Proceedings of Chemistry, Pharmacology, Pharmacokinetics and Synthesis of Biflavonoids
Round 1
Reviewer 1 Report
Manuscript entitled"Proceedings of chemistry, pharmacology, pharmacokinetics and synthesis of bioflavonoids" by authors Xinqian He et al is comprehensive review about the bioflavonoids and it's pharmacology including synthesis of the naturally occurring bioflavonoids.
Comments:
- Authors should include some of the medicinal use of the flavonoids in the introduction part (introduction part needs more information)
- Authors may split the results in to different tables. table 1 is very long, authors may consider separating them as per different classification
- Page# 27, line# 242: please clarify, "blavanoids"
- Authors may consider to present in vitro ADME data of flavonoids. There are reports available about flavonoids as pgp inhibitors and CYP3A4 (quercetin)
- References: Total of 331 references are listed but only 328 references are cited. Authors may cross verify their list of references.
Overall, this manuscript is comprehensive and has lot of information.
Author Response
Dear reviewer:
On behalf of my coauthors, we thank you very much for giving us an opportunity to revise our manuscript, we appreciate editor and reviewers very much for their positive and constructive comments and suggestions on our manuscript entitled “Proceedings of chemistry, pharmacology, pharmacokinetics and synthesis of biflavonoids”
We have studied reviewer’s comments carefully and have made revision, which marked in red in the paper. We have tried our best to revise our manuscript according to the comments. Attached, please find the revised version, which we would like to submit for your kind consideration.
Point 1: Authors should include some of the medicinal use of the flavonoids in the introduction part (introduction part needs more information)
Response 1: This article actually reviews biflavonoids. The title of this paper is wrong, we revised the correct title at first. At the request of the reviewer, I added the medicinal part of amentoflavone to make the introduction of biflavonoids more detailed.
Point 2: Authors may split the results in to different tables. table 1 is very long, authors may consider separating them as per different classification
Response 2: After modification, table 1 will be partially classified. Because table I belong to the classification of C-C type biflavonoids, the modification mainly divides Table 1 into Table 1-1 ~ 1-8, and classifies the pictures according to the modified table 1.
Point 3: Page# 27, line# 242: please clarify, "blavanoids"
Response 3: The word is wrong and has been modified to biflavonoids
Point 4: Authors may consider to present in vitro ADME data of flavonoids. There are reports available about flavonoids as pgp inhibitors and CYP3A4 (quercetin)
Response 4: This article actually reviews biflavonoids. And the ADME data of biflavonoids had not found the relevant literature, therefore, I did not add this part data on this review. But I add a table about pharmacokinetics.
Point 5: References: Total of 331 references are listed but only 328 references are cited. Authors may cross verify their list of references.
Response 5: The problem of references is that the order of references in the text is wrong and has been modified.
We would like to express our great appreciation to you and reviewers for comments on our paper. Looking forward to hearing from you.
Thank you and best regards.
Yours sincerely,
Xinqian He
Reviewer 2 Report
The review includes a description of the structural formulas of 586 flavonoids isolated at different times from various plants. However, this review does not describe the properties and mechanisms of the flavonoids.
- Extremely insignificant information on sections devoted to the use and pharmacokinetics.
- Flavonoids of gnafalium have been studied and described (for example, https://doi.org/10.1016/j.phytol.2009.11.002, etc.). Please include these flavonoids in your review.
- To visualize the data, provide the data in the form of tables indicating the flavonoid, plant, dose / concentration, effect, reference drugs, literary references confirming the activity of various classes of flavonoids in accordance with your tables 1-3. Please discuss, for each section of pharmacological properties, the effect of the structure of flavonoids on their activity.
- It is known that flavonoids have low bioavailability and bind to plasma proteins. This makes pharmacokinetic analysis and their application in medicine difficult. Please discuss this aspect. The flavonoid taxifolin (syn. with dihydroquercetin), found in various plants, has been extensively studied, including its pharmacokinetics (for example, https://doi.org/10.1016/j.phymed.2008.10.002, etc.). Provide the data in the form of a table with the main pharmacokinetic characteristics, including, doses, test systems, route of administration, method of analysis, literature reference.
- Flavonoids are associated with low toxicity (e.g. https://doi.org/10.1016/j.freeradbiomed.2004.04.034 and others). Discuss the toxicity data for flavonoids and their potential use in humans.
- Chemical synthesis of flavonoids is an important and interesting aspect, but it requires separate consideration. In this aspect, it is necessary to provide data confirming the activity of the synthesized molecules analogous to natural ones. In this review, it would be more relevant to consider biosynthesis in plants.
- The Conclusion section is devoted to traditional Chinese medicine. Please write it according to the text of the manuscript.
- There are many errors in the text of the manuscript.
Author Response
Dear reviewer:
On behalf of my coauthors, we thank you very much for giving us an opportunity to revise our manuscript, we appreciate editor and reviewers very much for their positive and constructive comments and suggestions on our manuscript entitled “Proceedings of chemistry, pharmacology, pharmacokinetics and synthesis of biflavonoids”
We have studied reviewer’s comments carefully and have made revision, which marked in red in the paper. We have tried our best to revise our manuscript according to the comments. Attached, please find the revised version, which we would like to submit for your kind consideration.
Point 1: Extremely insignificant information on sections devoted to the use and pharmacokinetics.
Response 1: This article actually reviews biflavonoids. The title of this paper is wrong, we revised the correct title at first. In this review, the use and pharmacokinetics is not the mainly content. We put the use of biflavonoids into the conclusion. And We added a table about the pharmacokinetics in the pharmacokinetics, which make the data of pharmacokinetics more intuitive.
Point 2: Flavonoids of gnafalium have been studied and described (for example, https://doi.org/10.1016/j.phytol.2009.11.002, etc.). Please include these flavonoids in your review.
Response 2: This review mainly describes biflavonoids, which belong to a class of flavonoids. Therefore, this review mainly focuses on biflavonoids, instead of flavonoids.
Point 3: To visualize the data, provide the data in the form of tables indicating the flavonoid, plant, dose / concentration, effect, reference drugs, literary references confirming the activity of various classes of flavonoids in accordance with your tables 1-3. Please discuss, for each section of pharmacological properties, the effect of the structure of flavonoids on their activity.
Response 3: The pharmacology reviewed in this paper is mainly aimed at the pharmacological research status of biflavonoids. In the antioxidant research, biflavonoids can reduce the level of oxidation more than flavonoids, and the antioxidant part in this paper had supplemented the relevant information from the original literature.
Point 4: It is known that flavonoids have low bioavailability and bind to plasma proteins. This makes pharmacokinetic analysis and their application in medicine difficult. Please discuss this aspect. The flavonoid taxifolin (syn. with dihydroquercetin), found in various plants, has been extensively studied, including its pharmacokinetics (for example, https://doi.org/10.1016/j.phymed.2008.10.002, etc.). Provide the data in the form of a table with the main pharmacokinetic characteristics, including, doses, test systems, route of administration, method of analysis, literature reference.
Response 4: Because this review mainly summarizes the pharmacokinetics of biflavonoids, a table of relevant data had been supplemented for the pharmacokinetics of biflavonoids according to the requirements of reviewer.
Point 5: Flavonoids are associated with low toxicity (e.g. https://doi.org/10.1016/j.freeradbiomed.2004.04.034 and others). Discuss the toxicity data for flavonoids and their potential use in humans.
Response 5: The toxicity of flavonoids had been study, but this review is a review of biflavonoids. As for the toxicity of biflavonoids, I made a review in the pharmacological part of cytotoxic activities and antitumor activities. LI Yun-Ying, in2019, have proved that the biflavonoids in Ginkgo biloba do have hepatorenal toxicity, which is a difficult problem for the later development of Ginkgo biloba extract as a preparation.
Point 6: Chemical synthesis of flavonoids is an important and interesting aspect, but it requires separate consideration. In this aspect, it is necessary to provide data confirming the activity of the synthesized molecules analogous to natural ones. In this review, it would be more relevant to consider biosynthesis in plants.
Response 6: In the synthesis of G168, the anti-inflammatory activity of this synthetic biflavonoid has been added. G168 emerged anti-inflammatory was through the inhibiting COX-2 mediated PGE2 production. This review is a summary of the synthesis of biflavonoids. Therefore, the existing methods for the synthesis of biflavonoids are summarized, including biosynthesis and the synthesis methods with biflavone structure.
Point 7: The Conclusion section is devoted to traditional Chinese medicine. Please write it according to the text of the manuscript.
Response 7: According to the requirements of the reviewer and the integrity of the manuscript, I have modified the unscientific part of the conclusion part about traditional Chinese medicine.
Point 8: There are many errors in the text of the manuscript.
Response 8: The relevant English grammatical errors in the text have been corrected according to the requirements of English native speaker.
We would like to express our great appreciation to you and reviewers for comments on our paper. Looking forward to hearing from you.
Thank you and best regards.
Yours sincerely,
Xinqian He
Reviewer 3 Report
The biggest shortcoming of this article is the formatting of the text and the correct expression of the substitution descriptors. The images are chaotic and in this form are absolutely unacceptable. I recommend authors to redesign the presentation of images into a clear form, ideally to create more images of structurally related substances so that they are easy to read (pay attention to the correct presentation of stereochemistry). The text does not seem well processed and in my opinion is chaotic and does not meet the standards of publishing in MDPI journals. It has great reserves in terms of English and grammar. Likewise, the text contains an unacceptable number of typographical errors (I assume that the title should not include bioflavanoids but biflavanoids). I strongly recommend formatting and grammar proofreading to native speakers. Authors must unify citation formatting that is inhomogeneous and contains a number of errors. My opinion is that in this form the article is unacceptable for publication in Molecules MDPI journal and I recommend a rejection rather than a major revision.
Author Response
Dear reviewer:
On behalf of my coauthors, we thank you very much for giving us an opportunity to revise our manuscript, we appreciate editor and reviewers very much for their positive and constructive comments and suggestions on our manuscript entitled “Proceedings of chemistry, pharmacology, pharmacokinetics and synthesis of biflavonoids”
We have studied reviewer’s comments carefully and have made revision, which marked in red in the paper. We have tried our best to revise our manuscript according to the comments. Attached, please find the revised version, which we would like to submit for your kind consideration.
Point 1: I recommend authors to redesign the presentation of images into a clear form, ideally to create more images of structurally related substances so that they are easy to read (pay attention to the correct presentation of stereochemistry).
Response 1: Because there are 586 biflavonoids in this review, if all compounds are drawn one by one and placed in the article, there will be too many pictures in the article. Therefore, we focus on drawing biflavonoids with the same skeleton and represent their substituent under the structure. The structures of most compounds in the review come from the original literature, especially those with strange isomers. According to the requirements of reviewer, we were combined and arranged the compound structure diagram.
Point 2: The text does not seem well processed and in my opinion is chaotic and does not meet the standards of publishing in MDPI journals. It has great reserves in terms of English and grammar.
Response 2: We had asked MDPI's paper editing function to modify the layout of the review. However, MDPI's paper editing had not yet finished the layout editing. When the layout of this paper finished, we will hand it on at first.
Point 3: Likewise, the text contains an unacceptable number of typographical errors (I assume that the title should not include bioflavanoids but biflavanoids).
Response 3: This article actually reviews biflavonoids. The title of this paper is wrong, we revised the correct title at first.
We would like to express our great appreciation to you and reviewers for comments on our paper. Looking forward to hearing from you.
Thank you and best regards.
Yours sincerely,
Xinqian He
Round 2
Reviewer 2 Report
While reading the revised manuscript, I have questions:
Flavonoids are associated with low toxicity (e.g. https://doi.org/10.1016/j.freeradbiomed.2004.04.034 and others). Discuss the toxicity data for biflavonoids and their potential use in humans. Compare the toxicity of biflavonoids to the toxicity of flavonoids.
Chemical synthesis of flavonoids is an important and interesting aspect, but it requires separate consideration. In this aspect, it is necessary to provide data confirming the activity of the synthesized molecules analogous to natural ones. In this review, it would be more relevant to consider biosynthesis in plants. In terms of the materials of your manuscript, the biosynthesis of biflavonoids is more important and interesting, rather than their chemical synthesis / semi-synthesis.
The manuscript does not contain data on Larix biflavonoids, isolated and described for a long time. Please include these compounds.
Author Response
Dear reviewer:
On behalf of my coauthors, we thank you very much for giving us an opportunity to revise our manuscript, we appreciate editor and reviewers very much for their positive and constructive comments and suggestions on our manuscript entitled “Proceedings of chemistry, pharmacology, pharmacokinetics and synthesis of biflavonoids”
We have studied reviewer’s comments carefully and have made revision, which marked in red in the paper. We have tried our best to revise our manuscript according to the comments. Attached, please find the revised version, which we would like to submit for your kind consideration.
Point 1: Flavonoids are associated with low toxicity (e.g. https://doi.org/10.1016/j.freeradbiomed.2004.04.034 and others). Discuss the toxicity data for biflavonoids and their potential use in humans. Compare the toxicity of biflavonoids to the toxicity of flavonoids.
Response 1: Thank you for your careful comments. In part 5.7, we added the toxicity analysis of flavonoids and compared it with the toxicity of biflavonoids, added the analysis of the relationship between different flavone units and toxicity, and analyzed the relationship between the connection position of biflavonoids and toxicity. And the data related to the toxicological experiment of biflavonoids were supplemented.
Point 2: Chemical synthesis of flavonoids is an important and interesting aspect, but it requires separate consideration. In this aspect, it is necessary to provide data confirming the activity of the synthesized molecules analogous to natural ones. In this review, it would be more relevant to consider biosynthesis in plants. In terms of the materials of your manuscript, the biosynthesis of biflavonoids is more important and interesting, rather than their chemical synthesis / semi-synthesis.
Response 2: Thanks. We had added the data about the activity of the synthesized biflavonoids in 7.2 part, and draw the figure about these synthesized biflavonoids a-f in figure 14. And we had added the data about the biosynthesis of biflavonoids in 7.1 part. Because the biosynthesis of biflavonoids involve the oxidative coupling of two flavonoid units, we mainly focus on the biosynthesis of flavonoids, show the biosynthesis of flavonoids on figure 13, and add a literature on the biosynthesis of biflavonoids, which is about changing the elicitors.
Point 3: The manuscript does not contain data on Larix biflavonoids, isolated and described for a long time. Please include these compounds.
Response 3: Thank you for your careful recommend. We had supplemented the data of spirobiflavone from Larix plants in part 4.3 and draw the structure in figure 11.
We would like to express our great appreciation to you and reviewers for comments on our paper. Looking forward to hearing from you.
Thank you and best regards.
Yours sincerely,
Xinqian He
Reviewer 3 Report
1. In the nomenclature „O“ -substituents should be in intalics
2. Unify the font size in the tables (somewhere the name starts with a lowercase letter, elsewhere a capital letter)
3. Add dashes to sugar substances, (e.g. 7-O-β-glucopyranoside)
4. When the authors insist on this form of images, it is necessary to unify the presentation of stereochemistry (e.g. substances 6, 4 have a dashed line instead of wedges).
Author Response
Dear reviewer:
On behalf of my coauthors, we thank you very much for giving us an opportunity to revise our manuscript, we appreciate editor and reviewers very much for their positive and constructive comments and suggestions on our manuscript entitled “Proceedings of chemistry, pharmacology, pharmacokinetics and synthesis of biflavonoids”
We have studied reviewer’s comments carefully and have made revision, which marked in red in the paper. We have tried our best to revise our manuscript according to the comments. Attached, please find the revised version, which we would like to submit for your kind consideration.
Point 1: In the nomenclature „O“ -substituents should be in intalics
Response 1: Thank you for your careful correction. We have modified the font format according to the reviewer's suggestions.
Point 2: Unify the font size in the tables (somewhere the name starts with a lowercase letter, elsewhere a capital letter)
Response 2: Thanks. We have all modified these mentioned issues in the manuscript.
Point 3: Add dashes to sugar substances, (e.g. 7-O-β-glucopyranoside)
Response 3: Thanks. We have added dashes to sugar substances
Point 4: When the authors insist on this form of images, it is necessary to unify the presentation of stereochemistry (e.g. substances 6, 4 have a dashed line instead of wedges).
Response 4: Thank you for your careful review. We have changed the unreasonable wedges to dashed line.
We would like to express our great appreciation to you and reviewers for comments on our paper. Looking forward to hearing from you.
Thank you and best regards.
Yours sincerely,
Xinqian He
Round 3
Reviewer 2 Report
I have no more questions.
