Biological Evaluation and Conformational Preferences of Ferrocene Dipeptides with Hydrophobic Amino Acids

Round 1

Reviewer 1 Report

The authors describe the biological evaluation and conformational analysis of enantiomeric dipeptides derived from 1′-aminoferro-cene-1-carboxylic acid and hydrophobic amino acids (AA = Val, Leu, Phe). The synthesis of the ferrocene dipeptides was reported in a previous author publication. Conformational analysis for the short ferrocene dipeptides were performed by experimental (IR, NMR, CD and X-21 ray) and theoretical (DFT) methods. The author also describes the X-ray crystal structure of compound D-2a. The introduction part clearly highlighted the significance of the work. In the chemistry part, the authors used robust and different experimental methods in the study and the results are well correlated from the different types of testing and analysis. The experimental part is informative and clear. The discussion part was well written, and the conclusion drawn was reliable. The manuscript is over all organized and uses appropriate language.

This work merits publication .

1-      Ferrocene derivatives are well known for their anticancer activity as well as peptidomimetic scaffolds. I would suggest considering anticancer activity for those well characterized compounds to further increase the impact and clinical usefulness and applications of the research.

Author Response

Thank you for your positive observations.

Reviewer 2 Report

The article can be published, taking into account the opinion of the editor-in-chief, after making the following corrections:

First, the article does not cite the fundamental review by D. R. van Staveren, N. Metzler-Nolte, Chem. Rev. 2004, 104, 5931.

Secondly, authors need to put aside their modesty and refer to all their related publications, such as Croat. Chem. Acta 2017, 90(4), 537–569 DOI: 10.5562/cca3246

In the reference to the synthesis of the compounds studied in the article [34], in the characteristics of "orange solids" there is no melting point, no elemental analysis data, no HRMS spectra. These data must be given in the text of the article, expanding the experimental part.

The representation of the change in the chemical shifts of protons depending on the amount of added DMSO is better presented for clarity not in the form of a table, but in the form of an overlay of spectra.

If HPLC chromatograms are given, then it is necessary to show the chromatogram of the separation of the racemic mixture, where the retention times of each enantiomer, can be seen.

Author Response

Thank you for providing your constructive and detailed review comments on our manuscript. We agree with all your suggestions, and we corrected point by point the manuscript accordingly.

First, the article does not cite the fundamental review by D. R. van Staveren, N. Metzler-Nolte, Chem. Rev. 2004, 104, 5931.

Reference mentioned in comment is added as a reference 7 in the revised manuscript.

Secondly, authors need to put aside their modesty and refer to all their related publications, such as Croat. Chem. Acta 2017, 90(4), 537–569 DOI: 10.5562/cca3246

Reference mentioned in comment is added as a reference 33 in the revised manuscript.

In the reference to the synthesis of the compounds studied in the article [34], in the characteristics of "orange solids" there is no melting point, no elemental analysis data, no HRMS spectra. These data must be given in the text of the article, expanding the experimental part.

Characterization details not described in Reference 34 are added in the Supplementary material because we believe they would burden an already extensive manuscript that focuses primarily on bioactivity and conformational analysis of the target compounds.

The representation of the change in the chemical shifts of protons depending on the amount of added DMSO is better presented for clarity not in the form of a table, but in the form of an overlay of spectra.

Overlay of ¹H-NMR spectra obtained during the titration with DMSO is added to Supplementary material.

If HPLC chromatograms are given, then it is necessary to show the chromatogram of the separation of the racemic mixture, where the retention times of each enantiomer, can be seen.

Although all target compounds were prepared from optically pure commercial amino acids, we submitted HPLC chromatograms as evidence of purity in addition to their retention times.