ABSTRACT
Type II beta-turn mimics and polyproline II helix mimics based upon diastereoisomeric 5.6.5 spiro bicyclic scaffolds have provided two pairs of Pro-Leu-Gly-NH(2) (PLG) peptidomimetics with contrasting dopamine receptor modulating activities. Compounds 1a and 3a were found to be positive allosteric modulators of the dopamine receptor, while the corresponding diastereoisomeric compounds 1b and 3b provided the first PLG peptidomimetics with the ability to decrease the binding of agonists to the dopamine receptor. The positive allosteric modulating activity of 3a supported the hypothesis that a polyproline II helix conformation is the bioactive conformation for the PLG analogue Pro-Pro-Pro-NH(2). The results also show that a change in the bridgehead chirality of the 5.6.5 scaffold brings about opposite effects in terms of the modulation of the dopamine receptor.
Subject(s)
Heterocyclic Compounds, 2-Ring/chemical synthesis , MSH Release-Inhibiting Hormone/chemistry , Peptides/chemistry , Receptors, Dopamine D2/metabolism , Spiro Compounds/chemical synthesis , Thiazolidines/chemical synthesis , Allosteric Regulation , Animals , Binding, Competitive , Cattle , Corpus Striatum/metabolism , Crystallography, X-Ray , Heterocyclic Compounds, 2-Ring/chemistry , Heterocyclic Compounds, 2-Ring/pharmacology , In Vitro Techniques , Molecular Mimicry , Oligopeptides/chemistry , Protein Structure, Secondary , Receptors, Dopamine D2/agonists , Spiro Compounds/chemistry , Spiro Compounds/pharmacology , Stereoisomerism , Structure-Activity Relationship , Thiazolidines/chemistry , Thiazolidines/pharmacologyABSTRACT
A stereoselective total synthesis of the cytotoxic natural products tubulysin U, tubulysin V, and its unnatural epimer epi-tubulysin V, is reported. Simplified analogues containing N,N-dimethyl-D-alanine as a replacement for the N-terminal N-Me-pipecolinic acid residue of the tubulysins are also disclosed. Biological evaluation of these natural products and analogues provided key information with regard to structural and stereochemical requirements for antiproliferative activity and tubulin polymerization inhibition.
Subject(s)
Oligopeptides/chemical synthesis , Oligopeptides/pharmacology , Pipecolic Acids/chemical synthesis , Pipecolic Acids/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Chromatography, High Pressure Liquid , Crystallography, X-Ray , Humans , Magnetic Resonance Spectroscopy , Oligopeptides/chemistry , Pipecolic Acids/chemistry , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A series of tubulysin analogs in which one of the stereogenic centers of tubuphenylalanine was eliminated were synthesized. All compounds were tested for antiproliferative activity towards ovarian cancer cells and for inhibition of tubulin polymerization. The dimethyl analogs were generally more active than the desmethyl analogs, and four analogs have tubulin polymerization IC(50) values similar to combretastatin A4 and the hemiasterlin analog HTI-286.
Subject(s)
Antineoplastic Agents/pharmacology , Cell Proliferation/drug effects , Ovarian Neoplasms/pathology , Phenylalanine/pharmacology , Tubulin Modulators/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Cell Line, Tumor , Female , Humans , Inhibitory Concentration 50 , Models, Chemical , Oligopeptides/pharmacology , Phenylalanine/analogs & derivatives , Phenylalanine/chemical synthesis , Stilbenes/pharmacology , Structure-Activity Relationship , Tubulin Modulators/chemical synthesisABSTRACT
An efficient route for the synthesis of the tubulysin family of antimitotic peptides was developed. Simplified tubulysin analogues were synthesized to define the minimum pharmacophore required for cytotoxicity. Simplified tubulysin analogues retain significant cytotoxicity and reveal important preliminary structure-activity relationships.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Oligopeptides/chemical synthesis , Oligopeptides/pharmacology , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Design , Drug Screening Assays, Antitumor , Humans , Molecular Conformation , Oligopeptides/chemistry , Structure-Activity Relationship , Time FactorsABSTRACT
A concise, stereoselective synthesis of alpha-substituted gamma-lactams is reported. gamma-Lactam scaffolds 2 and 3, possessing an Evans' chiral auxiliary and two types of N substituents, were successfully alkylated with different electrophiles to give alpha-substituted gamma-lactams with reasonable diastereoselectivities. The use of a masked carboxymethyl function off the lactam nitrogen provided a convergent means to alpha-substituted gamma-lactam dipeptide isosteres.
