ABSTRACT
1,2-Diamine derivatives are valuable building blocks to heterocyclic compounds and important precursors of biologically relevant compounds. In this respect, amino acid-derived ß-keto esters are a suitable starting point for the synthesis of ß,γ-diamino ester derivatives through a two-step reductive amination procedure with either simple amines or α-amino esters. AcOH and NaBH(3)CN are the additive and reducing agents of choice. The stereoselectivity of the reaction is still an issue, due to the slow imine-enamine equilibria through which the reaction occurs, affording mixtures of diastereoisomers that can be chromatographically separated. Transformation of the ß,γ-diamino esters into pyrrolidinone derivatives allows the configuration assignment of the linear compounds, and constitutes an example of their potential application in the generation of molecular diversity.
Subject(s)
Amino Acids/chemistry , Diamines/chemistry , Amination , Crystallography, X-Ray , Esters/chemistry , Models, Molecular , Oxidation-Reduction , Reducing Agents/chemistry , StereoisomerismABSTRACT
The in vitro cytotoxicity assays of several enantiopure (3S,4S)- and (3R,4R)-1,3,4,4-tetrasubstituted ß-lactams derived from amino acids have shown that the (3S,4S)-4-benzyl-1-p-methoxybenzyl-3-methyl-4-methoxycarbonyl derivative 2a, obtained from Phe, displays significant activity, which is comparable to that of the anticancer drug Doxorubicin against HT29 cell lines. Modifications at positions 1 and 4 of the ß-lactam ring led to identify the Tyr(2,6-ClBz) analogu 26d with similar activity data to those of 2a. The synthesis and SAR of all these tetrasubstituted ß-lactams are reported here.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , beta-Lactams/chemistry , beta-Lactams/pharmacology , Antineoplastic Agents/chemical synthesis , Cell Line, Tumor , Cell Proliferation/drug effects , Chemistry Techniques, Synthetic , Colonic Neoplasms/drug therapy , Humans , Stereoisomerism , Structure-Activity Relationship , beta-Lactams/chemical synthesisABSTRACT
SAR studies on an azetidine-containing dipeptide prototype inhibitor of HCMV are described. Three series of structurally modified analogues, involving substitutions at the N- and C-terminus, and at the C-terminal side-chain were synthesized and evaluated for antiviral activity. Aliphatic or no substituents at the C-carboxamide group, an aliphatic C-terminal side-chain, as well as a benzyloxycarbonyl moiety at the N-terminus were absolute requirements for anti-HCMV activity. The conformational restriction induced by the 2-azetidine residue into the dipeptide derivatives, identified by (1)H NMR as a γ-type reverse turn, seems to have influence on the activity of these molecules.
Subject(s)
Antiviral Agents , Azetidines , Cytomegalovirus Infections/drug therapy , Cytomegalovirus/drug effects , Dipeptides , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Azetidines/chemical synthesis , Azetidines/chemistry , Azetidines/pharmacology , Cytomegalovirus Infections/virology , Dipeptides/chemical synthesis , Dipeptides/chemistry , Dipeptides/pharmacology , Humans , Magnetic Resonance Imaging , Protein Structure, Secondary , Structure-Activity RelationshipABSTRACT
[reaction: see text] The base-promoted cyclization of optically pure N-(p-methoxybenzyl)-N-(2-chloro)propionyl amino acid derivatives resulted in a diastereo- and enantioselective approach to valuable 1,3,4,4-tetrasubstituted beta-lactams. The stereochemical outcome of the reaction is exclusively governed by the configuration of the N-(2-chloro)propionyl moiety.
