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Antineoplastic activity of linear leucine homodipeptides and their potential mechanisms of action

Lei, Yuna; Yang, Xiao-Xiab,d; Guo, Weib; Zhang, Fu-yongb; Liao, Xiao-Jianb; Yang, Hui-Fub; Xu, Shi-Haib; Xiong, Shenga,c

doi: 10.1097/CAD.0000000000000615

Galaxamide is a rare cyclic homopentapeptide composed of three leucines and two N-methyl leucines isolated from marine algae Galaxaura filamentosa. The strong antitumor activity of this compound makes it a promising candidate for tumor therapy. The synthesis of galaxamide, however, is a complex process, and it has poor water solubility. On the basis of its special chemical composition, we designed a series of linear leucine homopeptides. Among seven dipeptide derivatives, five compounds with terminal protection groups and methyl substitution of the hydrogen in the amido group showed remarkable inhibitory effects against various cancer cells. N-tertbutyl-D-leucine-N-methyl-D-leucinebenzyl (A7), the only stereomer condensed by two D-leucines, showed the highest antineoplastic activity. A7-treated cells showed cell cycle arrest and morphological changes typical of cells undergoing apoptosis. The population of Annexin-V positive/propidium iodide-negative cells also increased, indicating the induction of early apoptosis. A7 promoted the cleavage of caspase-9 and caspase-3, as well as increased intracellular Ca2+ levels and decreased the mitochondrial membrane potential. Collectively, certain linear leucine dipeptides derived from cyclic pentapeptide are able to inhibit tumor cell proliferation through cell cycle arrest and apoptosis induction. The N-methyl group in the side chain and the D/L conformation of the amino-acid residue are critical for their activity.

aDepartment of Cell Biology, Institute of Biomedicine

bDepartment of Chemistry, Jinan University

cNational Engineering Research Center of Genetic Medicine, Guangzhou

dZhaoqing Aquatic Technologies Popolarizing Center, Zhaoqing, People’s Republic of China

Correspondence to Sheng Xiong, PhD, Department of Cell Biology, 730 Building of Biology, Jinan University, 601 W Huangpu Avenue, Guangzhou 510632, Guangdong, People’s Republic of China Tel/fax: +86 208 522 2759; e-mail: or

Correspondence to Shi-Hai Xu, PhD, Department of Chemistry, Jinan University, Guangzhou 510632, Guangdong, People’s Republic of China Tel/fax: +86 208 522 8856; e-mail:

Received October 3, 2017

Accepted February 12, 2018

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