James M. Riordan

Bleomycin interactions with DNA studies on the role of the C-terminal cationic group of bleomycin A2 in association with and degradation of DNA

The role of the cationic dimethylsulfonium group of bleomycin A2 in the binding of the drug to poly(dA-dT) has been investigated by proton NMR studies on the S-demethylated derivative. In contrast to the parent drug, the demethyl congener shows no intercalation of the aromatic bithiazole group which is adjacent to the former cationic group. However, chemical studies show that the demethyl derivative retains the capability to degrade DNA in the presence of iron(II), albeit at a reduced rate and to a lesser extent than the intact bleomycin A2. Thus, the cationic group is necessary for the intercalation of the bithiazole portion of the drug molecule; however, intercalation is not essential for the degradation of DNA.

Studies on Bleomycin-DNA and Bleomycin-Iron Interactions

The bleomycins, a group of antitumor antibiotics (Figure 1), cause the degradation of DNA by a process requiring iron(II) and dioxygen (1,2). DNA degradation appears to involve two steps: association of the drug with the nucleic acid and degradation of the DNA. As part of studies directed toward achieving an understanding of how the bleomycins degrade DNA, we have examined various properties of the drug using a variety of chemical and physico-chemical techniques, including NMR and Mössbauer spectroscopy. We have studied both the interaction of the antibiotic with its target (DNA) as well as its association with its metal ion cofactor. This work has been performed on the intact drug and its derivatives as well as on synthetic models of the parent drug. This paper reviews and updates the recent work from this laboratory on the bleomycins.

5-Keto-Mannose (D-Lyxo-Hexos-5-Ulose) in Aqueous Solution-Isomeric Composition Dominated by α/β D-Fructofuranose Related Structures

Abstract Selective C-6 hydroxyl triphenylmethylation of methyl 2,3-O-isopropylidene-α-D-mannofuranose (1), followed by C-5 hydroxyl oxidation and sequential removal of protecting groups in aqueous acid, yielded D-lyxo-hexos-5-ulose (5-keto-mannose, 5) as a mixture of isomeric forms. The isomeric mixture of 5 in D2O solution was carefully examined using 1H and 13C NMR techniques and structural assignments were made for seven isomers. The most prevalent form of 5 observed was the ketofuranose isomer 2S, 5R-D-lyxo-hexo-5,2-furanos-5-ulose 1-hydrate (5a, 52%), with its 2S, 5S-ketofuranose anomer (5b) being the next most abundant (14%). Also identified in the mixture were the α and β-hexofuranos-5-uloses 5c (6%) and 5d (< 2%), the pyranose structure 1R,5R-lyxo-hexopyranos-5-ulose 5e (10%), and the anhydro isomer 1R,5R-1,6-anhydro-D-lyxo-hexopyranos-5-ulose (5f, 5%), present in 1 C 4 conformation. Limited spectral information suggests that the remaining isomer 5g (8%) is a hydrated acyclic aldehyde form of 5.

The Isomeric Composition of 6-Deoxy-D-XYLO-Hexos-5-Ulose in Aqueous Solution as Determined by 1H and 13C NMR

Abstract Acid hydrolysis of 6-deoxy-1,2-O-isop ropylidene-α-d-xylo-hexo-furanos-5-ulose (4) yielded gummy 6-deoxy-d-xylo-hexos-5-ulose (1) as an isomeric mixture of two furanose forms, 6-deoxy-α-d-xylo-hexo-furanos-5-ulose and 6-deoxy-β-d-xylo-hexofuranos-5-ulose, and a pyranose structure 1R, 5R-6-deoxy-d-xylo-hexopyranos-5-ulose. The combined percentage (64%) of the furanoses represents an unusually large amount of free carbonyl form for a sugar when compared to simple hexoses and 2-hexuloses. Isomeric structures were determined in deuterium oxide solution by 1H and 13C NMR.

The Isomeric Composition of D-Xylo-hexos-5-ulose (5-Keto-glucose) in Aqueous Solution

Abstract 1,2-O-Isopropylidene-α-D-xylo-hexofuranos-5-ulose (2) was deprotected in aqueous acid solution to give a mixture of at least six isomeric forms and one anhydro form of the parent ketoaldohexose, D-xylo-hexos-5-ulose (3), commonly referred to as 5-keto-glucose. Structural assignment of each form was made based on high field 1H and 13C NMR studies of the mixture in aqueous (D2O) solution. The dominant isomeric form of 3 was observed to have the pyranose structure 1R,5R-D-xlyo-hexo-pyranos-5-ulose (3a, 67 %) with the next most abundant form being an anhydro structure, 1S,5S-l,6-anhydro-D-xylo-hexopyranos-5-ulose (3c, 18 %). Included among the other isomers were the a and β-1,4-furanose (3d, 3e) and 1-aldehydrol β-5,2-furanose (3f) structures. The isomer present in least amount (3g, > 1 %) is assigned as the α-anomer of 3f. Experimentally determined JC-1,H-1 values were useful in support of assigned isomer structures.

Regiospecific Dehydration of Some Branched Cycloses and Cyclitols Derived From Activated 2,6-Heptodiulose Derivatives

Abstract The stereoselective base catalyzed conversion of tri-0-acetyl-l,7-dichloro-l,7-dideoxy-xylo-2,6-heptodiulose to d l-(2,3,4,6/5)-4,5,6-tri-0-acetyl-2-chloro-3-C-(chloromethyl)-3,4,5,6-tetrahydroxy-cyclohexanone has been described,1 and it has also been shown that branched cyclose formation from the corresponding 1,7-dibromo and 1,7-diazido-2,6-heptodiuloses also occurs in the same stereoselective manner.1 Reduction of the cyclose ketone function followed by appropriate deprotective leads to branched epi-inositols.1,2 The general structure of the starting 2,6-heptodiulose, and the product cyclose and cyclitol are given as I, II and III respectively.

Branched-chain halo- and animo-cyclitols: synthesis and an x-ray crystallographic study ☆

Abstract The base-catalyzed cyclizations of tri- O -acetyl-1,7-dibromo-1,7-dideoxy- xylo -2,6-heptodiulose ( 2 ), tri- O -acetyl-1,7-dichloro-1,7-dideoxy- xylo -2,6-heptodiulose ( 3 ), and tri- O -acetyl-1,7-di- C -azido-1,7-dideoxy- xylo -2,6-heptodiulose ( 4 ), to dL -4,5,6-tri- O -acetyl-2- C -bromo-3-C-(bromomethyl)- 2 , 3 , 4 , 6 / 5 -tetrahydroxycyclohexanone ( 5 ), dL -4,5,6-tri- O -acetyl-2-chloro-3- C -(chloromethyl)- 2 , 3 , 4 , 6 / 5 -tetrahydroxycyclohexanone ( 6 ), and dL -4,5,6-tri- O -acetyl-2- C -azido-3- C -(azidomethyl)- 2 , 3 , 4 , 6 / 5 -tetrahydroxycyclohexanone ( 7 ), respectively, are described. Reduction of the acetylated cycloses 5–7 by sodium borohydride proceeded with considerable stereoselectivity in producing branched epi -inositols, isolated as the tetraacetates 12 , 13 , and 18 . These latter compounds were used to prepare the corresponding unprotected cyclitols 24 , 25 , and 31 , and the branched amino- epi -inositols 27 , 29 , 30 , and 32 . The stereochemistry of the branched-chain cyclitols described appears to be the same as that of dL -1,4,5,6-tetra- O -acetyl-3-chloro-2- C -(chloromethyl)- epi -inositol ( 13 ), whose structure was confirmed by an X-ray crystallographic study.

Unsaturated, Branched, Six-Membered Carbocycles from 2,6-Diuloses

Abstract Mild treatment of 3,4,5-tri-O-acetyl-1,7-dibromo-1,7-dideoxyxylo-2,6-heptodiulose (2) with acetate ion in several solvents produced unsaturated, branched, six-membered carbocyclic compounds. 4S(R),5R(S),6R(S)-6-acetoxy-4-bromomethyl-4,5-epoxy-6-ethoxy-2-cyclohexenone (3) was the predominant cyclization product in ethanol solution, and the 6-methoxy analog (4) was the major product in methanol solution. Cyclization of 2, in acetone cleanly produced the cross-conjugated ketone 4S(R)-2-acetoxy-3-bromo-4-bromomethyl-4-hydroxy-2,5-cyclohexadien-1-one (5), and cyclization of the 1,7-dichloro analog of 2, compound 9, gave the corresponding dichlorocyclohexadien-1-one 11. Compound 8, the 4-O-acetyl derivative of 5, and 2,3,4,6-tetraacetoxybenzyl acetate (7) were derived from 2 in an acetic anhydride—potassium acetate mixture while the deoxycyclose D,L-(3,4,6/5)-4,5,6-tri-O-acetyl-3-C(iodomethyl)-3,4,5,6-tetrahydroxycyclohexanone (12) was the reductive cyclization product from treatment of an acetone solu...

INTRAMOLECULAR ALDOL CONDENSATIONS OF DELTA-DICARBONYL SUGARS - A NOVEL APPROACH TO THE SYNTHESES OF CYCLOSES

SUMMARY: The research described here focuses on the chemistry of some simple sugars referred to as “delta-dicarbonyl sugars”. We have synthesized a number of these compounds and investigated their potential use as progenitors of the six-membered carbocyclic ring system as it is found in cycloses and cyclitols. The work was initiated some ten years ago at the National Institutes of Health, in the laboratory of the late Hewitt G. Fletcher, Jr., and it is to his memory that we dedicate this paper.