An active insect kinin analog with 4-aminopyroglutamate, a novel cis-peptide bond, type VI beta-turn motif

The insect kinins are potent diuretic peptides that preferentially form a cis-Pro, type VI beta-turn. An insect kinin analog containing (2S,4S)-4-aminopyroglutamate, a novel cis-peptide bond, type VI beta-turn motif, demonstrates significant activity in the physiological range in a cricket diuretic assay. This is the first instance of a 4-aminopyroglutamate analog of a peptide with a preference for a type VI turn that demonstrates significant bioactivity. The results provide further confirmatory evidence for the active conformation of the insect kinins, and a new scaffold with which to design biostable, peptidomimetic analogs capable of disrupting critical insect kinin-regulated processes in insects.     

Analogs of arginine vasopressin modified in the N-terminal part of the molecule with a conformationally constrained cis-peptide bond motif.

The present work is part of our studies aimed at clarifying the influence of steric constraints in the N-terminal part of arginine vasopressin (AVP) and its analogs on the pharmacological activity of the resulting peptides. We describe the synthesis of eight new analogs of AVP or [3-mercaptopropionic acid (Mpa)]AVP (dAVP) substituted at positions 2 and 3 or 3 and 4 with two diastereomers of 4-aminopyroglutamic acid. The steric constraints provided by this modification turned out, however, so strong that all the peptides were inactive in all of the bioassays (pressor, antidiuretic and uterotonic tests).     

Comparison of insect kinin analogs with cis-peptide bond motif 4-aminopyroglutamate identifies optimal stereochemistry for diuretic activity

The insect kinins are present in a wide variety of insects and function as potent diuretic peptides, though they are subject to rapid degradation by internal peptidases. Insect kinin analogs incorporating stereochemical variants of (2S,4S)-4-aminopyroglutamate (APy), a cis-peptide bond motif, demonstrate significant activity in a cricket diuretic assay. Insect kinin analogs containing (2R,4R)-APy, (2S,4R)-APy and (2S,4S)-APy are essentially equipotent on an insect diuretic assay, with EC(50) values of about 10(-7)M, whereas the (2R,4S)-APy analog is at least 10-fold more potent (EC(50) = 7 x 10(-9)M). Conformational studies in aqueous solution indicate that the (2R,4S)-APy analog is considerably more flexible than the other three variants, which may explain its greater potency. The work identifies the optimal stereochemistry for the APy scaffold with which to design biostable, peptidomimetic analogs with the potential to disrupt critical insect kinin-regulated processes in insects.     

Design and synthesis of a novel enediynyl pentapeptide with predominantly beta-turn structural motif and its potential as a fluorescence-based chemosensor

A novel enediynyl pentapeptide in the protected form 1 was synthesized and characterized. It exists predominantly in beta-turn structural motif as revealed by variable temperature NMR and CD spectroscopy. In the presence of transition metal ions and gold nanoparticles, the fluorescence intensity of the peptide got enhanced with remarkable quantum yield with the Z-enediynyl -amino acid acting as a fluorophoric reporter. The interesting photophysical behaviors with alkali and alkaline earth metal ions are also reported.     

Interaction of iodinated enkephalin analogues with opiate receptors.

Radioiodinated derivatives of the metabolically stable enkephalin analogues, [DAla²,Leu⁵]- and [DAla²,DLeu⁵]-enkephalin, have been prepared. Such derivatives show sterospecific binding to receptors in brain homogenates and some neuroblastoma cell lines such as NG108-15 and N4TG1. The relative effects of levorphanol and dextrorphan and Na⁺ and Mn⁺⁺ ions on enkephalin binding in brain and cells indicate that the iodinated derivatives are interacting with opiate receptors. Levorphanol is considerably more potent in displacing specifically bound enkephalin than dextrorphan. Sodium ions at physiological concentrations decrease enkephalin binding whereas manganese ions enhance it. Unlabelled monoiodo derivatives retain high potency in the guinea-pig ileum, mouse vas deferens and receptor binding assays. Unlabelled diiodo derivatives show far lower potency in these assays. It is concluded that radio-iodinated derivatives containing one iodine per molecule retain high affinity for the opiate receptor but diiodo derivatives do not.     

The synthesis and biological evaluation of novel bridging nucleoside analogues.

Novel bridging nucleoside analogues were prepared by cycloaddition reactions between pyranose glycals and barbiturate-derived, reactive thionoimides in modest yields. In all of the reactions conducted, the major cycloadducts obtained were the bottom faced adducts resulting from endo addition to the glycal. The adducts were stable to a variety of acidic reaction conditions and several of the compounds showed moderate activities against HIV-1 in primary human lymphocytes. One compound displayed anti-herpes simplex virus type-1 activity in Vero cells. Cytotoxicity measurements were also obtained.     

The design, synthesis, and anti-tumor mechanism study of N-phosphoryl amino acid modified resveratrol analogues

A novel series of trans-N-phosphoryl amino acid modified resveratrol analogues were synthesized and evaluated in vitro for their cytotoxic effects against CNE-1 and CNE-2 cell lines. These analogues showed good anti-proliferative activity, among which 8d, 8e, 8j, and 9d displayed much stronger inhibition effect than resveratrol and 8d showed the most potent activity with IC(50) value at 3.45+/-0.82microM. The anti-tumor effects of 8d, 8e, 8j, and 9d were due to the induction of apoptosis, confirmed by the DNA fragmentation and flow cytometry analysis using PI (propidium iodide) staining and Annexin-V-FITC/PI staining assay. The PI staining assay also showed that 8d, 8e, 8j, and 9d caused cell cycles arrest at G(0)-G(1) phase which finally led to cell apoptosis. Further mechanism study on compound 8d against CNE-2 cells has shown the PARP cleavage, which is a hallmark of caspase-3 activation, as well as the activation of caspase-9, and the intracellular ROS generation. These results all suggest that 8d induced a mitochondrial-dependent apoptosis pathway.     

A bioactive somatostatin analog without a type II' beta-turn: synthesis and conformational analysis in solution.

A cyclic somatostatin analog [structure: see text] (1) has been synthesized. Biological assays show that this compound has strong binding affinities to somatostatin hsst2 and hsst5 receptor subtypes (5.2 and 1.2 nM, respectively, and modest affinity to hsst4 (41.1 nM)). Our conformational analysis carried out in DMSO-d6 indicates that this compound exists as two structures arising from the trans and cis configurations of the peptide bond between Phe7 and N-alkylated Gly8. However, neither conformer exhibits a type II' beta-turn. This is the first report of a potent bioactive somatostatin analog that does not exhibit a type II' beta-turn in solution. Molecular dynamics simulations (500 ps) carried out at 300 K indicate that the backbone of compound 1 is more flexible than other cyclic somatostatin analogs formed by disulfide bonds.     

Synthesis of novel 4'-cyclopropyl-5'-norcarbocyclic adenosine phosphonic acid analogues

Novel 4'-cyclopropyl-5'-norcarbocyclic adenosine phosphonic acid analogues were designed and racemically synthesized from propionaldehyde 5 through a de novo acyclic stereoselective route using triple Grignard addition and ring-closing metathesis (RCM) as key reactions. To improve cellular permeability and enhance the anti-HIV activity of this phosphonic acid, SATE phosphonodiester nucleoside prodrug 23 was prepared. The synthesized adenosine phosphonic acids analogues 17, 18, 19, 21, and 23 were subjected to antiviral screening against HIV-1. Compound 23 exhibits enhanced anti-HIV activity than its parent nucleoside phosphonic acid 18.     

2-Deoxy-2,3-didehydro-N-acetylneuraminic acid analogues structurally modified at the C-4 position: synthesis and biological evaluation as inhibitors of human parainfluenza virus type 1

To explore the influence of binding to human parainfluenza virus type 1 (hPIV-1), a series of 4-O-substituted Neu5Ac2en derivatives 6a-e was synthesized and tested for their ability to inhibit hPIV-1 sialidase. Among compounds 6a-e, the 4-O-ethyl-Neu5Ac2en derivative 6b showed the most potent inhibitory activity (IC50 6.3 microM) against hPIV-1 sialidase.     

The synthesis of 4-arylsulfanyl-substituted kainoid analogues from trans-4-hydroxy-L-proline

The potent neuroexcitatory activity of kainoid amino acids in the mammalian CNS places new analogues in high demand as tools for neuropharmacological research. A range of 4-arylsulfanyl-substituted kainoids has been synthesised in a parallel fashion via mesylate displacement by a number of aromatic and heteroaromatic thiolates upon (2S,3S,4R)-1-benzoyl-3-tert-butoxycarbonylmethyl-4-methanesulfo nyloxy pyrrolidine-2-carboxylic acid methyl ester 8, which is obtainable in eight steps from trans-4-hydroxy-L-proline 5.     

The enzymatic synthesis of ATP analogues.

The enzymatic synthesis of selected adenosine 5′-triphosphate analogues from their respective 5′-monosphosphates has been achieved using phosphoenolpyruvate synthetase. Adenosine 5′-monophosphate analogues altered at positions 1,6,7,8 or 9 of the purine ring, or at the ribose 2′- or 3′-positions are substrates with 30% conversion to the nucleoside 5′-triphosphate.     

A facile synthesis of novel pyrazolopyrimidine thioglycosides as purine thioglycoside analogues

The easy, convenient and high yielding preparation of new thioglycosides incorporating mercaptopyrazolo[1,5-a]pyrimidine moieties from readily accessible starting materials has been reported. The main step of this protocol is the formation of 7-mercaptopyrazolo[1,5-a]pyrimidine-6-carbonitrile derivatives 4a-d by condensation of sodium 2-cyano-3-ethoxy-3-oxoprop-1-ene-1,1-bis(thiolate) 1 with 4-(aryldiazenyl)-1H-pyrazole-3,5-diamines 3a-d to form target compounds 4a-d, which coupled with tetra-O-acetyl-α-D-glycopyranosyl bromides 5a,b in the presence of basic medium to provide the corresponding product purine thioglycoside analogs 6a-h. Ammonolysis of the latter compounds 6a-d at ambient temperature for 10 minutes, led to the free glycoside derivatives 7a-h, which were obtained in approximately quantitative yields. Their structures were created based on the spectroscopic and elemental data.     

Discovery of novel quinoline-based analogues of combretastatin A-4 as tubulin polymerisation inhibitors with apoptosis inducing activity and potent anticancer effect

A new series of quinoline derivatives of combretastatin A-4 have been designed, synthesised and demonstrated as tubulin polymerisation inhibitors. These novel compounds showed significant antiproliferative activities, among them, 12c exhibited the most potent inhibitory activity against different cancer cell lines (MCF-7, HL-60, HCT-116 and HeLa) with IC₅₀ ranging from 0.010 to 0.042 µM, and with selectivity profile against MCF-10A non-cancer cells. Further mechanistic studies suggest that 12c can inhibit tubulin polymerisation and cell migration, leading to G₂/M phase arrest. Besides, 12c induces apoptosis via a mitochondrial-dependant apoptosis pathway and caused reactive oxygen stress generation in MCF-7 cells. These results provide guidance for further rational development of potent tubulin polymerisation inhibitors for the treatment of cancer.

Highlights

• A novel series of quinoline derivatives of combretastatin A-4 have been designed and synthesised.
• Compound 12c showed significant antiproliferative activities against different cancer cell lines.
• Compound 12c effectively inhibited tubulin polymerisation and competed with [³H] colchicine in binding to tubulin.
• Compound 12c arrested the cell cycle at G₂/M phase, effectively inducing apoptosis and inhibition of cell migration.

     

The synthesis and antiviral activity of some 4'-thio-2'-deoxynucleoside analogues.

A practical 7-step synthesis of benzyl 3,5-di-O-benzyl-2-deoxy-1,4-dithio-D-erythro-pentofuranoside is described and the product has been used in the synthesis of some 4'-thio-2'-deoxynucleosides. These novel nucleoside analogues have potentially useful biological activity and are resistant to phosphorolysis.     

Efficient synthesis of fluorothiosparfosic acid analogues with potential antitumoral activity

In this paper, we describe a short synthesis of N-(phosphonoacetyl)-L-aspartate (PALA) analogues. The mono- and difluorinated thioacetamide precursors were prepared in one step from methyl (diethoxyphosphono)di- and monofluoromethyldithioacetates 8 and 11 as starting materials. Antiproliferating properties on a L1210 strain and ATCase inhibition of these new compounds are disclosed. ThioPALA(FF) 5c showed a remarkable cytotoxic activity towards murine leukemia L1210, when used as tetraester.