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Twenty-two naturally occurring and three unnatural lamellarins were synthesized and evaluated for their cytotoxicities against cancer cells. Across eleven cancer cell lines derived from six different cancer types, the IC(50) values of these compounds ranged from sub-nanomolar (0.08 nM) to micromolar (>97.0 microM). About one-fourth (6/25) and one-half (11/25) of these lamellarins are more potent than the positive control, etoposide, against at least six different cell lines and three different cell types, respectively. In general, lamellarins D, X, epsilon, M, N, and dehydrolamellarin J are significantly more potent than the other lamellarins. The IC(50) values were used to perform structure-activity relationship (SAR) studies by comparing the cytotoxic activities of several pairs of lamellarin structures that differ in selected substitution patterns. Our results not only reveal the importance of specific hydroxylation or methoxylation patterns for the first time, but also confirm prior findings and clarify some previous uncertainties.

Low oral bioavailability of therapeutic peptides and proteins generally results from their poor permeability through biological membranes and enzymatic degradation in the gastrointestinal tract. Since different secondary structures exhibit different physicochemical properties such as hydrophobicity, size and shape, changing the secondary structure of a therapeutic polypeptide may be another approach to increasing its membrane permeation. Poly(L-lysine) was used as a model polypeptide. The objectives of this study were to induce secondary structural changes in poly(L-lysine) and to determine the time course over which a given conformer was retained. In addition, the hydrophobicity of each secondary structure of poly(L-lysine) was assessed. The circular dichroism (CD) studies demonstrated that the conditions employed could successfully induce the desired secondary structural changes in poly(L-lysine). The alpha-helix conformer appeared to be more stable at 25 degrees C whereas the beta-sheet conformer could be preserved at 37 degrees C. On the other hand, the random coil conformer was retained at both temperatures. Significant losses of the alpha-helix and the beta-sheet conformers were observed when the pH was reduced. The change in ionic strength did not affect any of the conformers. The octanol/buffer partitioning studies indicated that the alpha-helix and the beta-sheet conformers exhibited significantly different (P < 0.05) hydrophobicities. In conclusion, variation of pH and temperature conditions can be used to induce secondary structural changes in poly(L-lysine). These changes are reversible when the stimuli are removed. The alpha-helix and the beta-sheet conformers of poly(L-lysine) are more lipophilic than the native random coil conformer. Thus, poly(L-lysine) may represent an ideal model polypeptide with which to further investigate the effects of secondary structure on membrane diffusion or permeation.

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