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Mar. Drugs 2016, 14(9), 161; doi:10.3390/md14090161

Design and Synthesis of Analogues of Marine Natural Product Galaxamide, an N-methylated Cyclic Pentapeptide, as Potential Anti-Tumor Agent in Vitro

1
Department of Chemistry, Life Science School, Jinan University, Guangzhou 510632, China
2
College of Pharmacy, Jinan University, Guangzhou 510632, China
3
Institute of Biomineralization and Lithiasis Research, Department of Chemistry, Life Science School, Jinan University, Guangzhou 510632, China
4
Alpert Medical School, Brown University, 55 Claverick St. 4th Floor, Providence, RI 02903, USA
*
Authors to whom correspondence should be addressed.
Academic Editor: Paul Long
Received: 2 August 2016 / Revised: 26 August 2016 / Accepted: 26 August 2016 / Published: 3 September 2016
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Abstract

Herein, we report design and synthesis of novel 26 galaxamide analogues with N-methylated cyclo-pentapeptide, and their in vitro anti-tumor activity towards the panel of human tumor cell line, such as, A549, A549/DPP, HepG2 and SMMC-7721 using MTT assay. We have also investigated the effect of galaxamide and its representative analogues on growth, cell-cycle phases, and induction of apoptosis in SMMC-7721 cells in vitro. Reckon with the significance of conformational space and N-Me aminoacid (aa) comprising this compound template, we designed the analogues with modification in N-Me-aa position, change in aa configuration from l to d aa and substitute one Leu-aa to d/l Phe-aa residue with respective to the parent structure. The efficient solid phase parallel synthesis approach is employed for the linear pentapeptide residue containing N-Me aa, followed by solution phase macrocyclisation to afford target cyclo pentapeptide compounds. In the present study, all galaxamide analogues exhibited growth inhibition in A549, A549/DPP, SMMC-7721 and HepG2 cell lines. Compounds 6, 18, and 22 exhibited interesting activities towards all cell line tested, while Compounds 1, 4, 15, and 22 showed strong activity towards SMMC-7221 cell line in the range of 1–2 μg/mL IC50. Flow cytometry experiment revealed that galaxamide analogues namely Compounds 6, 18, and 22 induced concentration dependent SMMC-7721 cell apoptosis after 48 h. These compounds induced G0/G1 phase cell-cycle arrest and morphological changes indicating induction of apoptosis. Thus, findings of our study suggest that the galaxamide and its analogues 6, 18 and 22 exerted growth inhibitory effect on SMMC-7721 cells by arresting the cell cycle in the G0/G1 phase and inducing apoptosis. Compound 1 showed promising anti-tumor activity towards SMMC-7721 cancer cell line, which is 9 and 10 fold higher than galaxamide and reference DPP (cisplatin), respectively. View Full-Text
Keywords: anti-tumor; apoptosis; cyclic pentapeptide; galaxamide analogues; macrocyclisation anti-tumor; apoptosis; cyclic pentapeptide; galaxamide analogues; macrocyclisation
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Lunagariya, J.; Zhong, S.; Chen, J.; Bai, D.; Bhadja, P.; Long, W.; Liao, X.; Tang, X.; Xu, S. Design and Synthesis of Analogues of Marine Natural Product Galaxamide, an N-methylated Cyclic Pentapeptide, as Potential Anti-Tumor Agent in Vitro. Mar. Drugs 2016, 14, 161.

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