Design and Synthesis of Analogues of Marine Natural Product Galaxamide, an N-methylated Cyclic Pentapeptide, as Potential Anti-Tumor Agent in Vitro.
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.
Department of Chemistry, Life Science School, Jinan University, Guangzhou 510632, China. jignesh.lunagariya@gmail.com.
Jignesh
J
Lunagariya
Department of Chemistry, Life Science School, Jinan University, Guangzhou 510632, China. shenghuizhong@foxmail.com.
Shenghui
S
Zhong
Department of Chemistry, Life Science School, Jinan University, Guangzhou 510632, China. 18826237580@163.com.
Jianwei
J
Chen
College of Pharmacy, Jinan University, Guangzhou 510632, China. tbaidf@jnu.edu.cn.
Defa
D
Bai
Institute of Biomineralization and Lithiasis Research, Department of Chemistry, Life Science School, Jinan University, Guangzhou 510632, China. poonambhadja@gmail.com.
Poonam
P
Bhadja
Department of Chemistry, Life Science School, Jinan University, Guangzhou 510632, China. gallopfeel@gmail.com.
Weili
W
Long
Department of Chemistry, Life Science School, Jinan University, Guangzhou 510632, China. tliaoxj@jnu.edu.cn.
Xiaojian
X
Liao
Alpert Medical School, Brown University, 55 Claverick St. 4th Floor, Providence, RI 02903, USA. xiaoli_tang@brown.edu.
Xiaoli
X
Tang
Department of Chemistry, Life Science School, Jinan University, Guangzhou 510632, China. txush@jnu.edu.cn.
Shihai
S
Xu
D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001688:Biological Products / Q000494:pharmacology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000972:Antineoplastic Agents, Phytogenic; D001688:Biological Products; D010456:Peptides, Cyclic; C533373:galaxamide; D002945:Cisplatin
anti-tumor; apoptosis; cyclic pentapeptide; galaxamide analogues; macrocyclisation