ABSTRACT
N-Methylation of peptides is an important synthetic tool in peptide-based medicinal chemistry. Herein, an optimized strategy for solid-phase synthesis of small but highly N-methylated cyclic peptides is described. The proposed route addresses several problems associated with the synthesis of peptides containing several sequential N-methyl-amino acids, such as in situ N-methylation, difficulty of acylation, epimerization, diketopiperazine formation, and stability at the NMe sites under trifluoroacetic acid exposure. The resulting NMe-IB-01212 exhibits micromolar activity and considerable stability.
Subject(s)
Depsipeptides/chemical synthesis , Cyclization , Isomerism , Methylation , Molecular Structure , Solid-Phase Synthesis TechniquesABSTRACT
An efficient route was developed for the synthesis of the Fmoc-protected dipeptide 4, isostere of Gly-Gly containing an alpha-methylene beta-amino acid; the conformationally restricted analogues of Leu-enkephalin, 3a, and Met-enkephalin, 3b, respectively, were prepared by changing 4 for Gly(2)-Gly(3) in the native compounds 3a and 3b whose biological activities were significantly lower than the parent compounds.
Subject(s)
Dipeptides/chemistry , Dipeptides/chemical synthesis , Enkephalin, Leucine/analogs & derivatives , Enkephalin, Leucine/pharmacology , Enkephalin, Methionine/analogs & derivatives , Enkephalin, Methionine/pharmacology , Neurotransmitter Agents/chemical synthesis , Neurotransmitter Agents/pharmacology , Amino Acid Sequence , Animals , Drug Design , Electric Stimulation , Enkephalin, Leucine/chemistry , Enkephalin, Methionine/chemistry , Glycylglycine/analogs & derivatives , Glycylglycine/chemical synthesis , Glycylglycine/chemistry , Guinea Pigs , Ileum , Male , Mice , Models, Molecular , Molecular Conformation , Molecular Mimicry , Molecular Structure , Myenteric Plexus/drug effects , Myenteric Plexus/physiology , Neurotransmitter Agents/chemistry , Receptors, Opioid, delta/agonists , Receptors, Opioid, mu/agonists , Stereoisomerism , Vas DeferensABSTRACT
Reactions of(4S,5R)-1-(3,4-Dimethyl-2-oxo-5-phenylimidazolidine)carbonyl-isocyanate (4) with appropriate Baylis-Hillman adducts 5 gave the corresponding acyl carbamates 6,7 as equimolar diastereomeric mixtures. These mixtures were treated with DABCO, to afford with moderate diastereoselection easily separable [2-(3",4"-dimethyl-2"-oxo-5"-phenylimidazolidine-1-carboxamido)(aryl)methyl]acrylates 8 and 9.
Subject(s)
Aza Compounds/chemistry , Carbamates/chemistry , Magnetic Resonance Spectroscopy , Molecular Structure , StereoisomerismABSTRACT
Bridged N-methyl amides are used as isosteres for depsi and thiodepsi bonds in thiocoraline. The introduction of NMe-amides in bridges mimics the thioester bonds without imposing steric hindrance and allows conservation of the hydrogen bonding map of the natural product. NMe-azathiocoraline was constructed by solid-phase N-methylation of the side chain of diaminopropionic acid (Dap). The three consecutive N-methyl amino acids could be coupled in good yields by using HATU/HOAt/DIEA in DMF, and the final octapeptide was also obtained on solid phase following a 4 + 4 fragment coupling approach. NMe-azathiocoraline (NMA) displayed nanomolar activity in the same order as the natural product and the same mode of action. In fact, modeling of NMe-azathiocoraline bonded to a TCGA sequence showed how the methyl groups remained further away from the DNA strand without changing the recognition pattern of thiocoraline. Moreover, NMe-azathiocoraline displayed an increased stability in human serum as compared to the parent natural product. This approach could be used in other depsipeptides and side chain to side chain cyclic peptides.
Subject(s)
Amides/chemistry , Depsipeptides/chemistry , Sulfides/chemistry , Breast Neoplasms/drug therapy , Carcinoma, Non-Small-Cell Lung/drug therapy , Cell Line , Cell Line, Tumor , Colon/drug effects , Depsipeptides/chemical synthesis , Depsipeptides/therapeutic use , Drug Stability , Esters/chemistry , Humans , Hydrogen Bonding , Male , Methylation , Protein ConformationABSTRACT
S-Trt Cys are used as precursors for the synthesis of protected NMe-Cys. N-Methylation of Alloc-Cys(Trt)-OH and Boc-Cys(Trt)-OH gives the corresponding N-methylated derivatives in good yields and purities, which can be further derivatized in solution to obtain a myriad of S-protected derivatives. To further broaden the scope of this methodology, the N (alpha)-amino protecting group of the NMe- S-protected Cys can be replaced easily either on the solid phase (from the Alloc precursor) or in solution (from the Boc precursor). Thus, this convenient route allows us to obtain many different protected NMe-Cys, which were of limited accessibility until now.
Subject(s)
Combinatorial Chemistry Techniques , Cysteine/analogs & derivatives , Cysteine/chemical synthesis , Cysteine/chemistry , Methylation , Molecular Conformation , SolutionsABSTRACT
New chiral chelating C2 bis-oxazoline-amide ligands (1) exhibiting a highly flexible molecular structure have been prepared in high yield through a versatile synthetic pathway. Combined crystallographic, variable temperature (VT)-NMR, IR, and ESI-MS studies have been carried out to investigate the nature of the 1-Pd complexes that are effective tools in controlling the stereochemical outcome of Pd-catalyzed allylic alkylations (ee up to 98%).
