Wenxia Zhou

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.

Studies of Bioactivity, Conformation and Pharmacokinetic Profiles of Site-Specific PEGylated Thymosin Alpha 1 Derivatives

Site-specific mono-PEGylations were performed in different conformational regions of Thymosin alpha 1 (T alpha 1) by introducing one cysteine residue into the chosen site and coupling with thiol-specific mPEG-MAL reagent. Results demonstrated that PEGylated sites and regions influenced the conformations and pharmacokinetic profiles of the peptide greatly with following order: alpha-helix, beta-turn, random coil and terminals, but little on the immunoactivity.

Poly(ethylene glycol) (PEG) Modifications and Conformational Analysis of Thymosin α 1

Results and Discussion According to the SAR results [1], the conjugating sites of Tα1 with PEG were chosen at the N-terminus, C-terminus, α-helix, β-turn, and the random coil regions. Referring to the method reported by Vanwetsswinkel et al [2,3], [Cys]Tα1 analogs (x: the chosen site) were synthesized firstly for conveniently introducing the covalent attachment mPEG-MAL into the chosen sites, and then the PEG conjugations were prepared as follows (Scheme 1) .