ABSTRACT
The 5-amino-1,2,3-triazole-4-carboxylic acid is a suitable molecule for the preparation of collections of peptidomimetics or biologically active compounds based on the triazole scaffold. However, its chemistry may be influenced by the possibility of undergoing the Dimroth rearrangement. To overcome this problem, a protocol based on the ruthenium-catalyzed cycloaddition of N-Boc ynamides with azides has been developed to give a protected version of this triazole amino acid. When aryl or alkyl azides are reacted with N-Boc-aminopropiolates or arylynamides, the cycloaddition occurs with complete regiocontrol, while N-Boc-alkyl ynamides yield a mixture of regioisomers. The prepared amino acids were employed for the preparation of triazole-containing dipeptides having the structural motives typical of turn inducers. In addition, triazoles active as HSP90 inhibitors (as compound 41, IC50 = 29 nM) were synthesized.
Subject(s)
Amino Acids/chemistry , Azides/chemistry , Carboxylic Acids/chemistry , Dipeptides/chemistry , HSP90 Heat-Shock Proteins/chemistry , Peptidomimetics/chemistry , Ruthenium/chemistry , Triazoles/chemical synthesis , Catalysis , Cycloaddition Reaction , HSP90 Heat-Shock Proteins/agonists , HSP90 Heat-Shock Proteins/antagonists & inhibitors , Inhibitory Concentration 50 , Triazoles/chemistry , Triazoles/pharmacologyABSTRACT
Ruthenium catalyzed 1,3-cycloaddition (click chemistry) of an azido moiety installed on dihydroxycumene scaffold with differently substituted aryl propiolates gave a new family of 1,4,5-trisubstituted triazole carboxylic acid derivatives that showed high affinity toward Hsp90 associated with cell proliferation inhibition, both in nanomolar range. The 1,5 arrangement of the resorcinol, the aryl moieties, and the presence of an alkyl (secondary) amide in position 4 of the triazole ring were essential to get high activity. Docking simulations suggested that the triazoles penetrate the Hsp90 ATP binding site. Some 1,4,5-trisubstituted triazole carboxamides induced dramatic depletion of the examined client proteins and a very strong increase in the expression levels of the chaperone Hsp70. In vitro metabolic stability and in vivo preliminary studies on selected compounds have shown promising results comparable to the potent Hsp90 inhibitor NVP-AUY922. One of them, (compound 18, SST0287CL1) was selected for further investigation as the most promising drug candidate.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , HSP90 Heat-Shock Proteins/antagonists & inhibitors , Triazoles/chemical synthesis , Triazoles/pharmacology , Animals , Antineoplastic Agents/metabolism , Blotting, Western , Catalysis , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Computational Biology , Flow Cytometry , HSP90 Heat-Shock Proteins/metabolism , Humans , Indicators and Reagents , Isoxazoles/chemical synthesis , Isoxazoles/pharmacology , Mice , Models, Molecular , Protein Binding , Resorcinols/chemical synthesis , Resorcinols/pharmacology , Ruthenium , Spectrometry, Fluorescence , Structure-Activity Relationship , X-Ray Diffraction , Xenograft Model Antitumor AssaysABSTRACT
The palladium-catalysed carbonylation of vinyl aziridines can give either the trans- or cis-beta-lactam preferentially or even the delta-lactam simply by adjusting the reaction parameters ([Pd], [CO], temperature).
Subject(s)
Aziridines/chemistry , Carbon/chemistry , Palladium/chemistry , Vinyl Compounds/chemistry , beta-Lactams/chemical synthesis , Catalysis , Stereoisomerism , Temperature , beta-Lactams/chemistryABSTRACT
A series of O-heteroaryl phenols have been synthesised and structurally characterised. Photo-Fries rearrangement of these compounds represents a useful way to access the corresponding C-heteroaryl derivatives. The activity of the new phenolic compounds as radical scavengers towards the 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonate) (ABTS(+*)) has been evaluated. 2-tert-Butyl-4-(4-phenyl-isoxazol-3-ylmethoxy)-phenol (compound 3c) showed the highest scavenger activity (IC50 value (i.e. the concentration that scavenged 50% of the radicals) 3.17 x 10(-6) M), which was one order of magnitude greater than that of the corresponding lead compound tert-butylhydroxy-anisole (BHA) (IC50 1.04 x 10(-5) M). In further experiments, compound 3c showed dose-dependent inhibition of the oxidation of linoleic acid, as well as methaemoglobin formation, promoted by the presence of the radical generator 2,2'-azobis(amidino-propane) hydrochloride (AAPH) and it was markedly more potent than BHA in these assays.
Subject(s)
Antioxidants/chemical synthesis , Heterocyclic Compounds/chemistry , Heterocyclic Compounds/chemical synthesis , Isoxazoles/chemical synthesis , Phenols/chemistry , Phenols/chemical synthesis , Antioxidants/chemistry , Free Radical Scavengers/chemical synthesis , Free Radical Scavengers/chemistry , Isoxazoles/chemistry , Structure-Activity RelationshipABSTRACT
[reaction: see text] 2,4-Dialkyl or aryl quinazolines have been prepared in three steps starting from easily available anilides. A photochemically induced Fries rearrangement of the anilides gave several ortho-aminoacylbenzene derivatives that were acylated at the NH2. These acylamides underwent rapid cyclization to 2,4-disubstituted quinazolines (and benzoquinazolines) in the presence of ammonium formate under microwave activation. This procedure is compatible with different functional groups and allowed also the preparation of new quinazolines derived from naturally occurring amino acids.
Subject(s)
Quinazolines/chemistry , Anilides/chemistry , Molecular Structure , Quinazolines/chemical synthesisABSTRACT
Different anilides derived from carboxylic acids and substituted anilines have been submitted to the photochemically induced Fries rearrangement giving the corresponding o-amino phenones under conditions that are compatible with the presence of acid-labile groups (such as N-Boc or TBDMSO) on R1 and R3. These compounds, not easily obtained in other ways, are useful building blocks for the preparation of benzocondensated heterocycles. After coupling with N-Boc amino acids and TFA-mediated deprotection, the products cyclized to the corresponding 3,5-disubstituted 1,4-benzodiazepin-2-ones, privileged structures predominantly active in the central nervous system. The same results were obtained by coupling with N-Cbz-protected alpha-amino acids followed by microwave assisted hydrogenolysis. When the Fries rearrangement was carried out on the anilide derived from N-Boc-Ala-OH and the further coupling done with N-Cbz-(OMe)Asp-OH, the formed benzodiazepines could be inserted in a peptide chain for the preparation of conformationally constrained peptidomimetics.
