Hemiasterlin Analogues with Unnatural Amino Acids at the N-Terminal and Their Inhibitory Activity on Tumor Cells

Hemiasterlin is a tripeptide with highly alkylated unnatural amino acids. It acts as a potent tumor cell growth inhibitor. From the comparison of the N-terminal between hemiasterlin and its analogues, a further modification was conducted on this position for a SAR study. Some unnatural amino acids with aryl or ureido groups were introduced into the N-terminal of hemiasterlin analogues to improve their hydrophobicity/hydrophilicity. Here 14 hemiasterlin analogues were synthesized. And their activities against tumor cell lines were evaluated. Discussions on SAR preliminarily indicated that no matter whether the N-terminals come from the aryl or alkyl units, sufficient steric bulk, lipophilicity and methylation of the N-terminal should be crucial factors to the cytotoxic activity.