In vitro screening demonstrates sequence-dependent antiproliferative superiority of Trp-X dipeptides in solid tumor cell lines, indicating molecular topology dictates anticancer potency.
Key Points
To evaluate how peptide backbone sequence inversion influences chemical accessibility and in vitro antiproliferative activity in tryptophan-derived dipeptides.
Synthesized two complementary series of dipeptide libraries (Trp-X and X-Trp) through directional chemical coupling.
Assayed antiproliferative activity across six human solid tumor cell lines (A549, HeLa, MIA PaCa-2, SW1573, T-47D, and WiDr), benchmarking against cisplatin and 5-fluorouracil.
The Trp-X sequence orientation demonstrated overall biological superiority over X-Trp, with steric hindrance at the β-carbon impairing precursor synthesis exclusively in the X-Trp series.
The lead conjugate Trp-Pro displayed single-digit sub-micromolar antiproliferative activity across all tested cancer cell lines (GI50 = 1.36–2.06 μM), outperforming cisplatin and 5-fluorouracil in drug-resistant lines.
Inverting the sequence reversed structure–activity relationships for specific residues such as L-phenylglycine and L-tyrosine, establishing that activity depends on directional molecular topology rather than aggregate lipophilicity.