Resolution of 7-chloro-4(4′-diethylamino-1′methylbutyl)aminoquinoline (chloroquine) into its enantiomers

Evidence is accumulating that 7-chloro-4-[4-diethylamino-1-methylbutyl] amino quinoline (chloroquine) displays considerable stereoselectivity in its metabolism, pharmacokinetics, macromolecular interactions, and biological activity. The availability of the enantiomers has been hampered by the failure of direct methods of resolution. We now describe a successful resolution in which the atropisomeric 1,1′-binaphthyl-2,2′-diyl hydrogen phosphate is used in a 1:1 ratio to form stereoselectively the 2:1 diastereomeric salt from one enantiomer of the base, leaving the other in solution. By this means both enantiomers of chloroquine may be readily isolated. © 1993 Wiley-Liss, Inc.     

Structure of β,D(1–>4′)-xylan hydrate

A structure is proposed for xylan hydrate as a result of investigations by x-ray fiber diffraction and computer-aided chain-packing methods. The unit-cell dimensions are a = b = 9.16 Å, c (fiber axis) = 14.85Å, γ = 120° and the proposed anti-parallel chain arrangement corresponds to a space group symmetry of P3₂21. Left-handed threefold screw helices are stabilized in this conformation by their interaction with chains of water molecules, so that a satisfactory hydrogen-bonding scheme is achieved. The proposed structure provides an explanation of the changes in the x-ray diagram with relative humidity and yields a very good structure factors agreement. An x-ray fiber diagram corresponding to a higher hydrate (xylan dihydrate) is presented. Comments are made on the possible role of xylan in nature and in technological processes.     

The absolute configuration of the enantiomers of 6-chloro-9-(4′-diethylamino-1′-methylbutyl)-amino-2-methoxyacridine (quinacrine)

Absolute configurations have been assigned to the enantiomers of the antimalarial drug quinacrine dihydrochloride. Condensation of (?)-(R)-4-amino-1-diethylaminopentane (from L -glutamic acid) with 6,9-dichloro-2-methoxyacridine gave (?)-(R)-6-chloro-9-(4′-diethylamino-1′-methylbutyl) amino-2-methoxyacridine [(?)-(R)-quinacrine] while (+)?(S)-quinacrine was obtained from the enantiomeric diamine.     

Uranyl nitrate complexes of some Schiff bases of 4-aminoantipyrine and certain carbonyl compounds

A series of nine complexes of uranyl nitrate with some Schiff bases derived from 4-aminoantipyrine and certain carbonyl compounds, such as benzaldehyde, 2-nitrobenzaldehyde, 3-nitrobenzaldehyde, 4- methylbenzaldehyde, 4-N,N-dimethylaminobenzaldehyde, 2-hydroxybenzaldehyde, 2-hydroxy-1-naphthaldehyde, acetylacetone and benzoylacetone have been synthesized. These complexes have been characterized by elemental analysis, molecular weight determination and IR spectral, conductance and magnetic studies. From these studies they can be formulated as [UO₂L₂(NO₃)₂], in which the first five ligands (in the order given above) and nitrate ions are coordinated bidentately, while the last four ligands (which have either a phenolic hydroxyl group or a side-chain carbonyl group as an additional site) act as terdentate ligands, and nitrate ions are coordinated monodentately. Hence the proposed general formula for the complexes suggests that the uranyl ion has a coordination number of eight in addition to the two oxygen atoms which have already been bonded to the U(VI) species.     

C4′ sugar oxidation of deoxyribonucleotide triphosphates by chromium(V) complexes

The Cr(V) complexes, bis(2-ethyl-2-hydroxybutyrato)oxochromate(V) ([OCr^V(ehba)₂]⁻) and (2,2-bis(hydroxymethyl)-2-(bis(2-hydroxyethyl)amino)ethanolato)oxochromate(V) ([OCr^V(BT)]²⁻), were reacted with a series of deoxyribonucleotide triphosphates. Oxidation of deoxyribose at C4′ was observed by measuring the amount of thiobarbituric acid reactive species (TBARS) produced in these reactions. For both compounds, the TBARS obtained with purine nucleotides was between 2.25 and 3.5 times greater than what was observed with pyrimidine nucleotide. This result suggests that the identity of the nucleic acid base can influence the hydrogen atom abstraction at C4′. Overall, the amount of product obtained with [OCr^V(BT)]²⁻ was significantly less than what was observed with [OCr^V(ehba)₂]⁻, indicating that these two Cr(V) model complexes may oxidize DNA differently.     

Synthesis and serotonin receptor binding properties of 5-substituted 3-(1′,2′,5′,6′-tetrahydropyridin-3′-yl) indoles

A semi-rigid 5-hydroxytryptamine (5-HT) analogue, RU28253 [5-methoxy-3-(1′,2′,5′,6′-tetrahydropyridin-3′-yl) indole], is a potent 5-HT₁ and 5-HT₂ agonist. It is isomeric to RU24969 [5-methoxy-3-(1′,2′,5′,6′-tetrahydropyridin-4′-yl) indole], a conformationally restricted 5-HT homologue, which has been extensively used in the study and classification of 5-HT receptors. A series of RU28253 derivatives with diverse substituents on indole 5-position were synthesized and their dissociation constants determined at the 5-HT₁ and 5-HT₂ receptors.     

(1′R,2′S,5′R)-Menthyl-(5R)-acetoxy-1,3-oxathiolan-(2R)-carboxylate: Synthesis and isomeric purity determination by HPLC

Chemoselective reduction of one isomer of the 1-menthylester of 1,3-oxathiolan-5-one-2-carboxylic acid produces a mixture of four lactol diastereomers from which the title compound was isolated after acylation. The isomeric purity and absolute stereochemistry were determined by spectroscopic methods, chiral HPLC techniques, and conversion to (?)-2′-deoxy-3′-thiacytidine (Lamivudine, 3TC^TM). © 1994 Wiley-Liss, Inc.     

Syntheses and molecular structures of ruthenium(II) complexes of the atropisomeric ligands 1,1′-biphenyl-2,2′-diamine and 3,3′-diamino-2,2′-bipyridine

The unique ligands of [Ru(bipy)₂(bpda)](PF₆)₂ (1, BPDA=1,1′-biphenyl-2,2′-diamine) and [Ru(bipy)₂(dabipy)](PF₆)₂ (2, DABIPY=3,3′-diamino-2,2′-bipyridine) are atropisomeric (exhibit hindered rotation about the sigma bonds that connect the two aromatic groups), so the complexes are diasteromeric with conformation isomers possible for the atropisomeric ligands and configurational isomers possible at the metal centers. Only one diastereomer is observed in the solid-state in both cases. The seven- (1) and five-membered (2) chelate ring of dabipy and bpda (the ligand is bound through its pyridyl groups) ligands are δ when the configuration at the metal is Δ. No evidence for atropisomerization is found in solution. For 1, we conclude bpda binds stereospecifically; however, the atropisomerization barrier of dabipy may be sufficiently low for 2 to preclude the observation of diastereomers by low-temperature NMR spectroscopy.     

Synthesis and evaluation of 4′-5′-dehydro-5′-fluoroaristeromycins as S-adenosyl-L-homocysteine (AdoHcy) hydrolase inhibitors

4′,5′-Dehydro-5′-fluoro analogs of aristeromycin were synthesized and shown to be potent inhibitors of recombinant rat liver AdoHcy hydrolase.     

Carbocyclic phosphonate analogs of 2′,3′-dideoxyadenosine-5′-monophosphate as substrates of 5-phosphoribosyl-1-pyrophosphate (PRPP) synthetate

Several carbocyclic phosphonate analogs of 2′,3′-dideoxyadenosine-5′-monophosphate (ddAMP) were pyrophosphorylated by E. coli 5-phosphoribosyl-1-pyrophosphate (PRPP) synthetase in the presence of PRPP. Structure-activity relationships are discussed.     

Differentiation of a human monocyte-like cell line by (2′–5′) oligoisoadenylate

Treatment of a human monocyte-like cell line (U-937) by (2'-5')ApApA, the 5' dephosphorylated product of (2'-5')oligo-isoadenylate [oligo(A)] synthetase, an interferon-induced enzyme, was able to induce differentiation, mimicking the effect of interferon treatment. Treatment of U-937 cells with (2'-5')ApApA resulted in morphologic changes, new (monocyte-associated) membrane antigen expression, and acquisition of the capacity to mediate antibody-dependent cellular cytotoxicity (ADCC). (2'-5')ApA and (3'-5')ApApA were without effect. A myeloid cell line (HL-60) which differentiates in response to other agents, but not to alpha-interferon, was not able to differentiate in response to (2'-5')ApApA, despite the ability of interferon to induce (2'-5')oligo (A) synthetase.     

Lanthanide perchlorate complexes of 4-chloroquinoline-1-oxide and 5-chloroisoquinoline-2-oxide

New lanthanide complexes of 4-chloroquinoline-1-oxide (CQNO) and 5-chloroisoquinoline-2-oxide (CIQNO) were synthesized. CQNO gave two sets of complexes, one set soluble in acetone with the formulae [Ln(CQNO)₈](ClO₄)₃, where LnNd to Yb, and [La(CQNO)₁₀](ClO₄)₃, and the other insoluble in acetone with the formulae [Ln(CQNO)₇]- (ClO₄)₃ where LnLa, Nd and Gd only. CIQNO gave complexes of the general composition [Ln-(CIQNO)₈](ClO₄)₃ where Ln La and Nd and [Ln(CIQNO)₇](ClO₄)₃ where LnGd to Yb. The isolated complexes CQNO and CIQNO were characterized by elemental analysis, electrolytic conductance, infrared, proton NMR and electronic spectral data.     

Chiral carbocylic nucleosides: The synthesis and antiviral activity of 4′-hydroxy and 4′-fluorocarbocyclic - 2′- deoxyguanosines

The chiral carbocyclic nucleosides 2 and 3 were prepared from aristeromycin. The 4′-hydroxy compound 2 displays good antiviral activity against HSV-1 and HSV-2 with low toxicity.     

Rapid synthesis of 2′,3′-dideoxy-3′β-fluoro-pyrimidine nucleosides from 2′-deoxypyrimidine nucleosides

A rapid synthesis of 2′,3′-dideoxy-3′-fluoro-β-d-threo-nucleosides bearing the pyrimidine canonical bases of nucleic acids has been developed in order to discover new nucleoside derivatives as potential antiviral drugs. However, when evaluated for their antiviral activity in cell culture experiments, none of these compounds showed any significant antiviral activity.     

Self-assembly of dideoxyguanosine (3′,3′) and (5′,5′)-monophosphates

The title compounds show a pronounced cation-directed ability to self-assemble in water and to gives columnar structures similar to four-stranded helices; for compound (5′→5′)-d(GpG), this leads to the formation of cholesteric and hexagonal liquid crystalline phases. Both phases are columnar and the cholesteric phase is left-handed. This behaviour is a further confirmation of the tendency of guanine derivatives to self-assemble to give stacked columnar structures whenever not impossible for structural reasons. The CD spectra of the aggregates in isotropic solutions are dominated by a negative exciton couplet centred around 250 nm associated to a left-handed columnar chirality. The shapes of the profiles, in the 220–300-nm region, for (5′→5′)-d(GpG) (in water or in saline solutions) and for (3′→3′)-d(GpG) (in KCl solution) are quasi-mirror images of those of poly(G) and (3′→5′)-d(GpG). The appearance of relatively intense CD signals around 280–300 nm in solution of (3′→3′)-d(GpG) in the presence of NaCl resembles that of (3′→5′)-d(GpG) in the presence of Rb⁺ or Na⁺. In the compounds investigated in this work, which present two equivalent ends, one observes the two CD features that have been associated, in the current literature, with the signature of four-stranded parallel and antiparallel structures: hence the origin of these CD bands cannot be found in the polarity of the strands. Self-assembly is favoured by the addition of extra salt and the stabilising effect of K⁺ is greater than that of Na⁺, in the case of (3′→3′)-d(GpG), an assembled species could be detected by CD only in the presence of extra salt. Chirality 10:734–741, 1998. © 1998 Wiley-Liss, Inc.     

1H-nmr studies on the dinucleoside monophosphates containing 2′-halogeno-2′-deoxypurinenucleosides: Effects of 2′-substitutes on conformation

Seven dinucleoside monophosphates containing 2′-halogeno-2′-deoxypurine nucleoside residue, dAfl-U, dAcl-U, dAbr-U, dAio-U, dGfl-U, and dIfl-C, were chemically synthesized and investigated by ¹H-nmr spectroscopy at 300 MHz. The sugar and backbone conformations of these compounds were analyzed by the spectral pattern of furanose proton resonances; and the extents of base-base interaction were estimated from chemical shifts and their temperature-dependent changes of base-proton resonances. It is found that the population of C_3′-endo conformer and the extent of base-base interaction decrease as the electronegativity of 2′-substituent decreases in dAx-U (x = fl, cl, br, and io) series. The C_3′-endo (³E) population and the base-base interaction in Nfl-U (N = A,G)-type dimers as well as dIfl-C are relatively higher than the corresponding natural ribo-dimers but can be recognized as grossly similar to the conformation of regular RNA dimers.     

Configurational statistics of polysaccharide chains. Part III. Linear β-(1 → 4′) xylan and mannan

The characteristic ratio C_N = 〈r²〉₀/Nl_v² of the β-D (1 → 4′)-linked polysaccharides xylan and mannan has been computed as a function of the angle τ at the bridge oxygen atom and the degree of polymerization N. The calculated values of the characteristic ratio C_N are very high relative to their free rotational dimensions. The characteristic ratio of these polysaecharides converges to the asymptotic value at low degree of polymerization at higher τ values. The low values of the calculated characteristic ratio of xylan compared to cellulose and mannan for the same τ value indicate that the former is more flexible and assumes a compact configuration. A pronounced difference in the values of the characteristic ratio C_N of cellulose and mannan has also been observed lower τ angles (<120°). On the other hand, nearly the same values of C_N have been obtained at higher τ angles (120°–125°), which suggests that, cellulose and mannan may have similar configuralons in certain solvents.