Synthesis of linear and cyclic disulfide heptapeptides of Longicalycinin A and evaluation of toxicity on cancerous cells HepG2 and HT-29

Document Type: Research article

Authors

1 Department of Pharmaceutical Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

2 Protein Technology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

3 Department of Organic Chemistry, Faculty of Chemistry, University of Kashan, Kashan, Iran.

4 Department of Chemistry, College of sciences, Yazd University, Yazd, Iran.

5 Department of Organic Chemistry, Faculty of Chemistry, University of Kashan, Kashan, I.R. Iran

Abstract

In this work, linear and cyclic disulfide heptapeptides of Longicalycinin A have been successfully synthesized by solid phase methodology with Fmoc /t-Bu and solution phase, respectively. 2-Chlorotrityl chloride resin (2-CTC) was used as a solid support. The synthesized linear disulfide analogue of Longicalycinin A was cleaved from the resin as a protected peptide. The final deprotection was performed by treatment with TFA 95% containing scavengers to achieve the deprotected linear disulfide analogue of Longicalycinin A which was characterized by different instrumental methods using LC-MS and FT-IR. Macrocyclization of deprotected linear peptide was done by an oxidating reagent. Linear and cyclic disulfide heptapeptides of Longicalycinin A were evaluated their toxic activity against cell lines of HepG2 and HT-29 using 3-(4,5-dimethylthiazol-2-yl)-2,‌5-diphenyltetrazolium bromide reagent in MTT assay. The synthetic analogues showed a relative good activity against cell lines of HepG2 and HT-29 with IC50 values from 10.33 µg/mL to 12.45 µg/mL, in comparison to the standard drug 5-fluorouracil (5-FU). Safety profiles of the synthesized linear and cyclic disulfide analogues of Longicalycinin A were also examined on skin fibroblast cells. Between the linear and cyclic disulfide heptapeptides of Longicalycinin A, the cyclic peptide showed a considerable toxic activity on the cancerous cell lines along with a low safety result on normal cells. Therefore, the linear disulfide heptapeptide of Longicalycinin A would be encouraging to develop new anticancer agents.

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