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A new approach for the synthesis of moenomycin trisaccharide analogues is reported in which three monosaccharide building blocks are used and allows the introduction of different substituents at the 6-position of unit E (Scheme 2). Furthermore, a new procedure for the introduction and manipulation of unit F is described (Scheme 3).

An approach for the synthesis of moenomycin A12 C-glycoside partial structures is reported.

Moenomycin has been highly selectively converted into amino derivative 3b. The primary amino group of this compound can be used to attach various fluorescent labels to moenomycin, through conversion of isothiocyanates into thioureas and squaric acid diesters into diamides. The application of some of the derivatives is outlined. (© Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)

Nuclease-resistant moenomycin-binding aptamers with dissociation constants in the range of 300 to 400 nM have been selected. Competition experiments have demonstrated that these aptamers recognize a disaccharide analogue of moenomycin. The results offer the opportunity of setting up a selective and sensitive assay for identifying moenomycin biosynthetic precursors.

Feeding experiments ( 13C and 15N-labeled precursors) shed light on the biosynthetic origin of the chromophore (unit A of 1), the N-acetyl groups, the 4-C-methyl group of the moenuronamide unit (part F of 1), the sugar units, and the lipid part (unit I of 1) of the antibiotic moenomycin A(1). The lipid part is completely isoprenoid and is constructed via the non-mevalonate pathway. The central C 10 part originates from a precursor like geranyl or linalyl diphosphate and is formed by a route involving ring formation between C-2 and C-6 of the monoterpene unit, two successive rearrangements to give a 7-membered ring intermediate and cleavage of the ring between C-5 and C-11 (moenocinol numbering).

Feeding experiments shed light on the biosynthetic origin of the chromopphore unit, the N-acetyl groups, the 4-C-methyl group of the moenuronamide unit, and the lipid part of moenomycin A. © 1997 Elsevier Science Ltd. All rights reserved.

A selective reaction at unit A of the antibiotic moenomycin A ( 1 ) has been developed: Reaction of 1 with o -nitrobenzenediazonium chloride cleanly yielded 12 . This compound is as active as moenomycin against Staph. aureus SG 511 and as an in-vitro transglycosylase inhibitor.

On reaction with singlet oxygen 1 provided a mixture of 2 and 3 which could not be separated. In-vivo , 2/3 were antibiotically of low activity whereas in the in-vitro assays at least one of the compounds inhibited the transglycosylase effectively.

The correct configuration at C-1 of the uronamide carrying the phosphate group is essential for antibiotic activity.

Isolation and structure elucidation of a new moenomycin antibiotic (C1, 1e) that lacks the branching methyl group in the 4-position of unit F are reported. The smallest antibiotically active degradation product of 1e is the trisaccharide derivative 3. This observation is in contrast to structure activity relations in the moenomycin A series where it was found that disaccharide 4a is fully active.

Isolation, structural assignment, and antibiotic efficiency of the new moenomycin antibiotics C3 (1b) and C4 (1c) is decribed. The previously published structure of pholipomycin (1d) is modified.

Compound 10c which is the galacturonamide analogue of 2, the smallest degradation product of moenomycin A (1) with full antibiotic activity, has been synthesized. 10c is devoid of antibiotic activity.

A flexible approach to ecdysteroids, chain elongated at C-26 and C-27, is reported. Key features are the addition of 5-lithio 2,3-dihydrofurans (3) to poststeron (10) and a stereoselective reduction of the 22-∞ group.

The effects of a new forskolin derivative, (13R)-spiroforskolin, on the ventricular cAMP-activated chloride current (I(Cl(cAMP))) and the atrial L-type calcium current (I(Ca,L)) were measured by means of whole-cell recording from isolated guinea-pig cardiac myocytes at 30 degrees C and 20-22 degrees C, respectively. In contrast to forskolin, the derivative contains a tetrahydrofuran rather than a tetrahydropyran moiety. (13R)-spiroforskolin activated I(Cl(CAMP)) in 58% of the ventricular myocytes studied. The concentration required for the half maximal effect (EC50 value) amounted to 9.6x10(-11) M and was lower than the EC50 value for forskolin (2.4x10(-8) M). (13R)-spiroforskolin evoked a smaller maximal I(Cl(cAMP)) amplitude than forskolin. The rundown of the (13R)-spiroforskolin-activated I(Cl(cAMP)) was faster than that of the forskolin-induced current. Neither forskolin nor (13R)-spiroforskolin in maximally effective concentrations increased I(Cl(cAMP)) in cells containing high concentrations of cAMP. Furthermore, as an activator of atrial I(Ca,L) (13R)-spiroforskolin displayed a smaller activation and a lower EC50 value (5.8x10(-10) M) than forskolin (EC50 value: 3.7x10(-7) M). The effect of (13R)-spiroforskolin was observed in only 30% of the atrial cells studied. None of the drugs exerted a stimulatory effect in atrial cells containing a high [cAMP]. The washout of the drug effect was significantly faster in (13R)-spiroforskolin- than in forskolin-treated atrial myocytes. We conclude that (13R)-spiroforskolin as a forskolin derivative displays unique characteristics. It is a more potent but less efficacious activator of cardiac ionic conductances than the parent compound. The results suggest that (13R)-spiroforskolin, like forskolin, most probably exerts its effects via stimulation of the adenylyl cyclase.

A new procedure for the conversion of deoxycholic acid (14) to bufadienolide (27) is reported.

1) Two high-yield procedures for the conversion of 1 to 4 are reported. 2) 11 was degraded to 34 in good overall yield via 17, 20, 26, 31, 29, and 30. Similarly, 34 was obtained from 12 and 13.

From the mannitol derivatives 8 and 37 both enantiomeric series of optically active glycerol derivatives are easily available as exemplified by the synthesis of known precursors of PAF (6) and ent-6.

Die Konfigurationsbestimmung der aus den Steroidketonen 1, 6 und 10 hergestellten diastereomeren 2,2-Dialkyl-1,3-oxathiolane gelang mit einer neuen und allgemeinen CD-Sektorregel. — Oxathiolane dieses Types sind bei erhohter Temperatur gegenuber Lithiumtetrahydridoaluminat in Dioxan nicht stabil. Als Zersetzungsprodukte wurden die entsprechenden Alkohole, Ethen und S2- identifiziert. Steroidal 1,3-Oxathioianes; Determination of Configuration by a New General CD Sector Rule, and Their Reduction with Lithium Tetrahydridoaluminate The configuration of the diasteriomeric 2,2-dialkyl-1,3-oxathiolanes prepared from the steroid ketones 1, 6, and 10 was determined using a new and general CD sector rule. — Oxathiolanes of this type are decomposed by lithium tetrahydridoaluminate in dioxane at elevated temperatures. The corresponding alcohols, ethene, and S2- have been identified as decomposition products.

Two routes for the conversion of 5α-cholest-7-ene-3β-ol (11) into 7, which has the typical ecdysteroid substitution pattern in rings B, C, and D, have been developed. Making use of one of the methods, 5,6-dihydroergosterol (31) was converted into the 38, possessing all the functionalities required for the synthesis of naturally occurring ecdysteroids.

The C 25 compound moenocinol ( 1 ) is synthesized starting from 7 , geranyl chloride, and Moiseenkov's C 5 unit.

1 was degraded to 24 in good overall yield via 7 , 10 , 16 , 21 , 19 and 20 ; similarly, 24 was obtained from 2 and 3 .

A stepwise degradation of the oligosaccharide part of moenomycin A (2) was performed. The degradation products were assayed for antibiotic activity both in vivo and in an E.coli cell-free system. Units E, F, G, H, and I haue been found to be essential for full biological ( in vitro ) activity. It is suggested that 2 is a competitive inhibitor of the peptidoglycan polymerase.