The discovery,synthesis and antimalarial evaluation of natural product-based polyamine alkaloids

Bioassay-guided fractionation of an antimalarial extract derived from the fungus Ramaria subaurantiaca afforded the known polyamine alkaloid, pistillarin. Nine pistillarin analogues were synthesised via EDC-mediated chemistry and these compounds along with the previously reported natural product polyamines, ianthelliformisamines A–C and spermatinamine, were evaluated against Plasmodium falciparum (3D7) parasites and a normal human cell line to determine parasite-specific activity. Spermatinamine (IC₅₀ 0.23 μM) and pistillarin (IC₅₀ 1.9 μM) were the two most potent antimalarials identified during these studies.     

Total synthesis of the natural isoprenylcysteine carboxyl methyltransferase inhibitor spermatinamine

The first total synthesis of spermatinamine, an inhibitor of isoprenylcysteine carboxyl methyltransferase (Icmt) with a bromotyrosine-spermine-bromotyrosine dimeric structure is described.     

An improved total synthesis of spermatinamine, an inhibitor of isoprenylcysteine carboxy methyltransferase

An improved total synthesis of spermatinamine, an inhibitor of the anticancer target, isoprenylcysteine carboxy methyltransferase (Icmt) was accomplished from the commercially available 3,4-dibromo-4-hydroxybenzaldehyde via a high yielding reaction sequence in an overall yield of 31%.     

Pseudoceramines A-D, new antibacterial bromotyrosine alkaloids from the marine sponge Pseudoceratina sp

Bioassay-guided fractionation of the CH(2)Cl(2)/MeOH extract of the Australian marine sponge Pseudoceratina sp. resulted in the purification of four new bromotyrosine alkaloids, pseudoceramines A-D (1-4), along with a known natural product, spermatinamine (5). The structures of 1-5 were determined by spectroscopic methods. Pseudoceramines A (1) and B (2) feature a rare bromotyrosyl-spermine-bromotyrosyl sequence, and pseudoceramine C (3) is the first example of bromotyrosine coupled with an N-methyl derivative of spermidine. Compounds 1-5 were screened for inhibition of toxin secretion by the type III secretion (T3S) pathway in Yersinia pseudotuberculosis. Compounds 2 and 5 inhibited secretion of the Yersinia outer protein YopE (IC(50) = 19 and 6 μM, respectively) and the enzyme activity of YopH (IC(50) = 33 and 6 μM, respectively).     

Synthesis and reactivity of new chelate-N-heterocyclic biscarbene complexes of ruthenium

The carbene-ligand precursors methylenebis(N-alkylimidazolium) iodide (alkyl = methyl, neo-pentyl) and ethylenebis(N-methylimidazolium) chloride have been used in the preparation of several new Ru(II)-p-cymene complexes where the ligand behaves as mono- and bidentate. The molecular structures of the two biscarbene-complexes are reported. From the data reported, we can conclude that steric reasons (mainly the bisimidazolium linkers, methylene/ethylene) are the main factors determining both reactivity and synthetic difficulties of the products reported.     

An optical study of phase transitions of poly (ethylene terephthalate-co-p-hydroxybenzoic acid) liquid crystal

The copolyester containing 40 mol % ethylene terephthalate (PET) and 60 mol % p-hydroxybenzoate (HB) units has been reported by several investigators to be biphasic in the solid and the liquid states. The reported thermal transitions in the two phases, however, are in part contradictory, perhaps partly due to different polymerization conditions. The present work is a study of the transitions in each of the two phases of this copolyester by polarized light microscopy and by light transmission measurements. By light transmission measurements, the two phases were found to have two different glass transition temperatures for the onset of segmental motion, consistent with two assignable temperatures (T.). Cold crystallization and melting in each of the two different phases was also detected. The results help clarify the nature of transitions and agree with the results of dynamic mechanical analysis on the same thermotropic liquid crystalline copolyester.     

Positive Allosteric Control of Guests Encapsulation by Metal Binding to Covalent Porphyrin Cages

The allosteric control of the receptor properties of two flexible covalent cages is reported. These receptors consist of two zinc(II) porphyrins connected by four linkers of two different sizes, each incorporating two 1,2,3-triazolyl ligands. Silver(I) ions act as effectors, responsible for an on/off encapsulation mechanism of neutral guest molecules. Binding silver(I) ions to the triazoles opens the cages and triggers the coordination of pyrazine or the encapsulation of N,N′-dibutyl-1,4,5,8-naphthalene diimide. The X-ray structure of the silver(I)-complexed receptor with short connectors is reported, revealing the hollow structure with a cavity well-defined by two eclipsed porphyrins. Rather unexpectedly, the crystallographic structure of this receptor with pyrazine as a guest molecule showed that the cavity is occupied by two pyrazines, each binding to the zinc(II) porphyrin in a monotopic fashion.     

Synthesis and structure of cuboctahedral and anticuboctahedral cages containing 12 quadruply bonded dimolybdenum units

The syntheses and structures of two clusters containing 12 Mo-Mo quadruple bonds, [Mo(24)(C(12)H(12)O(4))(24)](C(5)H(5)N)(12) and Mo(24)(C(8)H(4)O(4))(24), are reported. The 12 paddlewheel building blocks and 24 ligands self-assemble into cuboctahedral and anticuboctahedral polyhedra, respectively, depending on the manner in which the two halves of the cluster are aligned. These clusters contain twice as many dimolybdenum units as any previously reported cluster. Possible assembly mechanisms are also proposed.     

The synthesis of possible hydroxylated metabolites of 2-chlorophenothiazine derivatives

The synthesis of 7-hydroxy, 8-hydroxy and 7,8-dihydroxy prochlorperazines (3a) and per-phenazines (3b) is reported. The parent ehlorophenothiazines were prepared analogously to previously reported chlorpromazine (3e) metabolite syntheses. The prochlorperazine side chain was introduced in one step using 1-(3-chloropropyl)-4-methylpiperazine and the perphenazine side chain in two steps, first reaction with 1-bromo-3-chloropropane followed by reaction with 1-piperazineethanol. The methoxymethyleneoxy O-proteetive groups were removed under mild conditions using methanolic hydrogen chloride. The preparations of 7-hydroxydesmethylprochlorperazine and 7-hydroxychlorpromazine quaternary methyl iodide are also reported.     

Purification, subunit structure and inhibitor profile of cathepsin A.

Cathepsin A (EC 3.4.16.1), a lysosomal carboxypeptidase, has been purified 1374-fold from pig kidney. Purification steps included concanavalin A-Sepharose and phenyl-Sepharose chromatography and chromatofocusing. The specific activity (16.9 U/mg) of the purified enzyme was significantly higher than previously reported values. The enzyme preparation appeared homogeneous when analyzed by non-denaturing polyacrylamide gel electrophoresis and was free of detectable protease contamination. The molecular mass (M(r) = 97,000), isoelectric point (5.0), and sensitivity to inhibitors were consistent with reported properties of cathepsin A. However, the previously reported three-peptide chain structure was not observed. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis in the presence or absence of 2-mercaptoethanol demonstrated that the enzyme is composed of two M(r) 47,000 subunits, each of which dissociate in the presence of 2-mercaptoethanol into two polypeptide chains of 19,000 and 31,000.     

The reaction of methyl propiolate with 2-aminopyridines

The structure (III) reported by Lappin (2) for the diadducts formed by the reaction of methyl propiolate with 2-aminopyridines has been found to be incorrect. The correct structure (IV) has been proven by spectral studies and cyclisation to compound VII. In two cases new compounds having structures of the type (III) have been isolated. N.M.R. data are reported for all products.     

Formation constants for the complexes of levulinate and acetate with manganese(II), cobalt(II), nickel(II), copper(II), zinc(II) and hydrogen ions

Formation constants are reported for the levulinate complexes of manganese(II), cobalt(II), nickel(II), copper(II) and zinc(II) at 25 degrees in 0.1M chloride medium. In addition, results are presented for the corresponding acetate complexes for comparison. Protonation constants for the two ligands are also reported.     

Janus droplets: liquid marbles coated with dielectric/semiconductor particles

The manufacturing of water droplets wrapped with two different powders, carbon black (semiconductor) and polytetrafluoroethylene (dielectric), is presented. Droplets composed of two hemispheres (Janus droplets) characterized by various physical and chemical properties are reported first. Watermelon-like striped liquid marbles are reported. Janus droplets remained stable on solid and liquid supports and could be activated with an electric field.     

Synthesis of Diethylaminoethyl Carboxylic Esters

Dialkylaminoethyl carboxylic esters (1-5) with two biologically active moieties, carboxylic acid and dialkylaminoethanol were previously reported to show some biological activity in the presence of the coordinated effect of the two parts.     

Bisporphyrins with bischlorin features obtained by direct anodic coupling of porphyrins

The proximity of two or more porphyrin or chlorin-like structures has been shown to be crucial in numerous biological processes, such as electron transfers. The one-pot electrochemical synthesis of a dimeric tetraphenylporphyrin with one 1,2-(diphenylphosphonium)benzene as a spacer and of its porphyrin-monomer precursor are reported. These new compounds have been characterized by (1)H and (31)P NMR, ESR, and UV-visible spectroscopy and microanalysis. Electrochemical data are reported, and the redox behavior is analyzed for the monomers and the dimers. Important interactions between the two chromophores and a phosphonium-phosphonium interaction have been observed. UV-visible and (1)H NMR data along with electrochemical behavior suggest that the positive charge carried by the two phosphonium units is in part delocalized onto the pi system of the porphyrins, this gives an unexpected bis-porphyrin with bischlorin spectroscopic features.     

Synthesis of New Xanthones,I

Condensation of salicylic acid and C-methylphloroglucinol gave the already known 1,3-dihydroxy-2-methylxanthone ( 1 ) along with two new compounds: 1,3-dihydroxy-4-methylxanthone ( 2 ) and a second one tentatively presented as being 1,3-dihydroxy-2-methyl-4-(2-hydroxybenzoyl)xanthone ( 3 ). The UV., IR., NMR, and mass spectra for the two first compounds are reported and their structures discussed on the basis of δ-values for H(2), H(4), CH₃(4) and CH₃(2). The UV. and IR. spectra for the third compound are reported too.     

Dissociation constants of some organic acids

Dissociation constants of di(nonylphenyl)dithiophosphoric acid, di(nonylphenyl)phosphoric acid and 9-phenyltetracosansulphuric acid, determined by two methods, are reported.     

Practical preparation of 3,3-difluoropyrrolidine

A practical and cost-effective synthesis of 3,3-difluoropyrrolidine is reported. The synthesis involves the isolation of two intermediates, which are prepared via two efficient through processes: (1) a Claisen rearrangement followed by a Ru(VIII)-catalyzed oxidation to prepare the 2,2-difluorosuccinic acid and (2) an efficient cyclization to form N-benzyl-3,3-difluoropyrrolidinone followed by BH(3).Me(2)S reduction.     

Design and synthesis of a new binucleating ligand via cobalt-promoted C-N bond fusion reaction. Ligand isolation and its coordination to nickel,palladium, and platinum

A new polydentate bridging ligand, NH(4)C(5)N=NC(6)H(4)N(H)C(5)H(4)N (HL(2)), is synthesized by the cobalt-mediated phenyl ring amination of coordinated NH(4)C(5)N=NC(6)H(5). The green cobalt complex intermediate [Co(L(2))(2)](ClO(4)), [1](ClO(4)), and the free ligand HL(2) were isolated and characterized. The X-ray structure of [H(2)L(2)](ClO(4)) is reported. The ligand, upon deprotonation, behaves as a bridging ligand. It reacts with NiCl(2).6H(2)O and Na(2)[PdCl(4)] to produce dimetallic complexes, [Ni(2)Cl(2)(L(2))(2)], 2, and [Pd(2)(L(2))(2)](ClO(4))(2), [3](ClO(4))(2), respectively. X-ray structures of these two dimetallic complexes are reported. The structure of the dinickel complex, in particular, is unique. In this complex, the two deprotonated secondary amine nitrogens of the two [L(2)](-) ligands bind to two nickel centers simultaneously forming a planar Ni(2)N(2) arrangement. The complex [3](ClO(4))(2) is diamagnetic while the complex 2 is paramagnetic. The results of magnetic measurements on the dinickel complex in the temperature range 1.8-300 K are reported. The system can be described as a single spin S = 2 in the low-temperature range T < J/k whereas at high temperatures, T > J/k, it behaves as two independent spins S = 1.The reaction of [L(2)](-) with K(2)[PtCl(4)], however, yielded a monometallic platinum complex, [PtCl(3)(L(2))], 5, where the pyridyl nitrogen of the aminopyridyl function remained unused. The X-ray structure of the complex 4a is reported. The bond lengths along the ligand backbones in all the complexes indicate extensive pi-delocalization. Spectral data of the complexes are reported and compared.     

The Preparation of Dicompartmental Multifunctional Group Ligands

A convenient method for the preparation of the phenol-based ligands 1,6-bis(2-thiophenyl)-2,5-bis(2-hydroxy-3-hydroxymethyl-5-methylbenzyl)-2,5-diazahexane and 1,6-bis(5-methyl-2-thiophenyl)-2,5-bis(2-hydroxy-3-hydroxymethyl-5-methyl-benzyl)-2,5-diazahexane possessing two dissimilar compartments having multifunctional groups is reported. To synthesize these ligands, an equivalent of 1,6-bis(2-thiophene)-2,5-diazahexane or 1,6-bis(5-methyl-2-thiophene)-2,5-diazahexane and two equivalents of 2,2-dimethyl-6-methyl-8-(chloromethyl)benzo-1,3-dioxin were reacted in the presence of Na₂CO₃ in 1,4-dioxane, followed by acid hydrolysis of an acetonide-protecting group. Characterization data for the new compounds is reported.