Unlocking the Potential of Hydroxycinnamic Acid Bioconjugates: Tailored Derivatives for Biomedical, Cosmetic, and Food Applications
Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsThe authors have presented a comprehensive review of naturally derived bioconjugates from hydroxycinnamic acids for biomedical, cosmetic, and food applications. The significance of this study lies in its detailed exploration of the synthesis and benefits of these bioconjugates, highlighting their antioxidant properties, UV protection, and improved solubility and biocompatibility. However, several points require further attention. Firstly, the mechanistic details underlying the bioactivities of these bioconjugates need clearer elucidation. Secondly, the scalability and economic feasibility of the proposed synthesis methods should be addressed to ensure practical applicability. Additionally, more in-depth comparative studies with existing synthetic alternatives would strengthen the claims regarding the superior efficacy of natural bioconjugates. Lastly, while the environmental benefits of using natural products are well-stated, a life cycle assessment would provide a more robust argument for their sustainability. Overall, this review makes a meaningful contribution to the field but would benefit from addressing these critical aspects.
Questions:
1. Can the authors provide more detailed mechanistic insights into the bioactivities of the hydroxycinnamic acid-derived bioconjugates?
2. What are the challenges and solutions associated with the scalability and economic feasibility of the synthesis methods for these bioconjugates?
3. How do these naturally derived bioconjugates compare in efficacy with existing synthetic alternatives in similar applications?
4. Could the authors include a life cycle assessment to substantiate the environmental benefits of using natural hydroxycinnamic acid derivatives?
5. What specific modifications enhance the solubility and bioavailability of these bioconjugates, and how are these improvements measured?
6. Are there any potential side effects or biocompatibility issues that need to be considered for the biomedical applications of these bioconjugates?
The quality of the English language is high, with clear and precise phrasing. The similarity index of 22% is acceptable and indicates a good level of originality
Author Response
Reviewer 1-
The authors have presented a comprehensive review of naturally derived bioconjugates from hydroxycinnamic acids for biomedical, cosmetic, and food applications. The significance of this study lies in its detailed exploration of the synthesis and benefits of these bioconjugates, highlighting their antioxidant properties, UV protection, and improved solubility and biocompatibility. However, several points require further attention. Firstly, the mechanistic details underlying the bioactivities of these bioconjugates need clearer elucidation. Secondly, the scalability and economic feasibility of the proposed synthesis methods should be addressed to ensure practical applicability. Additionally, more in-depth comparative studies with existing synthetic alternatives would strengthen the claims regarding the superior efficacy of natural bioconjugates. Lastly, while the environmental benefits of using natural products are well-stated, a life cycle assessment would provide a more robust argument for their sustainability. Overall, this review makes a meaningful contribution to the field but would benefit from addressing these critical aspects.
Response- We thank the reviewer for the constructive comments to help improve our review manuscript. We have provided point by point response to the specific comments of the reviewer. The revised manuscript contains the revisions made by highlighting the track changes to facilitate the re-review process. We hope that in the present form this revised manuscript would meet your requirements to publish our work in your esteemed journal.
Questions:
1. Can the authors provide more detailed mechanistic insights into the bioactivities of the hydroxycinnamic acid-derived bioconjugates?
Response- We thanks the reviewer for the question. Wherever possible and as per the information made available by the investigating papers, we have provided the insights into bioactivities reported by these individual authors. Several papers have reported only the synthesis of these bioconjugates using chemical methods and compared the activities either with the parent hydroxycinnamic acids or well-known molecules. Therefore, the main idea to compile this review stems from the fact that, more studies especially the mechanism deriving ones are required to understand the effects in a better way.
- What are the challenges and solutions associated with the scalability and economic feasibility of the synthesis methods for these bioconjugates?
Response- Since most of the papers have reported lab-based synthesis, the challenges and solution associated with scale up and economic feasibility have to be addressed by further research in this area. In our mini-review introduction we have added a couple of papers discussing the recent advances in chemical and green synthesis of the starting hydroxy cinnamic acids from agricultural feedstock (at lab-scale), and bioproduction using engineered microorganisms. (Flourat, A. L et al ChemSusChem 2021, 14, 118-129 and Van Schijndel, J et al. Green Chem. Lett. Rev. 2017, 10, 404-411). Another paper, C. Peyrot, M.M. Mention, R. Fournier, F. Brunissen, J. Couvreur, P. Balaguer, F. Allais, Expeditious and sustainable two-step synthesis of sinapoyl-l-malate and analogues: towards non-endocrine disruptive bio-based and water-soluble bioactive compounds, Green Chemistry, 22 (2020) 6510-6518 has discussed the Green Metrics for synthesis of sinapoyl-l-malate and compared to the previous process reported by Allais, F. et al. Synthesis 2009, 21, 3571-3578 with an increase for both Atom Economy (AE) and the Process Atom Economy (PAE), indicating that more of the starting material was directly transferred into the product. We have already used the reference of the Peyrot et al Green Chem 2020 paper to mention the importance of sinapoyl-l-malate in section 2.1.
How do these naturally derived bioconjugates compare in efficacy with existing synthetic alternatives in similar applications?
Response- for example in section 3.0 we have discussed that isosorbide dihydroferulate (EC50 = 4.97 nmol) and isosorbide dihydrosinapate (EC50 = 2.98 nmol) were effective antioxidants comparable with Irganox 1010 (EC50 = 2.75 nmol) a commercial antioxidant derived from fossil fuel chemicals. Similarly in section 2.2 the glycerol-based dihydroferulates may also provide antioxidants capable of replacing the use of current petroleum-based active molecules such as Irganox 1010, BHT or BHA. These references are also mentioned in the conclusion section 6.0. yet another example in section 2.2- The hydrolysis rate using a commercial lipase from Rhizomucor miehei showed that 1,3-dipalmitoyl-2-p-methoxycinnamoyl-1,2,3-propanetriol 15 was hydrolyzed 2.8 times lower by lipase compared to octinoxate. In most cases, the synthesized bioconjugates were evaluated in the same study with a reference material and this has been mentioned throughout the manuscript.
Could the authors include a life cycle assessment to substantiate the environmental benefits of using natural hydroxycinnamic acid derivatives?
Response-We thank the reviewer for pointing us in this interesting direction. Considering the inputs and the processing for such an addition we feel that it will be a new paper by itself (example- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7237583/) to compile such information on all the hydroxycinnamic acid derivatives discussed in this mini-review. Therefore, currently we would not be able to include a life cycle assessment section.
What specific modifications enhance the solubility and bioavailability of these bioconjugates, and how are these improvements measured?
Response- We have provided specific examples for improvement in solubility, eg glycerol esters of sinapic and p-coumaric acid in section 2.2. 1-sinapoyl glycerol (1-SG) 12 and 1-p-coumaroylglycerol (1-CG) 13 (Figure 3) were designed and synthesized through a direct esterification reaction using a type A feruloyl esterase from Aspergillus niger. The esterification provided 6- and 11-times higher water solubilities at room temperature for 1-SG and 1-CG esters (2.0 mg/mL and 6.3 mg/mL) compared with sinapic and coumaric acid. The solubilities improved on boiling the solutions. Similarly the cyclodextrin inclusion complexes have improved the solubility issues of hydroxy cinnamic acid derivatives and the phase solubility profiles discussed within these references indicate these improvements.
Are there any potential side effects or biocompatibility issues that need to be considered for the biomedical applications of these bioconjugates?
Response- Since most of the hydroxycinnamic acids (ferulic acid, caffeic acid, p-coumaric acid and sinapic acid) are components of fruits, vegetables and herbs, these are biocompatible. Similarly, the coupling bioconjugates example, glycerol, fatty oils, polysaccharides, polyethylene glycols, starch or cellulose are all biocompatible materials therefore we assume there will not be any potential side effects. We hope that this review will motivate the scientific community to investigate in this field and develop such projects.
Reviewer 2 Report
Comments and Suggestions for AuthorsPlease see attached file for some specific details.
Comments for author File: 
Comments.pdf
Need some editing
Author Response
Figure 1. Change Tyrosinase to tyrosine
Response- Tyrosine corrected in the Figure 1 and legend.
Line 14 and 59, how these hydroxycinnamic acids are responsible for targeted delivery, what is the target, vague language, need more detailed information.
Response- We thank the reviewer for this comment. Targeted delivery examples have been discussed in the PEGlyation of ferulic acid for blood brain barrier (Section 4.0), Cyclodextrins, starch and galactomannan derivatives for colon specific delivery(Section 5.1, and 5.2 respectively). Therefore, the ‘targeted delivery’ terminology was used in the abstract and introductory sections at line 14 and 59.
Section 2.1, ω-. Is there typo here?
Response- No there is no typo error here. Greek letter ω especially denoting the last in position. Therefore in this context ω- signifies the end hydroxy position with respect to the acid group.
Line 64, UV filter properties or absorbing UV light?
Response- Changed to UV light filter/ absorbing properties
Abbreviations: line 82, SOD, LDH, MDA and elsewhere others in the whole manuscript; Line 88, DPPH
Response- these abbreviations were included in the abbreviations list at the end of manuscript.
Line 87 the glycerol ester is 4 and acid is 3, check description and numbers
Response- the necessary correction has been done
Line 103-104 redundant, remove
Response- the sentence has been revised.
Line 135-136, both gram positive and gram negative bacteria exhibit same MIC value of 6.25?
Response- Yes, as per the data presented in Gandhi et al both Gram-positive (Streptococcus mutans and Bacillus subtilis) and Gram-negative (Escherichia coli and Salmonella typhi) bacterial strains showed the MIC value of 6.25 µm mL−1 compared with streptomycin (1.5 µm mL−1).
Line 145, UV filters (or UV light absorbers)?
Response- Terminology had been adapted from the References 10. Now changed to UV light filter/ absorbing properties.
Line 158-159, natural hydroxycinnamic acid ….. natural……
Response- The ensuing sentence has been revised in accordance with the suggestion of the reviewer.
Line 228, stability to vesicles afforded by 10 and 11?
Response- Yes, as stated in the cited reference Evans et al Chemistry and Physics of Lipids 195 (2016) 1–11, the incorporation of products 10 and 11 within the vesicles resulted in “that were as or slightly more stable than the unloaded vesicles”.
Line 340-341, redundant, remove
Response- the sentence has been omitted.
Line 429, poly ethylene glycol is non-toxic, should be relatively non-toxic, therefore has a very minimal effect on…
Response- The sentence has been revised with the suggested change.
Line 460-464, how does pegylations changes antioxidant properties?
Response- With reference to the context of discussion at line 460-464, the authors Borges et al in Bioconjugate Chem. 2018, 29, 1677−1689 discussed that irrespective of the large PEGlyation, the effective entity for better antioxidant behaviour was the catechol group of caffeic acid followed by the ferulic group. This behaviour is seen for such products irrespective of the type of esterified group (Menezes et al European Journal of Medicinal Chemistry 2011 Vol. 46 Issue 2 Pages 773-777)
Figure 10, structures are poorly depicted
Response- Figure 10 shows the part structure of cellulose nanocrystals (CNC) grafted with diethyl sinapate and diethyl ferulate for UV absorbing applications. These were redrawn and adapted asper the original articles.
The manuscript is too long and can be condensed since most of description is made out of citations. Description can be very specific and compact so that most of repetitive sentences and redundancy can be avoided.
Response- We thank the reviewer for their comment. As far as possible, we have strived to discuss the most relevant topics in this mini-review to blend the traditional synthesis in chemistry, and showcase the applications of these molecules to several fields leading to further insights for developments in the interest of the broader chemical and scientific community. As per the advice of the reviewer several of redundant sentences have been revised or omitted. Considering the broad interdisciplinary readership of Chemistry further brevity to the text may result in a distorted style without much clarity and can reduce the understanding of Chemistry readers beyond their own specific field.
Word like sustainability, renewable sources used unneccesarily, since it is plant based molecules, they are falling into these category automatically, no need to emphasize on it.
Response- wherever possible the word “sustainable” and renewable sources has been omitted or modified to suit the context.
Round 2
Reviewer 1 Report
Comments and Suggestions for AuthorsThe authors have made significant improvements to the manuscript, addressing all the concerns raised by the reviewer in a comprehensive manner. They have provided detailed mechanistic insights into the bioactivities of hydroxycinnamic acid-derived bioconjugates, enhancing the understanding of their functionalities. Furthermore, the authors have acknowledged the challenges related to scalability and economic feasibility, incorporating relevant literature to support ongoing research in these areas. They have also strengthened the manuscript by including comparative studies, which effectively demonstrate the efficacy of natural bioconjugates relative to synthetic alternatives. Although a full life cycle assessment could not be included, the authors have articulated the reasoning for this and suggested it as a potential direction for future research. Additionally, they have clarified the specific modifications that enhance solubility and bioavailability, providing empirical data to substantiate these improvements. The discussion on biocompatibility and potential side effects is well-grounded, affirming the safety of the materials involved. Overall, the revisions have considerably elevated the quality and rigor of the manuscript, making it a valuable contribution to the field
Comments on the Quality of English LanguageThe English language is clear and well-structured, with only minor edits needed for improved readability and precision.
Author Response
Comments 1-The authors have made significant improvements to the manuscript, addressing all the concerns raised by the reviewer in a comprehensive manner. They have provided detailed mechanistic insights into the bioactivities of hydroxycinnamic acid-derived bioconjugates, enhancing the understanding of their functionalities. Furthermore, the authors have acknowledged the challenges related to scalability and economic feasibility, incorporating relevant literature to support ongoing research in these areas. They have also strengthened the manuscript by including comparative studies, which effectively demonstrate the efficacy of natural bioconjugates relative to synthetic alternatives. Although a full life cycle assessment could not be included, the authors have articulated the reasoning for this and suggested it as a potential direction for future research. Additionally, they have clarified the specific modifications that enhance solubility and bioavailability, providing empirical data to substantiate these improvements. The discussion on biocompatibility and potential side effects is well-grounded, affirming the safety of the materials involved. Overall, the revisions have considerably elevated the quality and rigor of the manuscript, making it a valuable contribution to the field
Response-
We thank the reviewer for the constructive comments to help improve our review manuscript. We have provided point by point response to the specific comments of the reviewer which have been well accepted. We hope that in the present form this revised manuscript would meet your requirements to publish our work in your esteemed journal.
Reviewer 2 Report
Comments and Suggestions for AuthorsThank you very much for accepting suggestions/comments
Author Response
Comments 1- Thank you very much for accepting suggestions/comments
Response- We thank the reviewer for the constructive suggestions and comments to help improve our review manuscript. We hope that in the present form this revised manuscript would meet your requirements to publish our work in your esteemed journal.
