rel-2-[4-Chloro-2-[(5R,6R,7S)-6-[5-(4-methoxyphenyl)-3-(2-naphthyl)-3,4-dihydropyrazole-2-carbonyl]-5-methyl-2-oxo-3,5,6,7-tetrahydrothiopyrano[2,3-d]thiazol-7-yl]phenoxy]acetic Acid

Round 1

Reviewer 1 Report

This manuscript described the synthesis of a hetero Diels-Alder adduct between a crotonamide and an arylidene thioxothiazolidinone. The obtained adduct was fully characterized by 1H, 13C NMR and mass spectrometry. The compound was evaluated as on a large panel of cancer cell lines but was found mainly inactive. Although this compound is one more example of the process described in the previous publication of the authors (N. Zelisko et al. / Tetrahedron 70 (2014) 720-729) I think this manuscript suitable for publication in Molbank provided the authors address the following points.

1.       The synthesis of heterodiene must be briefly discussed. The structure is even not in the Scheme 1.

2.       Line 65 The reference of the synthesis of 1 must be added.

3.       Although the endo selectivity of DA reaction should provide the depicted stereochemistry, how did the authors establish the relative stereochemistry of the adduct only with the present 1H spectrum that shows almost no coupling constant for the crucial triade H-5, H-6, H-7 ?

4.       Assignments of these 3 protons are questionable. Why the 5-H that bears a methyl (if the numbering is correct) is a doublet of doublet ?  Furthermore a glance at the spectrum shows that it is not. If H-7 is really the H bearing the phenoxyacetic acid group, why is it a doublet of doublet. It Should be only a doublet. Why there is no COSY and NOESY spectra to ascertain the alleged stereochemistry . It should be easy to get them on a 500 MHz spectrometer

5.       The numbering of the heterocyclic core must be added for structure 3 on Scheme  1.

6.       Line 42. The product is a 3,4-dimethybenzoyl and not a dimethoxybenzoyl derivative

7.       The Table 1 is really unclear. The middle column is useless. Since there is only one compound one row must be assigned to each cell line.

8.       The English must be deeply improved. For example:

Line 25 replace: value by valuable

Line51 The work [8] by the work of Metwally et al [8]

Line 52 replace with targeting by for targeting

Line 54 Take into account by Taking into

Line 88 croton does not exist it is a vinylic methyl

 

Author Response

Dear Reviewer,

We would like to thank you for the reviews and constructive comments that helped us to significantly improve the manuscript. Your suggestions have been incorporated in the revised manuscript (yellow highlight).

Additionally, we would like to address some of the issues you have raised:

1. The synthesis of heterodiene must be briefly discussed. The structure is even not in the Scheme 1.

Corrected as suggested. Synthesis was briefly discussed, structure of heterodiene (2a) have been presented in the scheme and the relevant reference added.

2. Line 65 The reference of the synthesis of 1 must be added.

Corrected as suggested – [15] in the reference list

3. Although the endo selectivity of DA reaction should provide the depicted stereochemistry, how did the authors establish the relative stereochemistry of the adduct only with the present 1H spectrum that shows almost no coupling constant for the crucial triade H-5, H-6, H-7 ?

Corrected as suggested

4. Assignments of these 3 protons are questionable. Why the 5-H that bears a methyl (if the numbering is correct) is a doublet of doublet ? Furthermore a glance at the spectrum shows that it is not. If H-7 is really the H bearing the phenoxyacetic acid group, why is it a doublet of doublet. It Should be only a doublet. Why there is no COSY and NOESY spectra to ascertain the alleged stereochemistry. It should be easy to get them on a 500 MHz spectrometer

Corrected as suggested. Thank you for your important comment. We performed the COSY and ROESY NMR spectra.

5. The numbering of the heterocyclic core must be added for structure 3 on Scheme

Corrected as suggested, the scheme with numbering was added (Figure 2) to the appropriate part of the manuscript

6. Line 42. The product is a 3,4-dimethybenzoyl and not a dimethoxybenzoyl derivative

Corrected as suggested

7. The Table 1 is really unclear. The middle column is useless. Since there is only one compound one row must be assigned to each cell line.

Corrected as suggested

8. The English must be deeply improved. For example:

Line 25 replace: value by valuable

Corrected as suggested

Line51 The work [8] by the work of Metwally et al [8]

Corrected as suggested

Line 52 replace with targeting by for targeting

Corrected as suggested

Line 54 Take into account by Taking into

Corrected as suggested

Line 88 croton does not exist it is a vinylic methyl

Corrected as suggested

 

Yours faithfully

Prof. Roman Lesyk

Reviewer 2 Report

Manuscript entitled ''  rel-2-[4-Chloro-2-[(5R,6R,7S)-6-[5-(4-methoxyphenyl)-3-(2-napht2 hyl)-3,4-dihydropyrazole-2-carbonyl]-5-methyl-2-oxo-3,5,6,7-tetr3 ahydrothiopyrano[2,3-d]thiazol-7-yl]phenoxy]acetic acid '' by Lesyk  et al. is dealing with synthesis of heterocyclic organic molecules by cycloaddition reaction and investigation of their bioactivity.

Article is well written and easy to follow. All news compounds are adequately described spectroscopically.  Anti-cancer study is well described. Reference section gives important literature related to the subject. There is a quality in this paper and it is of general interest to the readers of Molbank, interested in synthetic organic chemistry and medicinal chemistry. Hence, I would suggest that manuscript should be accepted for publication to Molbank with small changes.

 

Points to be addressed:

 

The source (reference) of heterodiene [4-chloro-2-(2-oxo-4-thioxothiazolidin-5-ylidenemethyl)-phenoxy]-acetic acid should be added

 

Page 2, Line 71, ''  Dielse-Alder    '' should be replaced by ''   Diels-Alder     ''

Page 4, Line 152, ''  was crushed into    '' should be replaced by ''    was poured into    ''

Author Response

Dear Reviewer,

We would like to thank you for the reviews and constructive comments that helped us to significantly improve the manuscript. Your suggestions have been incorporated in the revised manuscript (yellow highlight).

Additionally, we would like to address some of the issues you have raised:

The source (reference) of heterodiene [4-chloro-2-(2-oxo-4-thioxothiazolidin-5-ylidenemethyl)-phenoxy]-acetic acid should be added

Corrected as suggested – [15] in the reference list

Page 2, Line 71, ''Dielse-Alder'' should be replaced by ''Diels-Alder''

Corrected as suggested

Page 4, Line 152, ''  was crushed into    '' should be replaced by ''    was poured into''

Corrected as suggested

 

Yours faithfully

Prof. Roman Lesyk

Round 2

Reviewer 1 Report

I think the authors deeply improved their manuscript. They completely addressed the question about structure and stereochemistry of  compound 3. The added data unambiguously confirmed the proposed structure. They also corrected many style blunders. Thus, as it stands now, the manuscript can be published in Molbank.