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Publications - Bioorganic Chemistry

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Publications

Cacace, S.; Schröder, G.; Wehinger, E.; Strack, D.; Schmidt, J.; Schröder, J.; A flavonol O-methyltransferase from Catharanthus roseus performing two sequential methylations Phytochemistry 62, 127-137, (2003) DOI: 10.1016/S0031-9422(02)00483-1

Protein extracts from dark-grown cell suspension cultures of Catharanthus roseus (Madagascar periwinkle) contained several O-methyltransferase (OMT) activities, including the 16-hydroxytabersonine O-methyltransferase (16HT-OMT) in indole alkaloid biosynthesis. This enzyme was enriched through several purification steps, including affinity chromatography on adenosine agarose. SDS-PAGE of the purified protein preparation revealed a protein band at the size expected for plant OMTs (38–43 kDa). Mass spectrometry indicated two dominant protein species of similar mass in this band, and sequences of tryptic peptides showed similarities to known OMTs. Homology-based RT-PCR identified cDNAs for four new OMTs. Two of these cDNAs (CrOMT2 and CrOMT4) encoded the proteins dominant in the preparation enriched for 16HT-OMT. The proteins were closely related (73% identity), but both shared only 48-53% identity with the closest relatives found in the public databases. The enzyme functions were investigated with purified recombinant proteins after cDNA expression in Escherichia coli. Unexpectedly, both proteins had no detectable 16HT-OMT activity, and CrOMT4 was inactive with all substrates investigated. CrOMT2 was identified as a flavonoid OMT that was expressed in dark-grown cell cultures and copurified with 16HT-OMT. It represented a new type of OMT that performs two sequential methylations at the 3′- and 5′-positions of the B-ring in myricetin (flavonol) and dihydromyricetin (dihydroflavonol). The resulting methylation pattern is characteristic for C. roseus flavonol glycosides and anthocyanins, and it is proposed that CrOMT2 is involved in their biosynthesis.Purification and molecular characterization of an unusual flavonoid O-dimethyltransferase that explains the 3′,5′-methylation in flavonols and anthocyanins of Madagascar periwinkle.
Publications

Braga, A. L.; Rubim, R. M.; Schrekker, H. S.; Wessjohann, L. A.; de Bolster, M. W.; Zeni, G.; Sehnem, J. A.; The facile synthesis of chiral oxazoline catalysts for the diethylzinc addition to aldehydes Tetrahedron: Asymmetry 14, 3291-3295, (2003) DOI: 10.1016/j.tetasy.2003.08.029

A range of chiral 4-(1′-hydroxyalkyl)oxazoline catalysts can be obtained in a straightforward two step synthesis, starting from β-hydroxy amino acids like l-serine or l-threonine. Catalyst 4c forms a complex with diethylzinc, effective for the enantioselective addition to aldehydes resulting in high yields and enantiomeric excesses up to >99% even with aliphatic aldehydes. In the latter case the enantiomeric excess showed a marked dependence of the aldehyde's chain length.
Publications

Black, S. L.; Jales, A. R.; Brandt, W.; Lewis, J. W.; Husbands, S. M.; The Role of the Side Chain in Determining Relative δ- and κ-Affinity in C5‘-Substituted Analogues of Naltrindole J. Med. Chem. 46, 314-317, (2003) DOI: 10.1021/jm020997b

The role of the side chain in 5‘-substituted analogues of naltrindole has been further explored with the synthesis of series of amides, amidines, and ureas. Amidines (8, 13) had greatest selectivity for the κ receptor, as predicted from consideration of the message-address concept. It was also found that an appropriately located carbonyl group, in ureas (10) and amides (7), led to retention of affinity and antagonist potency at the δ receptor.
Publications

Bethke, J.; Karaghiosoff, K.; Wessjohann, L. A.; Synthesis of N,N-disubstituted selenoamides by O/Se-exchange with selenium–Lawesson's reagent Tetrahedron Lett. 44, 6911-6913, (2003) DOI: 10.1016/S0040-4039(03)01690-3

The selenium analogue of Lawesson's reagent, [PhP(Se)(μ-Se)]2 is an effective reagent for synthesizing N,N-disubstituted selenoamides. The reaction is carried out under mild conditions (room temperature) and affords the selenoamide in higher yield than using other selenation reagents.The selenium analogue of Lawesson's reagent, [PhP(Se)(μ-Se)]2 is an effective reagent for synthesizing N,N-disubstituted selenoamides.
Publications

Anh, N. T. H.; Sung, T. V.; Wessjohann, L.; Some homoisoflavonoidal compounds from Ophiopogon Japonicus Ker-gawler Vietnam J. Chem. 41, 117-121, (2003)

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Publications

Anh, N. T. H.; Sung, T. V.; Franke, K.; Wessjohann, L. A.; Phytochemical studies of Rehmannia glutinosa rhizomes Pharmazie 58, 593-595, (2003)

2,4-Dimethoxy-2-methyl-6H-pyran-3-one (1), a hitherto unknown natural product, and the calcium salt of rehmapicroside (2) have been isolated from rhizomes of the Vietnamese variety of Rehmannia glutinosa Libosch together with a series of known compounds: norcarotenoids (3–5), 2-formyl-5-hydroxymethylfurane (6), the iridoid rehmaglutin D (7), iridoid glycosides (8–12) and phenylethyl alcohol glycosides (13–17). Their structures were determined by mass and NMR spectroscopy.
Publications

Anh, N. T. H.; Sung, T. V.; Porzel, A.; Franke, K.; Wessjohann, L. A.; Homoisoflavonoids from Ophiopogon japonicus Ker-Gawler Phytochemistry 62, 1153-1158, (2003) DOI: 10.1016/S0031-9422(02)00515-0

From the ethyl acetate extract of the tuberous roots of Ophiopogon japonicus (Liliaceae) eight known and five new homoisoflavonoidal compounds were isolated. The new compounds are 5,7-dihydroxy-8-methoxy-6-methyl-3-(2′-hydroxy-4′-methoxybenzyl)chroman-4-one (1), 7-hydroxy-5,8-dimethoxy-6-methyl-3-(2′-hydroxy-4′-methoxybenzyl)chroman-4-one (2), 5,7-dihydroxy-6,8-dimethyl-3-(4′-hydroxy-3′-methoxybenzyl)chroman-4-one (3), 2,5,7-trihydroxy-6,8-dimethyl-3-(3′,4′-methylenedioxybenzyl)chroman-4-one (4) and 2,5,7-trihydroxy-6,8-dimethyl-3-(4′-methoxybenzyl)chroman-4-one (5). Their structures have been elucidated by mass and NMR spectroscopy. Compounds 4 and 5 are the first isolated homoisoflavonoids with a hemiacetal function at position 2.Five new and eight known homoisoflavonoids were isolated from the tuberous roots of the medicinal plant Ophiopogon japonicus (Liliaceae) and identified by spectroscopic data.
Publications

Richter, W. G.; Cappi, M. W.; Henkel, B.; Hess, S.; Surivet, J. P.; Baeschlin, D.; Hubschwerlen, C.; Höfle, G.; Wessjohann, L. A.; Eichelberger, U.; Second generation epothilones and their biological properties Clin. Cancer Res. 9, 6137, (2003)

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Publications

Raith, K.; Neubert, R.; Poeaknapo, C.; Boettcher, C.; Zenk, M. H.; Schmidt, J.; Electrospray tandem mass spectrometric investigations of morphinans J. Am. Soc. Mass Spectrom. 14, 1262-1269, (2003) DOI: 10.1016/S1044-0305(03)00539-7

In this study positive ESI tandem mass spectra of the [M+H]+ ions of morphinan alkaloids obtained using an ion trap MS were compared with those from a triple quadrupole MS. This allows to assess the differences of the tandem-in-time versus the tandem-in-space principle, often hampering the development of ESI MS/MS libraries. Fragmentation pathways and possible fragment ion structures were discussed. In order to obtain elemental composition, accurate mass measurements were performed. According to the MS/MS fragmentation pathway, the investigated compounds can be grouped into 4 subsets: (1) morphine and codeine, (2) morphinone, codeinone, and neopinone, (3) thebaine and oripavine, (4) salutaridine and salutaridinol. Salutaridinol-7-O-acetate shows a different fragmentation behavior because of the favored loss of acetic acid. Although most fragment ions occur in both ion trap and triple quad tandem mass spectra, some are exclusively seen in either type. For triple quad, quadrupole time-of-flight and FT-ICR MS/MS, the base peak of morphine results from an ion at m/z 165 that contains neither nitrogen nor oxygen. This ion is not found in ion trap MS/MS, but in subsequential MS3 and MS4.
Publications

Ounaroon, A.; Decker, G.; Schmidt, J.; Lottspeich, F.; Kutchan, T. M.; (R,S)-Reticuline 7-O-methyltransferase and (R,S)-norcoclaurine 6-O-methyltransferase of Papaver somniferum-cDNA cloning and characterization of methyl transfer enzymes of alkaloid biosynthesis in opium poppy Plant J. 36, 808-819, (2003) DOI: 10.1046/j.1365-313X.2003.01928.x

S‐Adenosyl‐l ‐methionine:(R,S )‐reticuline 7‐O‐methyltransferase converts reticuline to laudanine in tetrahydrobenzylisoquinoline biosynthesis in the opium poppy Papaver somniferum . This enzyme activity has not yet been detected in plants. A proteomic analysis of P. somniferum latex identified a gel spot that contained a protein(s) whose partial amino acid sequences were homologous to those of plant O‐methyltransferases. cDNA was amplified from P. somniferum RNA by reverse transcription PCR using primers based on these internal amino acid sequences. Recombinant protein was then expressed in Spodoptera frugiperda Sf9 cells in a baculovirus expression vector. Steady‐state kinetic measurements with one heterologously expressed enzyme and mass spectrometric analysis of the enzymatic products suggested that this unusual enzyme is capable of carrying through sequential O‐methylations on the isoquinoline and on the benzyl moiety of several substrates. The tetrahydrobenzylisoquinolines (R )‐reticuline (4.2 sec−1 mm −1), (S )‐reticuline (4.5 sec−1 mm −1), (R )‐protosinomenine (1.7 sec−1 mm −1), and (R,S )‐isoorientaline (1.4 sec−1 mm −1) as well as guaiacol (5.9 sec−1 mm −1) and isovanillic acid (1.2 sec−1 mm −1) are O‐methylated by the enzyme with the ratio k cat/K  m shown in parentheses. A P. somniferum cDNA encoding (R,S )‐norcoclaurine 6‐O‐methyltransferase was similarly isolated and characterized. This enzyme was less permissive, methylating only (R,S )‐norcoclaurine (7.4 sec−1 mm −1), (R )‐norprotosinomenine (4.1 sec−1 mm −1), (S )‐norprotosinomenine (4.0 sec−1 mm −1) and (R,S )‐isoorientaline (1.0 sec−1 mm −1). A phylogenetic comparison of the amino acid sequences of these O‐methyltransferases to those from 28 other plant species suggests that these enzymes group more closely to isoquinoline biosynthetic O‐methyltransferases from Coptis japonica than to those from Thalictrum tuberosum that can O‐methylate both alkaloid and phenylpropanoid substrates.
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