Synthesis and biological study of new galanthamine-peptide derivatives designed for prevention and treatment of Alzheimer's disease.

The Alzheimer's disease leads to neurodegenerative processes and affecting negatively million people worldwide. The treatment of the disease is still difficult and incomplete in practice. Galanthamine is one of the most commonly used drugs against the illness. The main aim of this work is design and synthesis of new derivatives of galanthamine comprising peptide moiety as well as study of their ß-secretase inhibitory activity and the anti-aggregating effect. All new derivatives of galanthamine containing analogues of Leu-Val-Phe-Phe (Aß17-Aß20) were synthesized in solution using fragment and consecutive condensation approaches. The new derivatives were characterized by melting points, NMR, and HPLC/MS. They were tested in vitro for ß-secretase inhibition activity by means of fluorescent method and were investigated in vitro for anti-aggregation activity on sheep platelet-rich plasma. Although the new compounds do not contain a structural element responsible for the ß-secretase inhibition, five of them show high or good ß-secretase inhibitory activity between 19.98 and 51.19% with IC50 between 1.95 and 5.26 nM. Four of the new molecules were able to inhibit platelet aggregation between 55.0 and 90.0% with IC50 between 0.69 and 1.36 µM. Four of the compounds were able to inhibit platelet aggregation and two of them have high anti-aggregating effects.

Synthesis, Anticancer Activity, Docking Calculations and Hydrolytic Stability Studies of Bioconjugates of Monofluorenated Analogue of BIM- 23052.

BACKGROUND: The fight against cancer has started since its discovery and has not subsided to nowadays. Currently, the hybrid molecules have become a promising alternative to the standard chemotherapeutics for the treatment of multi-causal diseases, including cancers. OBJECTIVE: Herein, we report the synthesis, biological evaluation, mathematical docking calculations and hydrolytic stability of the new bioconjugates of monofluorinated analogues of BIM-23052, containing second pharmacophore naphthalimide, caffeic acid or the tripeptide Arg-Gly-Asp. METHODS: All new molecules are obtained using standard peptide synthesis on solid support. Anticancer potential is studied against a panel of tumor cell lines included human mammary carcinoma cell lines MCF-7 (ER+, PR+ and Her-2-); MDA-MB-231 (ER-, PR- and Her-2-), as well as cell lines BALB 3T3 (mouse embryonic fibroblasts) and MCF-10A (human breast epithelial cell line). RESULTS: The IC50 values found in the MCF-10A cell line assay were used to calculate the selective index (SI). The highest SI relative to MCF-7, with a value of 2.62 is shown by the compound Npht- Gly-D-Phe-Phe(4-F)-Phe-D-Trp-Lys-Thr-Phe-Thr-NH2. In MCF-10 cells, the weakest antiproliferative effect was caused by the same compound (IC50 = 622.9 ± 23.91 µM), which makes this analogue a good candidate for the new anticancer medical drug. Unfortunately, the hydrolytic stability studies reveal that this bioconjugate is the most unstable of hydrolysis under physiological conditions in the body. CONCLUSION: Even with lower anticancer activity and selectivity in comparison with Npht-Gly-DPhe- Phe(4-F)-Phe-D-Trp-Lys-Thr-Phe-Thr-NH2, the compound Arg-Gly-Asp-D-Phe-Phe(4-F)-Phe- D-Trp-Lys-Thr-Phe-Thr-NH2 is the best candidate between three investigated bioconjugates for practical application due to combination of activity and stability profiles. Mathematical docking calculation also reveals that synthesized bioconjugates show selectivity according to different somatostatin receptors on the surface of different cell lines.

Synthesis and Biological Studies on (KLAKLAK)2-NH2 Analog Containing Unnatural Amino Acid ß-Ala and Conjugates with Second Pharmacophore.

(1) Background: Peptides are good candidates for anticancer drugs due to their natural existence in the body and lack of secondary effects. (KLAKLAK)2 is an antimicrobial peptide that also shows good anticancer properties. (2) Methods: The Solid Phase Peptide Synthesis (Fmoc-strategy) was used for the synthesis of target molecules, analogs of (KLAKLAK)2-NH2. The purity of all compounds was monitored by HPLC, and their structures were proven using mass spectrometry. Cytotoxicity and antiproliferative effects were studied using 3T3 NRU and MTT tests, respectively. For determination of antimicrobial activity, the disc-diffusion method was used. Hydrolytic stability at three pH values, which mimic the physiological pH in the body, was investigated by means of the HPLC technique. (3) Results: A good selective index against MCF-7 tumor cell lines, combined with good cytotoxicity and antiproliferative properties, was revealed for conjugates NphtG-(KLAKLAK)2-NH2 and Caf-(KLAKLAK)2-NH2. The same compounds showed very good antifungal properties and complete hydrolytic stability for 72 h. The compound Caf-(KLß-AKLß-AK)2-NH2 containing ß-Ala in its structures exhibited good antimicrobial activity against Escherichia coli K12 407 and Bacillus subtilis 3562, in combination with very good antiproliferative and cytotoxic properties, as well as hydrolytic stability. (4) Conclusions: The obtained results reveal that all synthesized conjugates could be useful for medical practice as anticancer or antimicrobial agents.