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The synthesis of new analogues of Arcyriaflavin A in which one indole ring is replaced by an aryl or heteroaryl ring is described. These new series of aryl[a]pyrrolo[3,4-c]carbazoles were evaluated as inhibitors of Cyclin D1-CDK4. A potent and selective D1-CDK4 inhibitor, 7a (D1-CDK4 IC(50)=45 nM), has been identified. The potency, selectivity profile against other kinases, and structure-activity relationship (SAR) trends of this class of compounds are discussed.

It was found that rhodosaminylanthraclinone-type anthracyclines are readily N-mono-demethylated upon irradiation with visible light, leading to 3′-N-methyl-α-L-daunosarninylanthracyclinones in good yields. The reaction is preferentially observed with rhodosaminylanthracyclinones in which OH-4′ of the sugar (rhodosamine) moiety is not further glycosylated. 3′-N-methyl-α-L-daunosaminyl anthracyclinones provide key compounds that can readily be further derivatized.

6-[4-Amidinobenzoyl]amino]-tetralone-2-acetic acid is a potent antagonist of GPIIb-IIIa. Substitution in the meta position of the benzamidine, or replacement with a heteroaryl amidine was tolerated in this series. Use of an acyl-linked 4-alkyl piperidine as an arginine isostere also provided active compounds. Compounds from this series provided substantial systemic exposure in the rat following oral administration.

Disubstituted isoquinolones 2 and 3 have affinity for GPIIb-IIIa and represent leads for further structural evaluation. Structure-activity studies centered on the bicyclic beta-turn mimic contained in these molecules indicated that this moiety could accommodate a variety of modifications. Specifically, monocyclic, 6, 5-bicyclic, and 6,7-bicyclic structures provide compounds with affinity for GPIIb-IIIa. Within the 6,6-series, isoquinoline, tetralin, tetralone, and benzopyran nuclei yield potent antagonists that are specific for GPIIb-IIIa. Attachment of the arginine isostere (benzamidine) to the supporting nucleus can be accomplished with an ether or amide linkage, although the latter enhances activity. Several compounds in this series provided measurable blood levels after oral dosing. Conversion of the acid moiety in these molecules to an ester generally provided compounds which gave greater systemic exposure after oral administration. Absolute bioavailabilities in the rat for the ethyl ester prodrug derivatives of the tetralin, tetralone, and benzopyran analogues of 3 were 28%, 23%, and 24%, respectively.

In the presence of trimethylsilyltrifluoromethanesulfonate as Lewis acid catalyst, β-acetates reacted, as glycosyl donors and with neighboring-group participation, with secondary hydroxyl groups of saccharides having low reactivity to give β-glycosidically linked di- and oligo-saccharides in high yields. The protecting groups of both compounds of the reaction had to be stable under acid conditions. Thus, the reaction of 1,2,3,4,6-penta-O-acetyl-β- d -galactopyranose with methyl 2-azido-4,6-di-O-benzoyl-2-deoxy-β- d -galactopyranoside gave, in 83% yield, methyl 2-azido-2,6-di-O-benzoyl-2-deoxy-3-O-(2,3,4,6-tetra-O-acetyl-β- d -galactopyranosyl)-β- d -galactopyranoside which is a useful building unit. The glycosidic reactions under Lewis acid catalysis and Koenigs—Knorr conditions are compared. The efficiency of the Lewis acid-catalyzed procedure was demonstrated by the further synthesis of di- and tri-saccharides, such as lactosamine and chitobiose derivatives, whereby hydroxyl groups having low reactivity could be glycosylated in good yields.

The synthesis of the trisaccharides O-beta-D-galactopyranosyl-(1 to 3)-O-(2-acetamido-2-deoxy-alpha-D-galactopyranosyl)-(1 to 6)-D-galactopyranose (15) and O-beta-D-galactopyranosyl-(1 to 3)-O-(2-acetamido-2-deoxy-alpha-D-galactopyranosyl)-(1 to 6)-D-glucopyranose (27) is described and the synthesis of alpha-D-glycosides by reaction of 3,4,6-tri-O-acetyl-2-azido-2-deoxy-beta-D-galactopyranosyl chloride with highly reactive hydroxyl groups is discussed. The trisaccharide 27 was coupled with serum albumin by formation of an imine intermediate and reduced to an amine, to yield a synthetic T-antigen. A similar coupling of 15 was unsuccessful.

It was determined that β-rhodomycin-II (rhodomycin A) (1), β-rhodomycin-I (rhodomycin B, betaclamycin T) (2) and γ-rhodomycin-I (iremycin) (3) may regioselectively be acylated at OH-4′ of the sugar (rhodosamine) moiety(ies), using a two-phase (chloroform/water) solvent system and sodium bicarbonate as a base. This report exemplarily describes the synthesis of the corresponding p-methoxybenzoate esters of 1, 2, and 3, i. e. derivatives 4–7, and highlights the structure elucidation of isomers 5a and 5b.

In the presence of trimethylsilyl triflate, 1,2,3,4,6-penta-O-acetyl-β- d -galactopyranose reacted with benzyl 4-O-acetyl-2,6-di-O-benzyl-β- d -galactopyranoside to give benzyl 2,6-di-O-benzyl-3-O-β- d -galactopyranosyl-β- d -galactopyranoside further converted into the synthetic block 1,2,4,6-tetra-O-acetyl-3-O-(2,3,4,6-tetra-O-acetyl-β- d -galactopyranosyl)-β- d -galactopyranose. This, in the presence of a Lewis acid catalyst and with the corresponding glycosyl acceptors, gave 8-methoxycarbonyloctyl 3-O-β- d -galactopyranosyl-β- d -galactopyranoside and 8-methoxycarbonyloctyl O-β- d -galactopyranosyl-(1→3)-O-β- d -galactopyranosyl-(1→3)-2-acetamido-2-deoxy-α- d -galactopyranoside.

Eine Blocksynthese zu O-Glycopeptiden ist durch Umsetzung des Disaccharidhalogenides 10 mit L-Serin- oder L-Threonin-haltigen Peptid-Derivaten moglich. So ergibt die Umsetzung von 10 mit 8 stereoselektiv das L-Ser-L-Ser-Derivat 15, an das α-glycosidisch zwei Disaccharid-Reste geknupft sind. Diese Methode wird jedoch durch geringe Loslichkeiten von Peptid-Derivaten in Dichlormethan begrenzt. Universeller anwendbar ist eine stufenweise Synthese von O-Glycopeptiden, bei der selektiv entblockierte Derivate von Disaccharid-Aminosauren nach den Methoden der Peptidchemie verknupft werden. So ergibt die Reaktion von 25 mit 29 in Gegenwart von EEDQ das Glycopeptid 30. Als bestes Entacylierungs-Reagenz fur die Deblockierung der Saccharid-Einheiten im letzten Schritt hat sich Kaliumcyanid/Methanol/Ethanol bewahrt. Hiermit erfolgt auch Abspaltung der Benzoylgruppen ohne β-Eliminierung oder Racemisierung des Peptidteiles. Building Units of Oligosaccharides, LXVI. — Synthesis of O-Glycopeptide Blocks of Glycophorine A block synthesis to O-glycopeptides can be realized by reaction of the disaccharide halide 10 with either L-serine- or L-threonine-containing peptide derivatives. Thus, the reaction of 10 with 8 yields stereoselectively the L-Ser-L-Ser derivative 15 in which two disaccharide residues are α-glycosidically linked to the peptide. However, this method is limited by the low solubilities of peptide derivatives in dichloromethane. A more general procedure represents the step-by-step synthesis of O-glycopeptides in which selectively deblocked derivatives of disaccharide amino acids are combined by using the methods of peptide syntheses. An example is the reaction of 25 with 29 in the presence of EEDQ yielding the glycopeptide 30. The reagent potassium cyanide in methanol/ethanol proved to be the most suitable deacylation reagent for the deblocking of the saccharide units in the last step. The benzoyl groups can be removed without β-elimination or racemization of the peptide part.

A regioselective β-glycosidation of lactose derivatives unsubstituted at OH-3′ and -4′ is possible, depending on the catalyst system applied. With silver silicate or silver carbonate as catalyst under heterogeneous conditions, β-glycosidation occurred selectively at the less reactive OH-4′ group of the acceptor, whereas with trimethylsilyl triflate or soluble mercury salt as catalyst under homogeneous conditions, it occurred almost exclusively at the more reactive OH-3′ group. The reactivity of the glycosyl donor, acceptor, and catalyst had to be properly matched for successful regioselective coupling. In this way, the trisaccharide unit of asialo- GM2-ganglioside, O-(2-acetamido-2-deoxy-β- d -galactopyranosyl)-(1→4)-(β- d - galactopyranosyl)-(1→4)- d -glucopyranose, and the tetrasaccharide unit of asialo- GM1-ganglioside, O-(β- d -galactopyranosyl)-(1→3)-(2-acetamido-2-deoxy-β- d -galactopyranosyl)- (1→4)-(β- d -galactopyranosyl)-(1→4)-β- d -glucopyranose were synthesized. This new method constitutes a very useful approach in the field of ganglioside synthesis.

The development of a block of α- d -Gal(1→3)- d -GalNAc is described which allows a simultaneously selective α-glycosidic coupling of some units to the OH-groups of hydroxy amino acids containing peptides to 0-glycopeptides.

Under the conditions of in situ anomerisation, the 2-azido-4,6-di-O-benzoyl-2-deoxy-3-O-(2,3,4,6-tetra-O-acetyl-β- d -galactopyranosyl)-α- d -galactopyranosyl bromide reacted directly and with high selectivity with the reactive hydroxyl groups of l -serine and l -threonine derivatives to form α-glycosidically-linked products. Thus, the glycopeptides containing l -serine and l -threonine are more accessible. The disaccharide block could also be coupled with other reactive hydroxyl compounds to give compounds that contain the T-receptor.

The syntheses of 7-O-α-L-daunosaminyl-∊-isorhodomycinone (6) and 7-O-α-L-rhodosaminyl-∊-isorhodomycinone (7) are described. The glycosyl donors 1,4-di-O-p-nitrobenzoyl-3-N-trifluoroacetyl-α,β-L-daunosamine and 1,4-di-O-acetyl-α,β-L-rhodosamine have proven to be the most suitable for the glycosylation of ∊-isorhodomycinone (∊-iso RMN) (3), using the TMS triflate method. Deblocking (0.5 N NaOH) of the protected glycoside 4 led to the desired 7-O-glycosyl-∊-isorhodomycinones 5 and 6. The daunosaminyl glycoside 6 was methylated (CH2O, NaCNBH3) to provide the rhodosaminyl derivative 7. The photolytic demethylation of this product selectively provided the 7-O-(3′-N-methyl-α-L-daunosaminyl)-∊-isorhodomycinone (8).