David E. Jackson

LIGNANS OF FORSYTHIA INTERMEDIA

Abstract Leaf and stem material of Forsythia intermedia contains four main lignans and their O -glucosides. These were identified as the dibenzylbutyrolactone derivatives (−)-arctigenin, arctiin [(−)-arctigenin 4′- O -glucoside], matairesinol and (−)-matairesinol 4′- O -glucoside, together with the furofuran lignans (+)-phillygenin, phillyrin [(+)-phillygenin 4- O -glucoside], (+)-epipinoresinol and (+)-epipinoresinol 4′- O -glucoside. The lignan contents varied according to tissue type and season. Full spectral data for the lignans are presented. The 1 H NOE difference spectra recorded for phillygenin and epipinoresinol necessitate the reversal of earlier chemical shift assignments for axial and equatorial protons on C-9 of furofuran lignans having one axial and one equatorial aryl group (the epi series).

Aryltetralin lignans from Podophyllum hexandrum and Podophyllum peltatum

Abstract Roots of Podophyllum hexandrum and P. peltatum contain the same range of ten aryltetralin lignans: podophyllotoxin, 4′-demethylpodophyllotoxin, α-peltatin, β-peltatin, desoxypodophyllotoxin, podophyllotoxone, isopicropodophyllone, 4′-demethyldesoxypodophyllotoxin, 4′-demethylpodophyllotoxone and 4′-demethylisopicropodophyllone, although the relative proportions are markedly different. The latter two compounds are previously unreported natural products, but 4′-demethylisopicropodophyllone may well be an artefact resulting from epimerization of 4′-demethylpodophyllotoxone. The peltatins have not previously been isolated from P. hexandrum .

Blind reconstruction of scanning probe image data

Scanning probe microscopy has proven to be an invaluable tool for the investigation of surface topography; however, the finite geometry of the imaging tip can often distort image data and complicate metrological investigations of surface features. Here, the derivation of a computational procedure for the estimation of the geometry of the scanning probe from the topographic image data alone is presented. The properties of the tip function extracted from such data permit an assessment of the sample‐related information content of an image. The technique is demonstrated by its application to simulated scanning probe microscopy image data, where its performance can be assessed, and by its application to experimental image data obtained from the scanning force microscope.

Matairesinol as precursor of Podophyllum lignans

Abstract The dibenzylbutyrolactone lignan (−)-[14C]matairesinol was efficiently incorporated into the aryltetralin lactone lignans podophyllotoxin, 4′-demethylpodophyllotoxin, β-peltatin, α-peltatin and 4′-demethyldesoxypodophyllotoxin in one or more of the plant systems Podophyllum hexandrum root, P. peltatum leaf or Diphylleia cymosa leaf. This demonstrates matairesinol to be a common precursor of the 3′,4′,5′-trimethoxy and 4′-hydroxy-3′,5′-dimethoxy groups of Podophyllum lignans, and it may represent the branch-point compound to the two series of compounds. No incorporation of matairesinol into the arylnaphthalene lactone lignan diphyllin in D. cymosa was detected.

Tumour-inhibitory aryltetralin lignans from Podophyllum pleianthum

Abstract Roots of Podophyllum pleianthum contain eight aryltetralin lignans: podophyllotoxin, desoxypodophyllotoxin, podophyllotoxone, isopicropodophyllone and the four corresponding 4′-demethyl derivatives. The lignan pattern is very similar to that of P. hexandrum. A useful TLC spray reagent for Podophyllum lignans is described.

Biosynthesis of Podophyllum lignans. II: Interconversions of aryltetralin lignans in Podophyllum hexandrum

Abstract Feeding experiments in Podophyllum hexandrum plants with labelled aryltetralin lignans have established much of the biosynthetic interrelationships existing amongst Podophyllum lignans. Thus, desoxypodophyllotoxin is converted into podophyllotoxin, which in turn is oxidized to podophyllotoxone, although this latter step appears to be reversible. A similar sequence is proposed for the corresponding 4′-demethyl derivatives. Although 4′-demethyldesoxy-podophyllotoxin is readily converted into 4′-demethylpodophyllotoxin, neither compound is incorporated into lignans of the 4′-methyl series such as podophyllotoxin. The Podophyllum lignans may be subdivided biogenctically into two groups, those with 3,4,5-trimethoxy substitution in the pendent aryl ring, and those with a 4-hydroxy-3,5-dimethoxy substituted pendent ring, although these probably arise from a common precursor. A biogenetic scheme interrelating all of the known Podophyllum aryltetralin lignans is proposed.

COSMIC(90): An improved molecular mechanics treatment of hydrocarbons and conjugated systems

SummaryFour modifications to the COSMIC molecular mechanics force field are described, which greatly increase both its versatility and the accuracy of calculated conformational energies. The Hill non-bonded van der Waals potential function has been replaced by a two-parameter Morse curve and a new H-H potential, similar to that in MM3, incorporated. Hydrocarbon energies in particular are much improved.A simple iterative Hückel pi-electron molecular orbital calculation allows modelling of conjugated systems. Calculated bond lengths and rotational barriers for a series of conjugated hydrocarbons and nitrogen heterocycles are shown to be as accurate as those determined by the MM2 SCF method.Explicit hydrogen-bonding potentials for H-bond acceptor-donor atom pairs have been included to give better hydrogen bond energies and lengths. The van der Waals radii of protonic hydrogens are reduced to 0.5 Å and the energy well depth is increased to 1.0 kcal mol-1.Two new general atom types, N+sp2 and O-sp3, have been introduced which allow a wide variety of charged conjugated systems to be studied. A minimum of parameterisation is required, as the new types are easily included in the Hückel scheme which automatically adjusts bond and torsional parameters according to the defined bond-order relationships.

Biosynthesis of podophyllum lignans—i. cinnamic acid precursors of podophyllotoxin in podophyllum hexandrum

Abstract Feeding experiments in Podophyllum hexandrum plants have established that phenylalanine, cinnamic acid and ferulic acid are good precursors of the two major aryltetralin lignans podophyllotoxin and 4′-demethylpodophyllotoxin. Sinapic and 3,4,5-trimethoxycinnamic acids were poorly utilized, showing that the substitution pattern of the pendent aryl ring is built up after coupling of the two phenylpropane units. Degradation studies on podophyllotoxin derived from [3-O 14 CH 3 ] ferulic acid show that the two halves of the lignan molecule are equally labelled supporting a biosynthetic sequence involving oxidative coupling of two similar phenylpropane precursors having the substitution pattern of ferulic acid. Although 3,4-methylenedioxycinnamic acid was readily incorporated, degradative studies prove that this compound is not incorporated intact, but via a metabolic sequence in which the methylenedioxy carbon atom enters the C 1 -pool and then labels the methylenedioxy and methoxyl substituents of podophyllotoxin. The rest of the skeleton is incorporated via ferulic acid, presumably by way of caffeic acid.

Cytotoxic lignans from Podophyllum, and the nomenclature of aryltetralin lignans

Abstract Roots of Podophyllum hexandrum and P. peltatum both contain (1 R ,2 R ,3 R )-desoxypodophyllotoxin [(1α,2α,3β)- desoxypodophyllotoxin] and the previously unreported (1 R ,2 R ,3 R )-podophyllotoxone [(1α,2α,3α)-podophyllotoxone]. Thermal isomerization of (loc,2ct,3fl)-podophyllotoxone readily occurs to yield (1α,2α,3α)-podophyllotoxone (isopicropodophyllone) with traces of (1α,2β,3β)-podophyllotoxone (picropodophyllone). Small amounts of (1α,2α,3α)-podophyllotoxone were also present in dried roots of P. hexandrum and P. peltatum . A more systematic nomenclature for podophyllotoxin derivatives and other aryltetralin lignans using α,β conventions is proposed.

Biosynthesis of lignans in Forsythia intermedia.

Abstract Feeding experiments with young shoots of Forsythia intermedia have shown that phenylalanine and ferulic acid are good precursors of the dibenzylbutyrolactone lignan arctigenin and the furofuran lignans phillygenin and epipinoresinol. Although matairesinol was incorporated into arctigenin, and epipinoresinol into phillygenin, in accord with late methylation steps in the biosynthetic pathway, some incorporation of label from one lignan class into the other was observed, particularly from epipinoresinol into arctigenin. This may indicate a high degree of catabolic activity followed by non-specific incorporation. [2′-14C,1′-3H]Coniferyl alcohol was incorporated into all three lignans with a significant increase in the 1H: 14C isotopic ratio. This supports the hypothesis that the lignans arise by oxidative coupling of two coniferyl alcohol units, rather than from two ferulic acid or coniferaldehyde units. The observed increase in isotopic ratio probably results from a primary isotope effect in the reversible oxidation-reduction reactions interrelating cinnamic acids and cinnamyl alcohols. A similar increase in isotopic ratio was measured during biosynthesis of the aryltetralin lactone lignan podophyllotoxin in Podophyllum hexandrum.