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Aza-amino acids and an azapeptide with a boron-containing substituent were developed for the first time. We synthesized p-boronophenylalanine (BPA)-like aza-amino acid (aza-BPA) and its analogs in which the α-carbon of the peptide is replaced by nitrogen and the boronate ester is situated at the ortho, meta, or para position of the phenyl group. The N- and C-terminals of aza-BPA were linked to α-amino acids to afford an α/aza/α-tripeptide. These compounds are expected to be used in boron neutron capture therapy, chemotherapy, and synthesis of functional materials.

Efficient copper(II) acetate-catalyzed N-arylation of carbamate-protected hydrazones was achieved under mild reaction conditions with organobismuthanes.

A “one-pot” strategy for the straightforward Mn(III)-mediated phosphinoylation of aldehyde hydrazones with diphenylphosphine oxide to furnish α-iminophosphine oxides is described. This mild and practical method allows the direct use of aldehydes as substrates in one pot to generate the hydrazones, which are then engaged “in situ” by the phosphorus reagent in the presence of Mn(OAc)3 oxidant. Thus, the requisite isolation of the hydrazones is not needed in this operation. Conducted mechanistic experiments implicate a pathway involving phosphorus-centered radicals.

A triazine ring derivatized with morpholine, an N-alkyl-N′-BOC-hydrazine (alkyl=isopropyl or benzyl) and the diethylacetal of glycinylpropionaldehyde undergoes spontaneous dimerization in good yields upon acid-catalyzed deprotection. The resulting 24-member macrocycles can be characterized by NMR spectroscopy, mass spectrometry, and single crystal X-ray diffraction. In the solid state, both homodimers adopt a taco-like conformation. Although each shows π–π stacking between the triazine rings, different patterns of hydrogen bonds emerge. The crystal structure of the isopropyl dimer shows that it includes two molecules of trifluoracetic acid per macrocycle. The trifluoroacetate anion charge balances the protonated triazines, which engage in bifurcated hydrogen bonds with the carbonyl acceptor of the distant glycine. This carbonyl also forms a hydrogen bond with the NH of the proximate glycine. The crystal structure of the benzyl derivative does not include trifluoracetic acid. Instead, two hydrogen bonds form, each between a glycine NH and the lone pair of the C=N nitrogen of the hydrazine group. In the solid state, both molecules present the alkyl side chains and morpholine groups in close proximity. A heterodimer is accessible in approximately statistical yields—along with both homodimers—by mixing the two protected monomers prior to subjecting them to deprotection.

Tetrahydrophthalazine derivatives have found important applications in pharmaceutical research, but existing synthetic methods are unable to access them regio- and stereoselectively. Here, a new approach is presented that addresses these challenges by utilizing a 6-endo-trig radical cyclization in the key step. The desired tetrahydrophthalazines can be accessed in high yields (55–98 %) and high diastereoselectivities for the trans-product (>95:5) starting either from readily accessible hydrazones, or from the corresponding aldehydes and substituted Boc-hydrazides in a one-pot process. The synthetic versatility of the tetrahydrophthalazine core was demonstrated by its straightforward conversion to dihydro-phthalazines, phthalazines, or pyrazolo dione derivatives. Furthermore, the N?N bond was reduced to afford a new route to 1,4-diamines.

1,2-Diazetidin-3-ones are readily accessible, small ring scaffolds that upon functionalization have the potential to produce diverse 3-dimensional structures for drug discovery. Thus, treatment of diazo hydrazides, obtained from simple hydrazides and malonyl half ester derivatives, followed by diazo transfer, with catalytic amounts of rhodium(II) acetate dimer results in intramolecular carbenoid N?H insertion to give 1,2-diazetidin-3-ones. Although subsequent functionalization reactions could be hampered by the lability of the 4-membered ring, a wide range of new derivatives was available by deprotection at N-1, and subsequent amide or urea formation. The structures of four four-membered rings was confirmed by X-ray crystallography; the compounds showed modest growth inhibitory activity in mammary carcinoma cells.

While the incorporation of one aza-amino acid in peptides has been proved to be beneficial for inducing a structure constraint, increasing the resistance towards proteolysis and improving the biological activity, only very rare examples of the incorporation of two or more consecutive aza-amino acids have been reported. In this work, we demonstrate that this fact is probably due to the unsuspected difficulty in synthesizing such peptide analogues, as illustrated by the synthesis of tripeptide derivatives containing two consecutive aza-amino acids. Herein, we report some general guidelines regarding the activation and the coupling of alkyl-hydrazides either mutually or with a natural amino acid, taking into account their nucleophilicity and the nature of their side chains.

We demonstrate a Au(i)-mediated three-component reaction to DNA-tagged highly substituted 6-oxa-1,2-diazaspiro[4.4]nonanes from either DNA-coupled aldehydes, hydrazides, or alkynols. The choice of the starting material coupled to the DNA tag was critial for the purity of the product as the DNA-aldehyde conjugate yielded the purest products, whereas the alkynol- and hydrazide conjugates returned complex product mixtures. The reaction was compatible with thymine-, cytosine-, and, surprisingly, with adenine-DNA, while guanine-containing DNA strands were degraded under the reaction conditions.

A computer-vision controlled liquid–liquid extraction system was used in the continuous-flow synthesis of a series of carbazate hydrazones. The system uses open-source software components (Python, OpenCV) and is simpler and potentially more economical, in terms of hardware, than one we have described previously.

An efficient, highly atom economic synthesis of hitherto unknown spirocyclic pyrazolidines in a one-pot process was developed. The gold-catalyzed three-component coupling of alkynols, hydrazines and aldehydes or ketones likely proceeds via cycloisomerization of the alkynol to an exocyclic enol ether and subsequent [3 + 2]-cycloaddition of an azomethine ylide. A library of 29 derivatives with a wide range of functional groups was synthesized in up to 97% yield. With this new method, every position in the final product can be substituted which renders the method ideal for applications in combinatorial or medicinal chemistry.

Emerging yeasts are among the most prevalent causes of systemic infections with high mortality rates and there is an urgent need to develop specific, effective and non-Toxic antifungal agents to respond to this issue. In this study 35 aldehydes, hydrazones and hydrazines were obtained and their antifungal activity was evaluated against Candida species (C. parapsilosis, C.Tropicalis, C. krusei, C. albicans, C. glabrata and C. lusitaneae) and Trichosporon asahii, in an in vitro screening. The minimum inhibitory concentrations (MICs) of the active compounds in the screening was determined against 10 clinical isolates of C. parapsilosis and 10 of T. asahii. The compounds 4-pyridin-2-ylbenzaldehyde] (13a) and tert-butyl-(2Z)-2-(3,4,5-Trihydroxybenzylidine)hydrazine carboxylate (7b) showed the most promising MIC values in the range of 16-32 μg/mL and 8-16 μg/mL, respectively. The compounds' action on the stability of the cell membrane and cell wall was evaluated, which suggested the action of the compounds on the fungal cell membrane. Cell viability of leukocytes and an alkaline comet assay were performed to evaluate the cytotoxicity. Compound 13a was not cytotoxic at the active concentrations. These results support the discovery of promising candidates for the development of new antifungal agents.

Strategies to inhibit kinases by targeting the substrate binding site offer many advantages, including naturally evolved selectivity filters, but normally suffer from poor potency. In this work we propose a strategy to design and prepare covalent substrate-competitive kinase inhibitors as a method to improve potency. We have chosen AKT as the model kinase for this work. Using the AKT-GSK3β cocrystal structure and a reactive cysteine near the substrate binding site, we have identified phenylalanine (Phe) as an appropriate scaffold for the covalent inactivator portion of these inhibitors. By synthesizing compounds that incorporate cysteine-reactive electrophiles into phenylalanine and testing these compounds as AKT inhibitors, we have identified Boc-Phe-vinyl ketone as a submicromolar inactivator of AKT. We also show that Boc-Phe-vinyl ketone (1) potently inhibits AKT1 and inhibits cell growth in HCT116 and H460 cells nearly as well as AKT inhibitors GSK690693 and MK-2206, (2) is selective for kinases that possess an activation loop cysteine such as AKT, (3) requires the vinyl ketone for inactivation, (4) has inactivation that is time-dependent, and (5) alkylates Cys310 of AKT as shown by mass spectrometry. Identification of Boc-Phe-vinyl ketone as a covalent inactivator of AKT will allow the development of peptide and small-molecule substrate-competitive covalent kinase inhibitors that incorporate additional substrate binding elements to increase selectivity and potency. This proof-of-principle study also provides a basis to apply this strategy to other kinases of the AGC and CAMK families.

The synthesis of biologically important 5-aryl-3H-[1,3,4]oxadiazol-2-ones has been carried out by heating the easily synthesized N′-(chloro-aryl- methylene)-tert-butylcarbazates on basic alumina surface under solvent-free condition. The dual characteristic of basic alumina as a solid support as well as a nucleophile is successfully exploited in these reactions. The method provides special attributions such as reduced reaction times, easier work-up procedures, and good to excellent yields as well as increased purity of products and most importantly environmentally friendly protocols. The basic alumina is easily recovered and utilized for further reactions several times without serious loss of activity.

Novel N-(N-Pg-azadipeptidoyl)benzotriazoles 20a-e couple efficiently with α-amino acids 21a-e, dipeptides 22a-c, aminoxyacetic acid 23a, depsidipeptide 23b, and α-hydroxy-β-phenylpropionic acid 27 yielding, respectively, azatripeptides 24a-g, azatetrapeptides 25a,b, a hybrid azatripeptide with an oxyamide bond 26a, a hybrid azatetrapeptide with an ester bond 26b, and a hybrid azatripeptide with an ester bond 28. A new protocol for the synthesis of N-Pg-azatripeptides 33a,b and 35a,b, each containing a natural amino acid at the N-terminus, avoids the low coupling rates of the aza-amino acid residue and enables the solution-phase synthesis of an azaphenylalanine analogue of Leu-enkephalin 40.

Behind the mask: Nitrogen-substituted isocyanates are rare and their synthetic potential is virtually untapped. Simple masked precursors can form amphoteric amino isocyanate intermediates in situ, and allows the synthesis of complex hydrazine derivatives upon addition with amines. This reactivity was used in a cascade substitution/hydroamination sequence, and in the assembly of azadipeptide analogues. Copyright

Hydrazine and azapeptide analogs were synthesized effectively by alkylation of alkylidene carbazates and semicarbazones. In comparisons of benzylidene, benzhydrylidene, and fluorenylidene tert-butyl carbazates in alkylations using bases of different pKb character, superior conversion was obtained using the fluorenone derivative. Mild alkylation conditions were found employing Et4NOH as base and used to convert fluorenylidene tert-butyl carbazate into 13 different protected hydrazines. Moreover, racemization was avoided during alkylation of fluorenylidene semicarbazide in the synthesis of aza-propargylglycinylphenylalanine tert-butyl ester, the protecting groups from which could be selectively removed.

An efficient solution-phase synthesis of aza-diketopiperazines (aza-DKP, triazinediones) is reported. A structurally diverse collection of c-[aza-alkylGly-Pro] derivatives and yet unreported 2,4,5-trisubstituted-1,2,4- triazine-3,6-diones has been synthesized starting from Fmoc-l-Pro-OH and various Fmoc-l-amino acids. To extend the practical value of this class of dipeptidomimetics, a general solid-phase synthesis approach amenable to library production was developed on both Wang-PS and HMBA-PS resins. The final acidic treatment of the resins in TFA/water mixture at room temperature enabled the rapid and quantitative cyclization/release highly pure triazinediones. The conformational preferences and the spatial organization of the three substituents of a representative 2,4,5-trisubstituted-1,2,4-triazine-3,6-dione were investigated by X-ray diffraction and 1H NMR spectroscopy.

A large variety of Boc-, Bz-, Ts-, and Fmoc- protected hydrazones were prepared via condensation of an equimolar amount of carbonyl-compound and the corresponding hydrazine using a ball-mill. Hydrazones were always obtained in a quantitative yield and no solvents were used at any step. In a second step, we realized the first solvent-free N-allylation and N-benzylation of these hydrazones.

A series of fluorinated cyclic hydrazine derivatives has been prepared in a straightforward manner using ring-closing metathesis (RCM) of fluorinated- and trifluoromethylated olefins as the key step. Georg Thieme Verlag Stuttgart.

The stereoselective synthesis of either trans- or cis-3,5-disubstituted pyrazolidines is accomplished via Pd-catalyzed carboamination reactions of unsaturated hydrazine derivatives. The products are obtained in good yield with up to >20:1 diastereoselectivity. Stereocontrol is achieved by modulating the degree of allylic strain in the transition state for syn-aminopalladation through a simple modification of the substrate N2-substituent. The pyrazolidine products can be further transformed to 3,5-disubstituted pyrazolines via deprotection/oxidation, or to substituted 1,3-diamines via N-N bond cleavage.

Based on an orthogonal protective group strategy dealing with N-protected hydrazine, we established for the first time a highly efficient synthetic pathway leading to 2,3-benzodiazepine-1,4-dione. Moreover, the versatile reactivities exhibited by this 2,3

The first kilogram-scale synthesis of the PPARα agonist LY518674 (1) is described. The de novo convergent synthetic approach involved coupling of two rapidly assembled components, triazolone formation via a novel acid-promoted cyclization reaction, and final step saponification, delivering the compound in 32.5% overall yield via eight total steps with a six-step longest linear sequence. A regioselective alkylation on the dianion of 4-hydroxyphenylbutyric acid allowed the direct preparation of one of the convergent coupling partners, carboxylic acid 12, and an unusual solvent effect enabled the installation of a urea group on a protected hydrazine, permitting the regiospecific preparation of the other coupling partner, semicarbazide mesylate 17. Sulfonic acids were found to effect the desired triazolone ring formation, affording 25 from the coupled precursor acyl semicarbazide 23. Following saponification of 25 to 1, a wide solubility differential between ethyl acetate extracts of 1 and solutions of 1 in anhydrous ethyl acetate was harnessed in the final crystallization step to deliver the final compound in high yield and purity. The novel acid-mediated triazolone formation was further evaluated on a range of additional substrates, showing the new methodology to be largely complementary to existing base-mediated triazolone syntheses.

Tosyl- and Boc-hydrazones were found to be effective nucleophiles in the Mitsunobu reaction. Tosyl hydrazones reacted cleanly with primary and secondary alcohols when co-administered to a cooled DBAD/PPh3 or DEAD/PPh 3 complex. Boc-h

A series of 44 dipeptide nitriles with various amino acids at the P 2 position and glycine nitrile at position P1 were prepared and evaluated as inhibitors of cysteine proteinases. With respect to the important contribution of the P2-S2 interaction to the formation of enzyme-inhibitor complexes, it was focused to introduce structural diversity into the P2 side chain. Nonproteinogenic amino acids were introduced, and systematic fluorine, bromine, and phenyl scans for phenylalanine in the P2 position were performed. Moreover, the N-terminal protection was varied. Kinetic investigations were carried out with cathepsin L, S, and K as well as papain. Changes in the backbone structure of the parent N-(tert-butoxycarbonyl)-phenylalanyl-glycine-nitrile (16), such as the introduction of an R-configured amino acid or an azaamino acid into P 2 as well as methylation of the P1 nitrogen, resulted in a drastic loss of affinity. Exemplarily, the cyano group of 16 was replaced by an aldehyde or methyl ketone function. Structure-activity relationships were discussed with respect to the substrate specificity of the target enzymes.

A highly chemo- and regioselective iridium-catalyzed allylic amination is described. The reaction of various hydrazones and hydrazides with allylic carbonates proceeds at ambient temperature in the presence of an [Ir(COD)Cl]2/pyridine catalyst,

Compounds of the general formula I and their use for treating medical disorders resulting from a deficiency in growth hormone.

Azapeptides, peptide analogues in which the α-carbon of one or more of the amino acid residues is replaced with a nitrogen atom, exhibit propensity for adopting β-turn conformations. A general protocol for the synthesis of azapeptides without racemization on solid phase has now been developed by introducing the aza-amino acid residue as an N-Boc-aza1-dipeptide. This approach has been validated by the synthesis of six N-Boc-aza 1-dipeptides and their subsequent introduction into analogues of the C-terminal peptide fragment of the human calcitonin gene-related peptide (hCGRP). By performing an aza-amino acid scan of such antagonist peptides, a set of aza-hCGRP analogues was synthesized to examine the relationship between turn secondary structure and biological activity.

New tool substances may help to unravel the physiological role of the human orphan receptor BRS-3 and its possible use as a drug target for the treatment of obesity and cancer. In continuation of our work on BRS-3, the solid- and solution-phase synthesis of a library of low molecular weight peptidomimetic agonists based on the recently developed short peptide agonist 4 is described. Functional potencies of the compounds were determined measuring calcium mobilization in a fluorometric imaging plate reader (FLIPR) assay. Focusing on the N-terminus, the D-Phe-Gln moiety of 4 was modified in a combinatorial SAR-oriented medicinal chemistry approach. With the incorporation of N-arylated glycine and alanine building blocks azaglycine, piperazine, or piperidine and the synthesis of semicarbazides and semicarbazones, a number of highly potent and selective compounds with a reduced number of peptide bonds were obtained, which also should have enhanced metabolic stability.

An efficient method of synthesis of N-t-butoxycarbonyl-azaamino acid ethyl esters has been described. This method consisted of three stages including: hydrazone formation, its reduction and acylation with ethyl chloroformate. The second step - reduction of the hydrazones to the appropriate hydrazides - was the most challenging. Some reducing agents have been tested, though NaBH3CN was found to lead to the final products with the highest yields in relatively short time and even to allow the selective reduction of C-N bond in the presence of nitro group.

There are disclosed novel synthetic peptides of the general formula (I) Compounds of formula (I) stimulate the release of growth hormone from the pituitary in humans and animals. A method for increasing the rate and extent of growth of animals to increase their milk and wool production or for the treatment of ailments, and the use of the compounds of formula (I) for the preparation of medicaments, are also disclosed.

The synthesis and identification of a novel series of inhibitors of integrin VLA-4 are described. Their in vitro activity and selectivity against closely related integrins are also presented.

Compounds of Formula I and their use for treating medical disorders resulting from a deficiency in growth hormone are disclosed, wherein R1, R2, R3a, R4a, R5a, G, J and D are as defined in the specification.

Novel peptide derivatives, compositions containing them, and their use for treating medical disorders resulting from a deficiency in growth hormone are disclosed. The peptides have the formula (I): STR1 wherein a, b, A, R1, L1, D, R3, R4, R2, L2, E and G are as defined in the specification. These peptides exhibit improved resistance to proteolytic degradation, and hence, improved bioavailability.

Molecular modeling and topographic considerations of the thrombin-specific sequences Boc-Asp-Pro-Arg-TS or Ac-d-Phe-Pro-Arg-TS (TS = transition state analog electrophilic center) and related scaffolds led to the design of novel P2-P4-azapeptidomimetic P1-argininal and P1-ketoargininamide derivatives (3a-j). The synthesis and biological activity of these potential serine protease inhibitors are presented.

A series of potent inhibitors of the HIV-1 protease containing a novel pseudo-symmetric dipeptide isostere 3 was synthesized via ring opening of a protected epoxide with various substituted hydrazines.

(Benzyloxycarbonyl)- and (tert-butoxycarbonyl)hydrazones are easily reduced by sodium cyanoborohydride in acidic medium. The method is an alternative to catalytic hydrogenation and allows ready access to both N-benzyloxycarbonyl and N-tert-butoxycarbonyl

5-Substituted-1,3,4-oxadiazolin-2-ones 2 were synthesized by the oxidation of carbo-t-butoxyhydrazones 1 of aromatic aldehydes with lead tetraacetate or, preferably, iodosobenzene diacetate.In some instances 5-acetoxy-1,3,4-oxadiazoles 3 were obtained along with 2.The oxidation of carboethoxyhydrazones 4 gave 2-ethoxy-1,3,4-oxadiazoles 5.

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