.edu/index.php?option=com_content&view=article&id=575:shape-available&catid=80:news&Itemid=466

A5: Thanks a lot for your suggestion. We have registered and downloaded the software. At present, We are learning to skillfully use it and hope to apply it to our data analysis in the future.

 

C6: Page 4 line 148 "in coordination chemistry, metal ions always have a tetra-, penta-, and hexa- coordination configuration"  This statement is completely incorrect, for example, the Fe3+ complex with EDTA has CN = 7, lanthanide compounds show CN on average from 7 to 10, and Ag+, Au+, Cu+ compounds prefer CN = 2, 3. If we are talking about zinc compounds, then this should be clarified.

A6: Thank you for your correction. We have revised and clarified the coordination complexes described in this sentence to zinc compounds.

 

C7: 7.P5 Line 177 and further ( Page 8 Table 2) - the values of the valence sums must be given with an error.

A7: Thank you for your suggestion. The Table 2 has been revised.

 

C8: The bands in the IR spectra (Page 7 Fig 4) are superimposed on each other, which makes the figure unsatisfactory. The numbers "881" can only be seen with good eyesight.

A8: Thanks a lot. The Fig. 4 have been revised.

 

C9: For a journal dedicated to catalysis, catalytic properties are not well researched. Is it even possible to study the reaction kinetics in the presence of a catalyst?

A9: Thank you for your question. Because of the nature of free radicals, they can exist for a very short time, which they usually last 10^–9 to 10^–4 seconds. Therefore, it is difficult to capture their instantaneous production. Analysis can only be performed using accumulations over a period of time. Current fluorescent probes also need to react with ROS to show the amount of ROS that they contact and react with. Therefore, a considerable part of ROS does not really contact with the probe and react, and then disappeared instantaneously. Slight differences in experimental methods and conditions may cause large experimental errors. Nowadays, few studies have been done on these issues, and these methods are not widely supported. This paper aims to introduce a novel polyoxometalate structure and its anti-tumor cells activity, and to explain the anti-tumor cells activity of ZSW by qualitative description of its ROS catalytic ability. Considering the study on the kinetics of ROS catalysts is a considerable amount of work, it can constitute an independent paper. Hence, in order to avoid the confusion of priority and logic of the paper, we decided not to investigate the ROS catalytic mechanism of ZSW in more detail in this paper.

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

Since the authors appropriatelly revised this manuscript, this version warrants publication in Catalysts.

Reviewer 3 Report

The authors have made the necessary corrections and the manuscript can be published.