4-Amino- and 4-Hydroxycyclohexane-1,1-dicarboxylic Acid Peptides

4-Amino-, 4-oxo-, and 4-hydroxy-cyclohexane-1 ,1-dicarboxylic acids have been inserted into di- and tri-peptides containing glycine, L-phenylalanine, L-cyclohexylalanine, and L-tyrosine. The geometries of 4-c-(IX A) and 4-t-(IX B) benzamidocyclohexane- r-1-carboxy-1-carbonyl-L-phenylalanine methyl esters and 4-c- -(XXIII A) and 4-t-(XXIII B) benzoxycyclohexane-r-1 -carbomethoxy- 1-carbonyl-L-cyclohexylalanine methyl esters were confirmed by their NMR spectra and intramolecular cyclisations of the cis isomers. The ring opening of 2-oxabicyclo[2.2.2]octan-3-one- 4-carbonyl-L-cyclohexylalanine methyl ester (XXIV) in methanolic hydrochloric acid afforded 4-c-hydroxycyclohexane-r- 1- -carbomethoxy-1-carbonyl-L-cyclohexylalanine methyl ester (XXI A) which on benzoylation was converted into the product identical with the isomer (XXIII A)

Polyfunctional Lysine Containing Tri- and Tetra-peptides

The synthesis of glycyl-L-histidyl-L-lysine, glycyl-L-lysyl- L-histidine, L-tyrosyl-L-histidyl-L-lysine, N-,N-e,-N-e-tribenzy loxycarbonyl derivative of L-histidyl-L-lysyl-L-lysine methyl ester, L-histidy 1-L-tyrosy 1-L-lysine, and L-tyrosy 1-L-histidy 1-L-lysyl-L-lysine by adoption of the azide coupling approach is described

Molecular targeting of prostate cancer cells by a triple drug combination down-regulates integrin driven adhesion processes, delays cell cycle progression and interferes with the cdk-cyclin axis

Background: Single drug use has not achieved satisfactory results in the treatment of prostate cancer, despite application of increasingly widespread targeted therapeutics. In the present study, the combined impact of the mammalian target of rapamycin (mTOR)-inhibitor RAD001, the dual EGFr and VGEFr tyrosine kinase inhibitor AEE788 and the histone deacetylase (HDAC)-inhibitor valproic acid (VPA) on prostate cancer growth and adhesion in vitro was investigated. Methods: PC-3, DU-145 and LNCaP cells were treated with RAD001, AEE788 or VPA or with a RAD-AEE-VPA combination. Tumor cell growth, cell cycle progression and cell cycle regulating proteins were then investigated by MTT-assay, flow cytometry and western blotting, respectively. Furthermore, tumor cell adhesion to vascular endothelium or to immobilized extracellular matrix proteins as well as migratory properties of the cells was evaluated, and integrin alpha and beta subtypes were analyzed. Finally, effects of drug treatment on cell signaling pathways were determined. Results: All drugs, separately applied, reduced tumor cell adhesion, migration and growth. A much stronger anti-cancer effect was evoked by the triple drug combination. Particularly, cdk1, 2 and 4 and cyclin B were reduced, whereas p27 was elevated. In addition, simultaneous application of RAD001, AEE788 and VPA altered the membranous, cytoplasmic and gene expression pattern of various integrin alpha and beta subtypes, reduced integrin-linked kinase (ILK) and deactivated focal adhesion kinase (FAK). Signaling analysis revealed that EGFr and the downstream target Akt, as well as p70S6k was distinctly modified in the presence of the drug combination. Conclusions: Simultaneous targeting of several key proteins in prostate cancer cells provides an advantage over targeting a single pathway. Since strong anti-tumor properties became evident with respect to cell growth and adhesion dynamics, the triple drug combination might provide progress in the treatment of advanced prostate cancer

Enantioselective component selection in multicomponent supramolecular gels

We investigate a two-component acid-amine gelation system in which chirality plays a vital role. A carboxylic acid based on a second generation l-lysine dendron interacts with chiral amines and subsequently assembles into supramolecular gel fibers. The chirality of the amine controls the assembly of the resulting diastereomeric complexes, even if this chirality is relatively "poor quality". Importantly, the selective incorporation of one enantiomer of an amine over the other into the gel network has been demonstrated, with the R amine that forms complexes which assemble into the most stable gel being primarily selected for incorporation. Thermodynamic control has been proven by forming a gel exclusively with an S amine, allowing the R enantiomer to diffuse through the gel network, and displacing it from the "solidlike" fibers, demonstrating that these gels adapt and evolve in response to chemical stimuli to which they are exposed. Excess amine, which remains unincorporated within the solidlike gel fiber network, can diffuse out and be reacted with an isocyanate, allowing us to quantify the enantioselectivity of component selection but also demonstrating how gels can act as selective reservoirs of potential reagents, releasing them on demand to undergo further reactions; hence, component-selective gel assembly can be coupled with controlled reactivity