Guanidino Derivatives Research Articles

N-Guanidino Derivatives of 1,5-Dideoxy-1,5-imino-d-xylitol are Potent, Selective, and Stable Inhibitors of β-Glucocerebrosidase.

A series of lipidated guanidino and urea derivatives of 1,5-dideoxy-1,5-imino-d-xylitol were prepared from d-xylose using a concise synthetic protocol. Inhibition assays with a panel of glycosidases revealed that the guanidino analogues display potent inhibition against human recombinant β-glucocerebrosidase with IC50 values in the low nanomolar range. Related urea analogues of 1,5-dideoxy-1,5-imino-d-xylitol were also synthesized and evaluated in the same fashion and found to be selective for β-galactosidase from bovine liver. No inhibition of human recombinant β-glucocerebrosidase was observed for the urea analogues. Computational studies provided insight into the potent activity of analogues bearing the substituted guanidine moiety in the inhibition of lysosomal glucocerebrosidase (GBA).

Effects of guanidino modified aminoglycosides on mammalian membranes studied using a quartz crystal microbalance.

The increase in bacterial and viral resistance to current therapeutics has led to intensive research for new antibacterial and antiviral agents. Among these, aminoglycosides and their guanidino derivatives are potent candidates targeting specific RNA sequences. It is necessary that these substances can pass across mammalian membranes in order to reach their intracellular targets. This study investigated the effects of the aminoglycosides kanamycin A and neomycin B and their guanidino derivatives on mammalian mimetic membranes using a quartz crystal microbalance with dissipation monitoring (QCM-D). Lipid bilayers as membrane models were deposited onto gold coated quartz crystals and aminoglycosides added afterwards. Notably, the guanidino derivatives exhibited an initial stiffening of the membrane layer indicating a quick insertion of the planar guanidino groups into the membrane. The guanidino derivatives also reached their maximum binding to the membrane at lower concentrations than the native compounds. Therefore, these modified aminoglycosides are promising agents for the development of new antimicrobial treatments.

Orthoester functionalized N-guanidino derivatives of 1,5-dideoxy-1,5-imino-d-xylitol as pH-responsive inhibitors of β-glucocerebrosidase.

Alkylated guanidino derivatives of 1,5-dideoxy-1,5-imino-d-xylitol bearing an orthoester moiety were prepared using a concise synthetic protocol. Inhibition assays with a panel of glycosidases revealed that one of the compounds prepared displays potent inhibition against human β-glucocerebrosidase (GBA) at pH 7.0 with IC50 values in the low nanomolar range. Notably, a significant drop in inhibitory activity is observed when the same compound is tested at pH 5.2. This pH sensitive activity is due to degradation of the orthoester functionality at lower pH accompanied by loss of the alkyl group. This approach provides a degree of control in tuning enzyme inhibition based on the local pH. Compounds like those here described may serve as tools for studying various lysosomal storage disorders such as Gaucher disease. In this regard, the most active compound was also evaluated as a potential pharmacological chaperone by assessing its effect on GBA activity in an assay employing fibroblasts from Gaucher patients.

Novel linear triaryl guanidines, N-substituted guanidines and potential prodrugs as antiprotozoal agents

A series of triaryl guanidines and N-substituted guanidines designed to target the minor groove of DNA were synthesized and evaluated as antiprotozoal agents. Selected carbamate prodrugs of these guanidines were assayed for their oral efficacy. The linear triaryl bis-guanidines 6a, b were prepared from their corresponding diamines 4a, b through the intermediate BOC protected bis-guanidines 5a, b followed by acid catalyzed deprotection. The N-substituted guanidino analogues 9c– f were obtained in three steps starting by reacting the diamines 4a, b with ethyl isothiocyanatoformate to give the carbamoyl thioureas 7a, b. Subsequent condensation of 7a, b with various amines in the presence of EDCI provided the carbamoyl N-substituted guanidine intermediates 8a– f which can also be regarded as potential prodrugs for the guanidino derivatives. Compounds 9c– f were obtained via the base catalyzed decarbamoylation of 8a– f. The DNA binding affinities for the target dicationic bis-guanidines were assessed by Δ T m values. In vitro antiprotozoal screening of the new compounds showed that derivatives 6a, 9c and 9e possess high to moderate activity against Trypanosoma brucei rhodesiense ( T.b.r.) and Plasmodium falciparum ( P.f.). While the prodrugs did not yield cures upon oral administration in the antitrypanosomal STIB900 mouse model, compounds 8a and 8c prolonged the survival of the treated mice.

Amine−Guanidine Switch: A Promising Approach to Improve DNA Binding and Antiproliferative Activities

A series of polyaromatic guanidino derivatives was synthesized and evaluated for growth inhibitory properties in several human carcinoma cell lines. The properties of these guanidino compounds were compared to those of their corresponding synthetic amino precursors. The size of the polyaromatic ring system as well as the length of the tether attached to the ring had a direct impact on the observed antiproliferative profiles, compound 14 having the broadest spectrum of activity. As both series intercalate DNA, guanidine derivatives showed a remarkable affinity for DNA and the guanidinium group appeared to be essential, yet not sufficient for caspase-3/7 activation. Compound 14 also showed significant in vivo activity against breast cancer cell xenografts in NOG/SCID mice. These results suggest that the electronic nature of chain tethering an intercalator not only influences the DNA-binding process but also controls the antitumoral activity of the whole compound.

Halichondria sulfonic acid, a new HIV-1 inhibitory guanidino-sulfonic acid, and halistanol sulfate isolated from the marine sponge Halichondria rugosa Ridley & Dendy

A new sulfur-containing guanidino derivative, halichondria sulfonic acid (1) showing anti-HIV-1 activity, and halistanol trisulfate (2) with anti-tumor activity have been isolated from the marine sponge Halichondria rugosa Ridley & Dendy collected in the Chinese Southern Sea. The structure of 1 was elucidated by analysis of spectroscopic and crystal data.

A systematic study of ligand intermolecular interactions in crystals of copper(II) complexes of bidentate guanidino derivatives

The synthesis and X-ray structures of four neutral copper(II) complexes and one cationic complex incorporating bidentate alkyl N-(4-oxo-5,5-diphenyl-4,5-dihydro-1 H-imidazol-2-yl)imidocarbamate ligands are reported. The neutral complexes, which possess potential doublet (DA) hydrogen bonding motifs, form supramolecular structures based on synthons involving hydrogen bonding or phenyl embraces. The formation of sheets within the crystal through combination of these synthons, and the occurrence of guest molecules trapped in cavities between the sheets, are described. The cationic complex forms an extended hydrogen-bonded structure that incorporates nitrate ions. The structures of the five complexes are compared with others reported previously for complexes of related ligands.

A systematic study of ligand intermolecular interactions in crystals of copper(II) complexes of bidentate guanidino derivatives

The synthesis and X-ray structures of copper(II) complexes of the bidentate ligands, N-(4-oxo-5,5-diphenyl-4,5-dihydro-1 H-imidazol-2-yl)- N′-phenylguanidino, 2-uanidinobenzimidazolo and N-(4-oxo-3-phenyl-1,3-diazaspiro[4.4]non-1-en-2-yl)guanidino, are reported. These complexes, which possess potential doublet (DA) or triplet (DAD) hydrogen bonding motifs, can form supramolecular structures based on synthons involving hydrogen bonding or phenyl embraces. The changes in supramolecular structure resulting from small changes in ligand structure, as well as from the use of different solvents for their crystallisation, are examined. The structures adopted are compared with others reported previously for complexes of related ligands.

Use of Onium Salt-Based Coupling Reagents in Peptide Synthesis1

Peptide coupling methods derived from onium salts based on 1-hydroxybenzotriazole (HOBt) and 1-hydroxy-7-azabenzotriazole (HOAt) are becoming incorporated in synthetic strategies more frequently than the classical carbodiimide methods. We have correlated the reactivity of various onium salts derived from HOXt (X = A, B), with the structure of the reagents in question. Thus, we confirmed that the aza derivatives are more reactive than the parent benzotriazole derivatives in both activation and coupling. In addition, the activation step is determined by the structure of the carbon skeleton. Thus, pyrrolidino derivatives appear to be reagents of choice relative to the piperidino analogues or those derived from trialkylamines. Furthermore although phosphonium salts are slightly less reactive than the corresponding aminium/uronium salts, the former should be used for the activation of hindered species, since the latter may lead to the formation of guanidino derivatives.

Synthesis of (1 → 6)-carbodiimide-tethered pseudooligosaccharides via aza-Wittig reaction

The synthesis of unsymmetrical sugar carbodiimides through aza-Wittig coupling of sugar derived iminophosphoranes and isothiocyanates is reported. The reaction is particularly fast and efficient in the case of phosphoranylide derivatives of 6-azido-6-deoxysugars and glycosyl isothiocyanates, and has been exploited in the one-pot preparation of (1 → 6)-linked pseudodi- and trisaccharides incorporating carbodiimide bridges as convenient precursors for the corresponding ureido, thioureido, and guanidino derivatives. Kinetic considerations suggest that sugar phosphazides, formed in the early stages of the Staudinger reaction of triphenylphosphine and sugar azides, are the reactive intermediates.

Anti-Helicobacter pylori agents. 1. 2-(Alkylguanidino)-4-furylthiazoles and related compounds.

A series of 2-(alkylguanidino)-4-[5-(acetamidomethyl)furan-2-yl]thiazoles and related compounds were synthesized and evaluated for antimicrobial activity against Helicobacter pylori, inhibitory effect on gastric acid secretion, and histamine H2-receptor antagonist activity. Introduction of alkyl substituents on the guanidino moiety resulted in a significant increase in antimicrobial activity, which was associated with the alkyl chain length. Of the compounds obtained, the n-hexylguanidino derivative 13 demonstrated a 250-fold improvement in activity (MIC = 0.11 micrograms/mL) over the unsubstituted guanidino derivative 7. Alkyl-substituted guanidino derivatives also displayed gastric antisecretion and H2-antagonist activities. However, a simple correlation between the alkyl chain length and the activities was not found in these assays. Replacement of the guanidine with other bioisosteric groups (thiourea, urea, or (dimethylamino)methyl) resulted in loss of all activities tested. Thus the guanidino moiety was found to be essential for activity in this series of compounds.

Identification and characterization of imidazoline-binding sites from calf striatum

‘Non-adrenoceptor’-binding sites for [ 3H]clonidine (I 1-sites) and [ 3H]idazoxan (I 2-sites) are identified in calf striatum membranes. The pharmacological profile of both subtypes was investigated by competition binding with the imidazolines idazoxan, cirazoline, Bu 224 (2-(4,5-dihydroimidaz-2-yl)-quinoline) and Bu 239 (2-(4,5-dihydroimidaz-2-yl)-quinoxaline); the guanidino derivatives clonidine, moxonidine, guanabenz, amiloride and agmatine; the oxazoline rilmenidine and the imidazole histamine. The competition experiments indicate that both populations of imidazoline-binding sites in calf striatum consist of a high- (H) and a low-affinity (L) compartment. The monoamine oxidase (MAO) inhibitors pargyline (non-selective) and deprenyl (MAO-B-selective) have micromolar affinity for the I 1-sites and much lower affinity for the I 2-sites. The venom of the marine snail Conus geographus is the most potent of the 13 tested Conus venom preparations. None of the tested venoms is able to discriminate between both sites.

Preparation, crystal and molecular structure, and evaluation of plant growth regulating activity of guanidinoalkanephosphinates and phosphonates

AbstractA series of previously unknown α‐guanidinoalkanephosphonous, α‐ and β‐guanidinoalkanephosphonic acids has been prepared in order to study their structures and biological activity. Aminoalkanephosphonous and phosphonic acids have been converted into their guanidino derivatives by means of S‐methylisothiourea hydroiodide or cyanamide amidination. The crystal and molecular structures of three guanidino acids have been determined by single‐crystal X‐ray diffraction. The plant growth regulating activity of all synthesized guanidinoalkanephosphinates and phosphonates has been evaluated on Lepidium sativum. © 1995 John Wiley & Sons, Inc.

Synthesis of the potent influenza neuraminidase inhibitor 4-guanidino Neu5Ac2en. X-Ray molecular structure of 5-acetamido-4-amino-2,6-anhydro-3,4,5-trideoxy-D-erythro-L-gluco-nononic acid

An efficient and high-yielding synthesis of 4-guanidino Neu5Ac2en, the potent anti-influenza A and B compound, is described. The route exploits a stereospecific introduction of the key nitrogen functionality at C-4 via an oxazoline intermediate. Three different methods for the final-step conversion of the 4-amino into 4-guanidino derivatives are described. To explore the structure–activity relationship in this region of the molecule, a series of substituted guanidino derivatives were synthesized and their activity is described.

Is guanidino succinate a precursor for nitric oxide synthesis in rat vascular tissue?

Although L-Arginine (L-Arg) is considered the physiological precursor of nitric oxide (NO) synthesis in endothelial cells, recent experiments suggested that another guanidino derivative, guanidino succinate, may also serve as a major source of NO in this tissue. We tested this hypothesis in rat aortas, using two experimental situations in which L-Arg had previously shown significant activity, i.e., the ability to counteract contractile responses to the L-Arg analogue NG-nitro-L-arginine methyl ester (L-NAME) and the relaxation observed after prolonged incubation in physiologic buffer. Rat aortic rings, with or without endothelium, were suspended in organ chambers for recording of isometric tension and were contracted by phenylephrine (PE). After a brief incubation period (0.5 h), L-Arg, D-Arg, or guanidino succinate induced only minor relaxations in rings with or without endothelium. In the presence of L-NAME, L-Arg (but not the D-enantiomer), induced concentration-dependent relaxations of rings with endothelium (relaxation to L-Arg 10(-3) M 52 +/- 13%), reflecting a reversal by L-Arg of the L-NAME-induced potentiation of the contraction to PE. In contrast to L-Arg, guanidino succinate was less effective in the presence than in the absence of L-NAME (relaxation to guanidino succinate 10(-3) M before L-NAME 37 +/- 8% and after L-NAME 14 +/- 3%).(ABSTRACT TRUNCATED AT 250 WORDS)

Inhibition of a Tumour Protease with 3,4-Dichloroisocoumarin, Pentamidine-Isethionate and Guanidino Derivatives

Guanidinobenzoatase (GB) is a cell surface proteolytic enzyme capable of degrading fibronectin, and is associated with tumour cells and cells capable of migration. The location of active GB in sections has been demonstrated with 9-aminoacridine (9-AA), a competitive inhibitor of GB. 3,4-Dichloroisocoumarin (3,4-DCI) and pentamidine isethionate (PI) are inhibitors of trypsin-like enzymes. It has now been demonstrated that 3,4-DCI, PI, and guanidino derivative compounds are significant inhibitors of GB, on the surfaces of lung squamous cell carcinoma cells in frozen sections and free GB in solution. Dexamethasone acetate (DMA) and medroxy-progesterone (MP) did not show any significant inhibition of GB activity. These molecules lack a reactive chloride or guanidino groups and are thought to react at the nuclear level, rather than directly on this cell surface protease. Kinetic studies have shown that 3,4-DCI, PI and guanidino derivatives are reversible competitive inhibitors of GB, as determined in vitro on the purified enzyme. The inhibition resulting with 3,4-DCI was a time-dependent process. It is suggested that these inhibitors interact with GB by binding to its active site, resulting in the formation of enzyme-inhibiter complexes (GB-I). The GB-I complexes can be dissociated with SDS treatment, resulting in the regain of GB activity.

Synthesis and activity of butirosin derivatives with 5''-amidino and 5''-guanidino substituents.

The preparation and antibacterial activity of the 5''-guanidino (6) and 5''-amidino (7) derivatives of 4'-deoxybutirosin A (1) as well as the 5''-guanidino derivative (8) of butirosin A are described. The key intermediates, tetra-N-benzyloxycarbonyl-5''-azido derivatives were selectively reduced with NiCl2-NaBH4 to give the corresponding 5'-amino derivatives. Subsequent guanidination or amidination followed by deblocking afforded the final compounds 6, 7 and 8. The 5''-guanidino derivatives (6 and 8) were more active against Gram-positive and Gram-negative bacteria than the corresponding 5''-hydroxy derivatives (1 and butirosin A). Compound 6 was also active against a variety of methicillin-resistant Staphylococcus aureus (MRSA).

Synthesis and activity profiles of new dermorphin-(1-4) peptide analogues.

A new series of 12 dermorphin tetrapeptides, W-Tyr-D-MetO-Phe-Xaa-Y (W = H, H2NC = (NH); Xaa = Gly, Sar, D-Ala; Y = OH, OCH3, NH2) were prepared by traditional methods in solution and tested for opioid activity. In binding studies based on displacement of mu, delta, and kappa opioid receptor selective radiolabels from guinea pig brain membranes, the new analogues showed a negligible affinity for the kappa binding site and a preference for mu- over delta-receptors with an evident dependence on N- and/or C-terminal modifications; H-Tyr-D-MetO-Phe-Gly-OCH3 was shown to be one of the most selective mu-receptor ligands reported to date. All these tetrapeptides display dose-related naloxone-reversible antinociceptive effects following intracerebroventricular (icv) or subcutaneous (sc) administrations in mice. In comparison to morphine, H-Tyr-D-MetO-Phe-Sar-NH2 and the guanidino derivative H2NC = (NH)-Tyr-D-MetO-Phe-Gly-NH2 showed lower affinity for mu, delta, and kappa sites but exceptionally stronger analgesia: respectively they are 560 and 1550 times as potent an analgesic as morphine. Among analogues tested after sc administration, H-Tyr-D-MetO-Phe-Sar-NH2 and H-Tyr-D-MetO-Phe-D-Ala-OH displayed the highest activities; they were respectively 22 and 30 times more potent than morphine on a molar basis. These results indicate that N- or C-terminal modifications and substitution at position 2 or 4 of dermorphin-(1-4) peptide do not only influence the affinity of the resulting analogues to opioid receptors but also may favorably alter their pharmacokinetic properties.

The design of fluorescent probes which bind to the active centre of guanidinobenzoatase. Application to the location of cells possessing this enzyme.

Cells possessing a known enzymic activity may be located by fluorescent probes designed to act as competitive inhibitors of this enzyme. We have prepared a series of dansyl N-substituted guanidino derivatives which bind to the active centre of guanidinobenzoatase. 9-Aminoacridine also acts as a competitive inhibitor and behaves similarly to these guanidino derivatives. These fluorescent probes have been used to locate tumour cells possessing this enzyme in thin sections of fixed tissue by employing fluorescent microscopy.

Chemical modification of canavanine with p-nitrophenylglyoxal. Factors influencing the chemistry and reactivity of alpha-dicarbonyl-guanidino reactions.

The role of structural features and deprotonation of guanidino derivatives on chemical reactions with p-nitrophenylglyoxal has been investigated. Canavanine, an arginine analog, reacts to form a yellow product, which absorbs maximally at 350 nm (epsilon = 6500) and at 278 nm (epsilon = 14 500). Elemental analysis, fast atom bombardment mass spectral analysis, n.m.r. and i.r. studies suggest that the product is a 5-(p-nitrophenyl)4-oxo-2 imidazoline derivative of canalaline. Kinetic studies show that the second order rate constant for the reaction increases with increasing pH in the range of pH 7-11.0. It is concluded that the pH dependence of the reaction can be explained by general base catalysis and not simply by a deprotonation of the guanidinoxy side chain. The reaction of arginine, polyarginine, and other derivatives differs markedly from that of canavanine. The results suggest that change in the tautomeric equilibria between the imino and amino forms of the guanidino group may partly account for differences in reaction of canavanine and arginine and the reactions of specific arginyl residues in proteins.