The Structure of an Antibiotic Kanamycin

The antibiotic kanamycin was degraded with methanolic hydrogen chloride and was determined to be composed of three compounds: deoxystreptamine, 6-amino-6-deoxy-d-glucopyranose and 3-amino-3-deoxy-d-glucopyranose. From the chemical and physical data on the antibiotic and its fragments, kanamycin was shown to be O-α-6-amino-6-deoxy-d-glucopyranosyl-(1→4 or 6)-O-[α-3-amino-3-deoxy-d-glucopyranosyl-(1→6 or 4)]-1,3-diamino-1, 2, 3-trideoxy-myo-inositol.     

Synthesis of kanamycin A analogs containing a 6-amino-6-deoxyglycofuranose moiety

Three kanamycin A analogs containing 6-amino-6-deoxyglycofuranoses have been prepared as candidates for potential activity against resistant bacteria producing 6'-N-acetyltransferase. They are 4-O-(6-amino-3,5,6-trideoxy-alpha-D-, -beta-D-, and -beta-L-erythro -hexofuranosyl)-6-O-(3-amino-3-deoxy-alpha-D-glucopyranosyl)-2,5-dideoxy-5-epi-5-fluorostreptamine. Structure-activity relationships of these compounds are discussed.     

X-ray crystal structure of galabiose, O-alpha-D-galactopyranosyl-(1---4)-D-galactopyranose

O-alpha-D-Galactopyranosyl-(1---4)-D-galactopyranose, C12H22O11, Mr = 342.30, crystallises in the orthorhombic space group P2(1)2(1)2(1), and has alpha = 5.826(1), b = 13.904(3), c = 17.772(4) A, Z = 4, and Dx = 1.579 g.cm-3. Intensity data were collected with a CAD4 diffractometer. The structure was solved by direct methods and refined to R = 0.063 and Rw = 0.084 for 2758 independent reflections. The glycosidic linkage is of the type 1-axial-4-axial with torsion angles phi O-5' (O-5'-C-1'-O-1'-C-4) = 98.1(2) degrees, psi C-3 (C-3-C-4-O-1'-C-1') = -81.9(3) degrees, phi H (H-1'-C-1'-O-1'-C-4) = -18 degrees, and psi H (H-4-C-4-O-1'-C-1') = 35 degrees. The conformation is stabilised by an O-3 . . . O-5' intramolecular hydrogen-bond with length 2.787(3) A and O-3-H . . . O-5' = 162 degrees. The glycosidic linkage causes a folding of the molecule with an angle of 117 degrees between the least-square planes through the pyranosidic rings. The crystal investigated contained 56(1)% of alpha- and 44(1)% of beta-galabiose as well as approximately 70% of the gauche-trans and approximately 30% of the trans-gauche conformers about the exocyclic C-5'-C-6' and C-5-C-6 bonds. The crystal packing is governed by hydrogen bonding that engages all oxygen atoms except the intramolecular acceptor O-5' and the glycosidic O-1' oxygen atoms.     

Further probing of the substrate specificities and inhibition of enzymes involved at an early stage of glycosylphosphatidylinositol (GPI) biosynthesis

1-D-6-O-(2-amino-2-deoxy-alpha-D-glucopyranosyl)-1-O-hexadecyl-myo-inositol (14), 1-D-6-O-(2-amino-2-deoxy-alpha-D-glucopyranosyl)-myo-inositol 1-(octadecyl phosphate) (18), 1-D-6-O-(2-amino-2-deoxy-beta-D-glucopyranosyl)-myo-inositol 1-(1,2-di-O-hexadecanoyl-sn-glycerol 3-phosphate) (24), 1-D-6-O-(2-amino-2-deoxy-alpha-D-mannopyranosyl)-myo-inositol 1-(1,2-di-O-hexadecanoyl-sn-glycerol 3-phosphate) (30) and the corresponding 2-amino-2-deoxy-alpha-D-galactopyranosyl analogue 36 have been prepared and tested in cell-free assays as substrate analogues/inhibitors of alpha-(1 --> 4)-D-mannosyltransferases that are active early on in the glycosylphosphatidylinositol (GPI) biosynthetic pathways of Trypanosoma brucei and HeLa (human) cells. The corresponding N-acetyl derivatives of these compounds were similarly tested as candidate substrate analogues/inhibitors of the N-deacetylases present in both systems. Following on from an early study, 1-L-6-O-(2-amino-2-deoxy-alpha-D-glucopyranosyl)-2-O-methyl-myo-inositol 1-(1,2-di-O-hexadecanoyl-sn-glycerol 3-phosphate) (44) was prepared and tested as an inhibitor of the trypanosomal alpha-(1 --> 4)-D-mannosyltransferase. A brief summary of the biological evaluation of the various analogues is provided.     

Cloning,overexpression, and purification of aminoglycoside antibiotic 3-acetyltransferase-IIIb: conformational studies with bound substrates

Aminoglycoside 3-acetyltransferase-IIIb (AAC3), which acetylates N3 amine of aminoglycoside antibiotics, was cloned from P. Aeruginosa and purified from overexpressing E. coli BL21 (DE3) cells. Bound conformations of kanamycin A and ribostamycin, in the active site of the enzyme that modifies the essential N3B of aminoglycoside antibiotics, were determined by NMR spectroscopy. Experimentally determined interproton distances were used in a simulated annealing protocol to determine enzyme-bound conformations of both antibiotics. Two conformations, consistent with the NOE restraints, were determined for ribostamycin. The only difference between the two conformers was the orientation of the A ring with respect to the rest of the molecule. The average glycosidic dihedral angles were Phi(1A) = -22 degrees +/- 3 and Psi(1A) = -42 degrees +/- 1 (conformer 1) and Phi(1A) = -67 degrees +/- 0.7 and Phi(1A) = -59 degrees +/- 0.8 (conformer 2). Three conformers were determined for the enzyme-bound kanamycin A. Two conformers of kanamycin A were matched well with the two conformers of ribostamycin when the A and the B rings of the antibiotics were superimposed. Conformations of kanamycin A and ribostamycin were compared to those of other aminoglycosides that are bound to different enzymes and RNA. The results lend further support to our earlier hypothesis that the A and B rings of aminoglycosides adopt a conformation that is recognized not only by the aminoglycoside-modifying enzymes but also by RNA (Serpersu, E. H., Cox, J. R., Digiammarino, E. L., Mohler, M. L., Akal, A., Ekman, D. R., and Owston, M. (2000) Cell Biochem. Biophys. 33, 309-321). These results may be useful in designing new antibiotics to combat the antibiotic resistance against infectious diseases.     

The crystal structure of the alpha-cellobiose.2 NaI.2 H(2)O complex in the context of related structures and conformational analysis

The crystal structure of beta-D-glucopyranosyl-(1-->4)-alpha-D-glucopyranose (alpha-cellobiose) in a complex with water and NaI was determined with Mo K(alpha) radiation at 150 K to R=0.027. The space group is P2(1) and unit cell dimensions are a=9.0188, b=12.2536, c=10.9016 A, beta=97.162 degrees. There are no direct hydrogen bonds among cellobiose molecules, and the usual intramolecular hydrogen bond between O-3 and O-5' is replaced by a bridge involving Na+, O-3, O-5', and O-6'. Both Na+ have sixfold coordination. One I(-) accepts six donor hydroxyl groups and three C-H***I(-) hydrogen bonds. The other accepts three hydroxyls, one Na+, and five C-H***I(-) hydrogen bonds. Linkage torsion angles phi(O-5) and psi(C-5) are -73.6 and -105.3 degrees, respectively (phi(H)=47.1 degrees and psi(H)=14.6 degrees ), probably induced by the Na+ bridge. This conformation is in a separate cluster in phi,psi space from most similar linkages. Both C-6-O-H and C-6'-O-H are gg, while the C-6'-O-H groups from molecules not in the cluster have gt conformations. Hybrid molecular mechanics/quantum mechanics calculations show <1.2 kcal/mol strain for any of the small-molecule structures. Extrapolation of the NaI cellobiose geometry to a cellulose molecule gives a left-handed helix with 2.9 residues per turn. The energy map and small-molecule crystal structures imply that cellulose helices having 2.5 and 3.0 residues per turn are left-handed.     

Component volumes of unsaturated phosphatidylcholines in fluid bilayers: a densitometric study

The specific volumes of six 1,2-diacylphosphatidylcholines with monounsaturated acyl chains (diCn:1PC, n=14-24 is the even number of acyl chain carbons) in fluid bilayers in multilamellar vesicles dispersed in H(2)O were determined by the vibrating tube densitometry as a function of temperature. From the data obtained with diCn:1PC (n=14-22) vesicles in combination with the densitometric data from Tristram-Nagle et al. [Tristram-Nagle, S., Petrache, H.I., Nagle, J.F., 1998. Structure and interactions of fully hydrated dioleoylphosphatidylcholine bilayers. Biophys. J. 75, 917-925.] and Koenig and Gawrisch [Koenig, B.W., Gawrisch, K., 2005. Specific volumes of unsaturated phosphatidylcholines in the liquid crystalline lamellar phase. Biochim. Biophys. Acta 1715, 65-70.], the component volumes of phosphatidylcholines in fully hydrated fluid bilayers at 30 degrees C were obtained. The volume of the acyl chain CH and CH(2) group is V(CH)=22.30 A(3) and V(CH2) =A(3), respectively. The volume of the headgroup including the glyceryl and acyl carbonyls, V(H), and the ratio of acyl chain methyl and methylene group volumes, r=V(CH3):V(CH2) are linearly interdependent: V(H)=a-br, where a=434.41 A(3) and b=-55.36 A(3) at 30 degrees C. From the temperature dependencies of component volumes, their isobaric thermal expansivities (alpha(X)=V(X)(-1)(partial differential V(X)/ partial differential T) where X=CH(2), CH, or H were calculated: alpha(CH2)=118.4x10(-5)K(-1), alpha(CH)=71.0x10(-5)K(-1), alpha(H)=7.9x10(-5)K(-1) (for r=2) and alpha(H)=9.6x10(-5)K(-1) (for r=1.9). The specific volume of diC24:1PC changes at the main gel-fluid phase transition temperature, t(m)=26.7 degrees C, by 0.0621 ml/g, its specific volume is 0.9561 and 1.02634 ml/g at 20 and 30 degrees C, respectively, and its isobaric thermal expansivity alpha=68.7x10(-5) and 109.2x10(-5)K(-1) below and above t(m), respectively. The component volumes and thermal expansivities obtained can be used for the interpretation of X-ray and neutron scattering and diffraction experiments and for the guiding and testing molecular dynamics simulations of phosphatidylcholine bilayers in the fluid state.     

Dinuclear macrocyclic polyamine zinc(II) complexes: syntheses, characterization and their interaction with plasmid DNA

The syntheses, characteristics of dinuclear macrocyclic polyamine zinc complexes and their interaction with plasmid DNA are reported. The two cyclen (1,4,7,10-tetraazacyclododecane) moieties are bridged by rigid and flexible linkages. The crystal structures of Zn2C27H43N8O15Cl4 [5c.(ClO4)3.2H2O] and Zn2C30H43N10O13Cl3 [5e.(ClO4)3.H2O] have been determined. The complexes crystallize in the monoclinic space group C2/c and P2(1)/c with the following unit cell parameters: 5c.(ClO4)3.2H2O: a=32.568(4)A, b=14.8593(17)A, c=19.443(2)A, alpha=90.00 degrees , beta=119.435(4) degrees , gamma=90.00 degrees , Dc=1.551 mg/m3, FW=956.71, F(000)=3932; 5e.(ClO4)3.H2O: a=15.807(2)A, b=16.756(2)A, c=16.161(2)A, alpha=90.00 degrees , beta=97.062(4) degrees , gamma=90.00 degrees , Dc=1.546 mg/m3, FW=988.83, F(000)=2032. The distance between the two Zn(II) ions is about 4.0 A. The structures show that two zinc ions can synergistically interact with the substrate DNA. With this novel structural characteristics, the dinuclear macrocyclic polyamine Zn(II) complexes via the synergetic effect between the two zinc ions can catalyze the cleavage of plasmid DNA (pUC18) with unprecedented speed at physiological conditions.     

Basis for the equilibrium constant in the interconversion of l-lysine and l-beta-lysine by lysine 2,3-aminomutase

l-beta-lysine and beta-glutamate are produced by the actions of lysine 2,3-aminomutase and glutamate 2,3-aminomutase, respectively. The pK(a) values have been titrimetrically measured and are for l-beta-lysine: pK(1)=3.25 (carboxyl), pK(2)=9.30 (beta-aminium), and pK(3)=10.5 (epsilon-aminium). For beta-glutamate the values are pK(1)=3.13 (carboxyl), pK(2)=3.73 (carboxyl), and pK(3)=10.1 (beta-aminium). The equilibrium constants for reactions of 2,3-aminomutases favor the beta-isomers. The pH and temperature dependencies of K(eq) have been measured for the reaction of lysine 2,3-aminomutase to determine the basis for preferential formation of beta-lysine. The value of K(eq) (8.5 at 37 degrees C) is independent of pH between pH 6 and pH 11; ruling out differences in pK-values as the basis for the equilibrium constant. The K(eq)-value is temperature-dependent and ranges from 10.9 at 4 degrees C to 6.8 at 65 degrees C. The linear van't Hoff plot shows the reaction to be enthalpy-driven, with DeltaH degrees =-1.4 kcal mol(-1) and DeltaS degrees =-0.25 cal deg(-1) mol(-1). Exothermicity is attributed to the greater strength of the bond C(beta)-N(beta) in l-beta-lysine than C(alpha)-N(alpha) in l-lysine, and this should hold for other amino acids.     

Etoposide: a new approach to the synthesis of 4-O-(2-amino-2-deoxy-4,6-O-ethylidene-beta-D-glucopyranosyl)-4'-O- demethyl-4-epipodophyllotoxin

Synthesis of 3-O-acetyl-2-benzyloxycarbonylamino-2-deoxy-4,6-O-ethylidene- alpha-(7 alpha) and-beta-D-glucopyranose (7 beta) and their 3-O-chloroacetyl analogues (11 alpha and 11 beta) are described. Condensation (BF3-etherate, ethyl acetate, -20 degrees) of 7 alpha with 4'-O-benzyloxycarbonyl-4'-O-demethyl-4-epipodophyllotoxin (8) afforded mainly the beta-glycoside 9 beta (alpha, beta-ratio 1:9). Condensation of 11 alpha beta with 8 or the 4'-O-chloroacetyl analogue 13 gave mainly the 4-O-(2-benzyloxycarbonylamino-3-O-chloroacetyl-2-deoxy-4,6-O-ethyl idene-beta-D- glucopyranosyl)-epipodophyllotoxin 12 beta or 15 beta. Glycosidation of podophyllotoxin (14) with 11 alpha beta (during which the aglycon epimerized at C-4 under the action of BF3-etherate) afforded alpha- (16 alpha) and beta-glycoside (16 beta) in the ratio 1:5. Removal of the chloroacetyl groups from 12 beta, its alpha analogue 12 alpha, and 15 beta gave the 4-O-(2-benzyloxycarbonylamino-2-deoxy-4,6-O-ethylidene-alpha-(17 alpha) and -beta-D-glucopyranosyl)-4'-O-demethyl-epipodophyllotoxins (17 beta and 20 beta), respectively. Hydrogenolysis of the benzyloxycarbonyl groups then gave 4-O-(2-amino-2-deoxy-4,6-O-ethylidene-alpha- (18 alpha) and -beta-D-glucopyranosyl)-4'-O-demethyl-4-epipodophyllotoxin (18 beta). Reductive alkylation of 18 beta and 18 alpha afforded the 2"-deoxy-2"-dimethylamino-etoposide 3 and its alpha analogue 19 alpha.     

Study on synthesis, structure, and DNA-binding of lanthanide complexes with 2-carboxylbenzaldehyde thiosemicarbazone

2-Carboxylbenzaldehyde thiosemicarbazone (HL), and its three lanthanide (III) complexes, LnL(3) x 4H(2)O [Ln(III)=La, Sm, Eu], have been synthesized in water. The complexes were characterized by elemental analyses, molar conductivity and IR spectra. The crystal structure of [Sm(2)L(6)(CH(3)OH)(4)] x 7.5CH(3)OH x 0.5H(2)O obtained from methanol solution was determined by X-ray diffraction analysis, crystallized in the triclinic system, space group P-1, Z=1, a=12.217 (2)A, b=14.706 (2)A, c=15.035 (2)A, alpha=111.84(1) degrees , beta=103.47(1) degrees , gamma=104.24(1) degrees , R(1)=0.0290. It has symmetrical (mu-OCO)(2), (mu-O)(2) and disamarium(III) units. The coordination geometry of each Sm(III) ion is a distorted tetradecahedron with nine oxygen atoms. In addition, the DNA-binding properties of the ligand and its complexes have been investigated by absorption, fluorescence, and viscosity measurements. The experimental results indicate that the ligand and the Sm-complex can bind to DNA, but the other two complexes cannot; the binding affinity of the Sm-complex is higher than that of the ligand and the intrinsic binding constant K(b) of the complex is 3.22 x 10(5)M(-1).     

Synthesis and chemical behaviour of D-glucosyl esters of glutamic acid having the side-chain carboxyl group involved in the glycosidic linkage.

Simultaneous and stepwise deprotection of the fully benzylated D-glucosyl esters of 1-benzyl N-benzyloxycarbonyl- and N-tert-butyloxycarbonyl-L-glutamic acid (1 and 5, respectively) have been examined. Catalytic hydrogenation of 1 led to intramolecular aminolysis to give pyroglutamic acid and D-glucose, but similar treatment in the presence of trifluoroacetic acid afforded both anomers of 1-O-(L-gamma-glutamyl)-D-glucopyranose, which were characterized as trifluoroacetates (2alpha and 2beta) and converted into 2,3,4,6-tetra-O-acetyl-1-O-[1-methyl N-(acetyl)-L-glutam-5-oyl]-D-glucopyranose (4) which was also prepared by a definitive method. Hydrogenolysis of 5 gave both anomers of 1-O-[N-(tert-butyloxycarbonyl)-L-gamma-glutamyl]-D-glucopyranose (6), which, upon treatment with trifluoroacetic acid at - 10 degrees, afforded 2alpha and 2beta, respectively. The structure of 6beta was established by its conversion into 2,3,4,6-tetra-O-acetyl-1-O-[1-methyl N-(tert-butyloxycarbonyl)-L-glutam-5-oyl]-beta-D-glucopyranose (7beta), whereas similar treatment of 6alpha gave a mixture of 1,3,4,6-tetra-O-acetyl-2-O-[1-methyl N-(tert-butyloxycarbonyl)-L-glutam-5-oyl]-alpha-D-glucopyranose (9) and 7alpha. A 1 leads to 2 acyl migration occurred during esterification of the aglycon carboxyl group of 6alpha with diazomethane to give 2-O-[1-methyl N-(tert-butyloxycarbonyl)-L-glutam-5-oyl]-alpha-D-glucopyranose (8).     

Crystal structure of the dimeric beta-cyclodextrin complex with 1,12-dodecanediol

The structure of the complex of beta-cyclodextrin (beta-CD) with 1,12-dodecanediol has been determined at 173 K and refined to a final R=0.0615 based on 22,386 independent reflections. The complex crystallizes in the triclinic space group P1; with a=17.926(4), b=15.399(3), c=15.416(3) A, alpha=103.425(4), beta=113.404(4), gamma=98.858(4) degrees, D(c)=1.362 Mg cm(-3) and V=3651.4(13) A(3) for Z=1. One molecule of the diol is located as a guest in the hydrophobic cavity of a beta-CD-dimer, forming a [3]pseudorotaxane. The guest molecule shows a disorder over two positions. The hydroxyl groups of the diol emerge from the primary faces of the beta-CD dimer and form several hydrogen bonds with water molecules lying in the interstitial space, similarly to dimeric complexes of beta-CD with other alpha,omega-bifunctional guests.     

Semisynthetic epsilon-isorhodomycins: their synthesis using glycals and their structure-activity relationship

Syntheses and structure-activity relationships of 7-O-(3-amino-2,3,6-trideoxy-a-L-lyxo- (18), -L-arabino- (20) and -L-ribo- hexopyranosyl)-epsilon-isorhodomycins (25) and their 3'-dimethylamino derivatives 22, 23 and 26 are described. Condensation (trimethylsilyl triflate, molecular sieves 4 A, 10:1 dichloromethane-acetone, -15 degrees) of epsilon-isorhodomycinone (epsilon-isoRMN, 6) with 1,5-anhydro-4-O-p-nitrobenzoyl-3-trifluoroacetamido-L-lyxo- (5) -L-arabino- (9) or -L-ribo-hex-l-enitols (10) afforded mainly the 7-O-a-glycosyl-epsilon-isoRMNs 7, 11, and 12. Similar glycosylation of 6 with 1,5-anhydro-3-azido-4-O-p-nitrobenzoyl-2,3,6-trideoxy-L-arabino-hex-1-++ +enitol (15) yielded a-glycoside 16. Removal (M NaOH) of the p-nitrobenzoyl and trifluoroacetyl groups from 7, 11, and 12 gave the 7-O-(3-amino-2,3,6-trideoxy-a-L-hexopyranosyl)-epsilon-isoRMNs 18, 20, and 25. Reductive alkylation (CH2O, NaCNBH3) of these products afforded the 3'-N,N-dimethyl analogues 22, 23, and 26. The cytotoxic effect (IC50) of the semisynthetic epsilon-isorhodomycins was tested in vitro in leukemia cell line L1210.     

Pharmacokinetics of kanamycin in the bullfrog, Rana catesbeiana

1. Kanamycin disposition was studied in bullfrogs (Rana catesbeiana) following single doses IP. Both plasma t1/2 and Vd of the drug increased with increasing time after drug indicating redistribution and tight binding of kanamycin to deep tissue compartments. 2. Kanamycin was eliminated unchanged with a t1/2 plasma = 27 hr; perilymph = 89 hr; endolymph = 183 hr; aqueous humor = 54 hr; and CSF = 58 hr. 3. Kanamycin was absorbed by frogs from environmental water. 4. Environmental conditions must be carefully specified and monitored, as well as the physiological state of the animals when studying the effects of drugs on Amphibia.     

Heme-copper/dioxygen adduct formation relevant to cytochrome c oxidase: spectroscopic characterization of [(6L)FeIII-(O2 2−)-CuII]+

In the further development and understanding of heme-copper dioxygen reactivity relevant to cytochrome c oxidase O(2)-reduction chemistry, we describe a high-spin, five-coordinate dioxygen (peroxo) adduct of an iron(II)-copper(I) complex, [((6)L)Fe(II)Cu(I)](BArF(20)) (1), where (6)L is a tetraarylporphyrinate with a tethered tris(2-pyridylmethyl)amine chelate for copper. Reaction of 1 with O(2) in MeCN affords a remarkably stable [t(1/2) (rt; MeCN) approximately 60 min] adduct, [((6)L)Fe(III)-(O(2) (2-))-Cu(II)](+) (2) [EPR silent; lambda(max)=418 (Soret), 561 nm], formulated as a peroxo complex based on manometry (1:O(2)=1:1; spectrophotometric titration, -40 degrees C, MeCN), mass spectrometry {MALDI-TOF-MS: (16)O(2), m/z 1191 ([((6)L)Fe(III)-((16)O(2) (2-))-Cu(II)](+)); (18)O(2), m/z 1195}, and resonance Raman spectroscopy (nu((O-O))=788 cm(-1); Delta(16)O(2)/(18)O(2)=44 cm(-1); Delta(16)O(2)/(16/18)O(2)=22 cm(-1)). (1)H and (2)H NMR spectroscopy (-40 degrees C, MeCN) reveals that 2 is the first heme-copper peroxo complex which is high-spin, with downfield-shifted pyrrole resonances (delta(pyrrole)=75 ppm, s, br) and upfield shifted peaks at delta= -22, -35, and -40 ppm, similar to the pattern observed for the mu-oxo complex [((6)L)Fe(III)-O-Cu(II)](BAr(F)) (3) (known S=2 system, antiferromagnetically coupled high-spin Fe(III) and Cu(II)). The corresponding magnetic moment measurement (Evans method, CD(3)CN, -40 degrees C) also confirms the S=2 spin state, with mu(B)=4.9. Structural insights were obtained from X-ray absorption spectroscopy, showing Fe-O (1.83 A) and Cu-O (1.882 A) bonds, and an Fe...Cu distance of 3.35(2) A, suggestive of a mu-1,2-peroxo ligand present in 2. The reaction of 2 with cobaltocene gives 3, differing from the observed full reduction seen with other heme-Cu peroxo complexes. Finally, thermal decomposition of 2 yields 3, with concomitant release of 0.5 mol O(2) per mol 2, as confirmed quantitatively by an alkaline pyrogallol dioxygen scavenging solution.     

Synthesis and antitumor activity of new D-galactose-containing derivatives of doxorubicin

A general scheme of synthesis of antibiotic doxorubicin derivatives is based on the 13-dimethyl ketal of 14-bromodaunorubicin (4). The interaction of 4 with melibiose (5), lactose (6), 3-methoxy-4-O-(2,3,4,6-tetra-O-acetyl-beta-D-galactopyranosyl)-4-oxybenzaldehyde (12) or 4-O-(2,3,4,6-tetra-O-acetyl-beta-D-galactopyranosyl)-4-oxybenzaldehyde (13) by reductive alkylation followed by hydrolysis of the corresponding intermediate bromoketals produced 3'-N-[alpha-D-galactopyranosyl-(1-->6)-O-1-deoxy-D-glucit-1-yl]doxorubicin (7), 3'-N-[beta-D-galactopyranosyl-(1-->4)-O-1-deoxy-D-glucit-1-yl]doxorubicin (8), 3'-N-[3"-methoxy-4"-O-(beta-D-galactopyranosyl)-4"-oxybenzyl]doxorubicin (16), and 3'-N-[4"-O-(beta-D-galactopyranosyl)-4"-oxybenzyl]doxorubicin (17). Cytotoxic and antitumor activity of the synthesized drug candidates compared to the parent doxorubicin was studied using various experimental models, in particular, on mice bearing lymphocyte leukemia P-388 at single and multiple i.v. injection regimens.     

Synthesis, crystal structure, and molecular conformation of N-Boc-L-Phe-dehydro-Leu-L-Val-OCH3

The peptide N-Boc-L-Phe-dehydro-Leu-L-Val-OCH3 was synthesized by the usual workup procedure and finally by coupling the N-Boc-L-Phe-dehydro-Leu-OH to valine methyl ester. It was crystallized from its solution in methanol-water mixture at 4 degrees C. The crystals belong to the triclinic space group P1 with a = 5.972(5) A, b = 9.455(6) A, c = 13.101(6) A, alpha = 103.00(4) degrees, beta = 97.14(5) degrees, gamma = 102.86(5) degrees, V = 690.8(8) A, Z = 1, dm = 1.179(5) Mg m-3 and dc = 1.177(5) Mg m-3. The structure was determined by direct methods using SHELXS86. It was refined by block-diagonal least-squares procedure to an R value of 0.060 for 1674 observed reflections. The C alpha 2-C beta 2 distance of 1.323(9) A in dehydro-Leu is an appropriate double bond length. The bond angle C alpha-C beta-C gamma in the dehydro-Leu residue is 129.4(8) degrees. The peptide backbone torsion angles are theta 1 = -168.6(6) degrees, omega 0 = 170.0(6) degrees, phi 1 = -44.5(9) degrees, psi 1 = 134.5(6) degrees, omega 1 = 177.3(6) degrees, phi 2 = 54.5(9) degrees, psi 2 = 31.1(10) degrees, omega 2 = 171.7(6) degrees, phi 3 = 51.9(8) degrees, psi T3 = 139.0(6) degrees, theta T = -175.7(6) degrees. These values show that the backbone adopts a beta-turn II conformation. As a result of beta-turn, an intramolecular hydrogen bond is formed between the oxygen of the ith residue and NH of the (i + 3)th residue at a distance of 3.134(6) A.(ABSTRACT TRUNCATED AT 250 WORDS)     

X-ray analysis of 3-O-(6-O-acetyl-2,4-diazido-3-O-benzyl-2,4-dideoxy-alpha-D-gl glucopyranosyl)-1,6-anhydro-2,4-diazido-2,4-dideoxy-beta-D- glucopyranose, a disaccharide having an unusual alpha-D-(1----3) linkage

The crystal structure of 3-O-(6-O-acetyl-2,4-diazido-3-O-benzyl-2,4-dideoxy-alpha-D- glucopyranosyl)-1,6-anhydro- 2,4-diazido-2,4-dideoxy-beta-D-glucopyranose, C21H24N12O7, mol. wt. 556.5, was investigated by X-ray analysis. The disaccharide crystallizes in the triclinic space group P1, with a = 889.3(5), b = 869.6(5), and c = 999.5(6) pm, and alpha = 105.83(4) degrees, beta = 116.22(4) degrees, gamma = 88.42(4) degrees, Z = 1, and rho = 1.394 g.cm-3. Phase determination failed with direct methods, but, as the 1,6-anhydride component of the molecule was already known from a previous structure analysis, the vector-search method could be applied in solving the structure. Diffractometer data were refined to an R value of 0.063 (Rw = 0.080) for 2102 observed reflections. The anhydro-bridged system has a distorted 1C4(D) conformation, in agreement with that of other anhydropyranoses so far investigated. A comparison shows that, for the specific kind of distortion, mainly the anti-reflex effect is responsible, whereas 1,3-diaxial interactions have a minor influence. The nonbridged ring adopts an almost perfect 4C1(D) conformation. The anomeric effect is observed in both of the sugar-ring systems in terms of bond-length shortening. The disaccharide has an alpha-D-Glc-4C1-(1a----3e)-D-Glc-1C4 glycosidic linkage. No previous X-ray investigation of a compound of this type is known. The pyranoid rings are almost perpendicular to each other. The phi, psi angles of the glycosidic linkage are +78.1(5) and -86.0(4) degrees.(ABSTRACT TRUNCATED AT 250 WORDS)     

苍白秤钩风(Diploclisia Glaucescens)中的木脂素——左旋丁香脂素的晶体结构研究

通过X 射线单晶衍射法测定了标题化合物的晶体结构。结果表明 :晶体属正交晶系 ,P2 12 12 1空间群 ,a =8 6 0 10 (3) ,b =13 0 830 (9) ,c =18 1130 (11) ,V =2 0 38 2 0 (2 0 ) 3 ,Z =4 ,Mr =4 18 4 9,Dx =1 36 9g/cm3 ,λ(MoKα) =0 710 73 ,μ(MoKα) =1 12cm-1,F(0 0 0 ) =888。在 0 <2θ <5 0°范围内共收集了 1988个独立衍射点 ,其中可观测衍射点 196 3个 [Ⅰ≥ 8σ(Ⅰ ) ]。晶体结构用直接法解出 ,经全矩阵最小二乘法修正 ,最终偏离因子Rf=0 0 6 2 ,Rw=0 0 5 5。