Inclusion complexes of ß-cyclodextrin with tricyclic drugs: an X-ray diffraction, NMR and molecular dynamics study.

Tricyclic fused-ring cyclobenzaprine (1) and amitriptyline (2) form 1:1 inclusion complexes with ß-cyclodextrin (ß-CD) in the solid state and in water solution. Rotating frame NOE experiments (ROESY) showed the same geometry of inclusion for both 1/ß-CD and 2/ß-CD complexes, with the aromatic ring system entering the cavity from the large rim of the cyclodextrin and the alkylammonium chain protruding out of the cavity and facing the secondary OH rim. These features matched those found in the molecular dynamics (MD) simulations in solution and in the solid state from single-crystal X-ray diffraction of 1/ß-CD and 2/ß-CD complexes. The latter complex was found in a single conformation in the solid state, whilst the MD simulations in explicit water reproduced the conformational transitions observed experimentally for the free molecule.

Synthesis and Structural Properties of Aza[n]helicene Platinum Complexes: Control of Cis and Trans Stereochemistry.

The synthesis and structural characterization of azahelicene platinum complexes obtained from cis-PtCl2(NCEt)(PPh3) and from ligands that differ in terms of both the position of the nitrogen atom and the number of fused rings are reported. These square-planar complexes of the general formula PtCl2(nHm)(PPh3) (n = 4, 5; m = 5, 6) display mainly a cis configuration. However, by X-ray crystallographic analysis, we show that for both PtCl2(4H6)(PPh3) and PtCl2(5H6)(PPh3) there is chirality control of the cis/trans stereochemistry. Indeed, starting from a racemic mixture of aza[6]helicene, platinum complexes with a cis configuration are invariably obtained, and the more thermodynamically stable trans isomers are formed when using enantiopure ligands. We further corroborated these results by NMR analysis in solution.

Synthesis of robalzotan, ebalzotan, and rotigotine precursors via the stereoselective multienzymatic cascade reduction of α,ß-unsaturated aldehydes.

A stereoselective synthesis of bicyclic primary or secondary amines, based on tetralin or chroman structural moieties, is reported. These amines are precursors of important active pharmaceutical ingredients such as rotigotine (Neupro), robalzotan, and ebalzotan. The key step is based on a multienzymatic reduction of an α,ß-unsaturated aldehyde or ketone to give the saturated primary or secondary alcohol, in a high yield and with a high ee. The catalytic system consists of the combination of an ene-reductase (ER; i.e., OYE2 or OYE3 belonging to the Old Yellow Enzyme family) with an alcohol dehydrogenase (ADH), applying the in situ substrate feeding product removal technology. By this system the formation of the allylic alcohol side product and the racemization of the chirally unstable α-substituted aldehyde intermediate are minimized. The primary alcohols were elaborated via a Curtius rearrangement. The combination of OYE2 with a Prelog or an anti-Prelog ADH allowed the preparation of the secondary alcohols with ee > 99% and de > 87%. The absolute configuration of the primary amines was unambiguously assigned by comparison with authentic samples. The stereochemistry of secondary alcohols was assigned by X-ray crystal structure and NMR analysis of Mosher esters.

Synthesis and structure-activity relationship studies of novel tubulysin U analogues--effect on cytotoxicity of structural variations in the tubuvaline fragment.

Tubulysins are cytotoxic natural products with promising anti-cancer properties, originally isolated from myxobacterial cultures. Structurally, tubulysins are tetrapeptides, incorporating three unusual (Mep, Tuv and Tup) and one proteinogenic amino acid (Ile). Here we describe the synthesis and structure-activity relationship studies of novel tubulysin U and V analogues, with variations in the central Tuv fragment, which is known to be of paramount importance for tubulysins' potency and hence cytotoxicity, but has seldom been modified in previous studies. Specifically, we replaced the natural iso-propyl and acetoxy functionalities with other structurally related groups. In general, the new analogues showed much lower potency relative to native tubulysin U. However, one of the synthetic analogues (1f) having a MOM function replacing the acetyl group exhibited a 22 nM IC50 on the HT-29 cell line which is comparable to the IC(50) displayed by tubulysin U (3.8 nM). Furthermore, the synthetic methodology reported herein was found to be flexible enough to deliver different core-modified tubulysin analogues and hence may be regarded as a scalable and convenient strategy for the chemical generation of novel tubulysin analogues.

Quantum mechanics calculations, basicity and crystal structure: the route to transition metal complexes of azahelicenes.

Quantum mechanics density functional calculations provided gas-phase electron distributions and proton affinities for several mono- and diaza[5]helicenes; computational results, together with experimental data concerning crystal structures and propensity to methylation of the nitrogen atom(s), provide a basis for designing azahelicene complexes with transition metal ions.

Redetermination of Mg(2)B(25) based on single-crystal X-ray data.

The crystal structure of Mg(2)B(25), dimagnesium penta-eicosa-boride, was reexamined from single-crystal X-ray diffraction data. The structural model previously reported on the basis of powder X-ray diffraction data [Giunchi et al. (2006 ▶). Solid State Sci.8, 1202-1208] has been confirmed, although a much higher precision refinement was achieved, leading to much smaller standard uncertainties on bond lengths and refined occupancy factors. Moreover, all atoms were refined with anisotropic displacement parameters. Mg(2)B(25) crystallizes in the ß-boron structure type and is isostructural with other rhombohedral compounds of the boron-rich metal boride family. Magnesium atoms are found in inter-stitial sites on special positions (two with site symmetry .m, one with .2 and one with 3m), all with partial occupancies.

Calcium acamprosate: a triclinic polymorph.

The title compound, poly[bis-(µ(3)-4-acetamido-propane-sulfon-ato)-calcium], [Ca(C(5)H(10)NO(4)S)(2)](n), is a triclinic polymorph of the previously reported monoclinic structure [Toffoli et al. (1988 ▶). Acta Cryst. C44, 1493-1494]. The triclinic modification was found to have an all-trans configuration of the acetamido-propane chain, in contrast with the monoclinic polymorph which shows an angle of 74.66 (8)° between the S-C-C-C chain plane and that of the amide group. The Ca(2+) cation is situated on an inversion centre and is hexa-coordinated by six O atoms belonging to different anions in a distorted octa-hedral geometry. This arrangement leads to a layered structure parallel to (011). The layers are held together by N-H⋯O hydrogen bonds and by short C-H⋯O inter-actions, both involving the sulfonate O atoms not coordinated to the Ca(2+) cations. The structure was determined from a crystal twinned by non-merohedry [twin law ([Formula: see text]00, 0[Formula: see text]0, -0.335 -0.85 1), with a fractional contribution of the minor twin domain of 46.7 (1)%].

Clostebol acetate.

The title compound, C(21)H(29)ClO(3) [systematic name (8R,9S,10R,13S,14S,17S)-4-chloro-3-oxoandrost-4-en-17ß-yl acetate], is a 4-chloro derivative of testosterone, used as an anabolic androgenic agent or applied topically in ophthalmological and dermatological treatments. The absolute configurations at positions 8, 9, 10, 13, 14 and 17 were established by refinement of the Flack parameter as R, S, R, S, S, and S, respectively. Rings B and C of the steroid ring system adopt chair conformations, ring A has a half-chair conformation, while ring D is in a C(13) envelope conformation. Ring B and C, and C and D are trans fused. In the crystal, molecules are linked by a weak C-H⋯O interaction.

Microbial transformations of the taxan ring of 10-DAB by some strains of the fungus Curvularia lunata: formation of the bis-abeotaxanes wallifoliol and 4-deacylwallifoliol.

The fermentation of 10-deacetylbaccatine III (10-DAB) (1) with Curvularia lunata afforded 4-deacylwallifoliol (4) and wallifoliol (5), the only natural taxoid with the unusual 5/6/6/6/4 ring system. The X-ray structure of compound 4 is reported. The skeletal rearrangements induced by the microbial enzymatic systems are also discussed.

Trihexyphenidyl hydro-chloride: a powder diffraction study.

IN THE CATION OF THE TITLE COMPOUND [SYSTEMATIC NAME: 1-(3-cyclo-hexyl-3-hy-droxy-3-phenyl-prop-yl)piperidinium chloride], C(20)H(32)NO(+)·Cl(-), the cyclo-hexyl and piperidine rings are in chair conformations. In the crystal structure, cations and anions are linked into chains along the c-axis direction via O-H⋯Cl and N-H⋯Cl hydrogen bonds. Weak inter-molecular C-H⋯Cl inter-actions link further these chains into layers parallel to the bc plane. The salt, obtained from a racemic solution, was found to crystallize in the chiral P2(1)2(1)2 space group, indicating that, in the absence of any evident chirality-inducing process, the polycrystalline powders consist of an equivalent mixture of R and S enanti-omers, forming a racemic conglomerate.

Validating a strategy for molecular dynamics simulations of cyclodextrin inclusion complexes through single-crystal X-ray and NMR experimental data: a case study.

A theoretical and experimental study about the formation and structure of the inclusion complex (-)-menthyl-O-beta-D-glucopyranoside 1 with beta-cyclodextrin (beta-CD) 2 is presented as paradigmatic case study to test the results of molecular dynamics (MD) simulations. The customary methodological approach-the use of experimental geometrical parameters as restraints for MD runs-is logically reversed and the calculated structures are a posteriori compared with those obtained from NMR spectroscopy in D(2)O solution and single crystal X-ray diffraction so as to validate the simulation procedure. The guest molecule 1 allows for a broad repertoire of intermolecular interactions (dipolar, hydrophobic, hydrogen bonds) concurring to stabilize the host-guest complex, thus providing the general applicability of the simulation procedure to cyclodextrin physical chemistry. Many starting geometries of the host-guest association were chosen, not assuming any a priori inclusion. The simulation protocol, involving energy minimization and MD runs in explicit water, yielded four possible inclusion geometries, ruling out higher-energy outer adducts. By analysis of the average energy at room temperature, the most stable geometry in solution was eventually obtained, while the kinetics of formation showed that it is also kinetically favored. The reliability of such geometry was thoroughly checked against the NOE distances via the pair distribution functions, that is, the statistical distribution of intermolecular distances among selected diagnostic atoms calculated from the MD trajectories at room temperature. An analogous procedure was adopted both with implicit solvent and in vacuo. The most stable geometry matched that found with explicit solvent but major differences were observed in the relative stability of the metastable complexes as a consequence of the lack of hydration on the polar moiety of the guest. Finally, a control set of geometrical parameters of the thermodynamically favored complex matched the corresponding one obtained from the X-ray structure, while local conformational differences were indicative of packing effects.

Polymorphism of linezolid: a combined single-crystal, powder diffraction and NMR study.

Linezolid (S)-N-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl] acetamide is one of the first commercially available (and most widely used) oxazolidinone antibiotics. It was selectively prepared as two anhydrous polymorphic forms, labelled form II and IV in accordance with preliminary reports in the patent literature. Form II has been characterized by single-crystal X-ray diffraction methods (orthorhombic, P2 1 2 1 2 1, a=6.536(1), b=9.949(1), c=24.807(3)A, V=1613.1(3)A3, Z=4, Z'=1), while powders of form IV could be fully characterized by employing ab initio powder diffraction methods (triclinic, P1, a=6.5952(7)A, b=10.9875(10)A, c=12.9189(14)A, alpha=110.683(4) degrees , beta=88.186(6) degrees , gamma=105.826(6) degrees , V=840.5(2)A(3), Z=Z'=2). The interconversion of form II into form IV was studied by TG, DSC and thermodiffractometry, which indicated a quantitative (endothermic and irreversible) transformation (in air) just above 160 degrees C. On cooling from the melt, linezolid gives an oily material, stable at RT, which can be crystallized into form IV by controlled heating near 100 degrees C. These materials were further characterized by high-resolution 1H and 13C NMR studies, as well as by 13C solid-state NMR.

Isolation and characterisation of a phenolic impurity in a commercial sample of duloxetine.

A phenolic impurity of duloxetine hydrochloride was isolated and characterised (MS, NMR, X-ray-analysis).

Final Demonstration of the Co-Identity of Lipiarmycin A3 and Tiacumicin B (Fidaxomicin) through Single Crystal X-ray Analysis.

Lipiarmycin A3 and tiacumicin B possess the same chemical structure and have been considered identical till recently, when some authors have suggested the possibility of a minor difference between the chemical structures of the two antibiotics. In this work we performed a comparative X-ray analysis of lipiarmycin A3 and tiacumicin B. Although the commercial samples of the aforementioned compounds crystallize into two different crystal systems-evidently due to the different crystallization conditions-their chemical structures are identical. These results confirmed the previous assigned chemical structure of lipiarmycin A3 and its absolute configuration as well as its co-identity with the chemical structure of tiacumicin B, providing the definitive proof that these pharmaceutical compounds are identical in all respects.

Single crystal and powder diffraction characterization of three polymorphic forms of Acitretin.

Acitretin [all-trans-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoic acid or 3-methoxy-2-methyl-17-nor-1,2,3,4-tetradehydroretinoic acid], a widely marketed oral synthetic retinoid, introduced for clinical use as effective therapy against psoriasis, was found to crystallize in three polymorphic modifications (hereafter, I, II, and III), the crystal structures of which have been determined by single-crystal diffractometry (form I) or X-ray powder diffraction methods (form II and III) from conventional laboratory data only. In these latter cases, real space techniques (simulated annealing and whole-profile pattern matching) have been employed. Polymorph I crystallizes in space group P2(1), Z = 8, with unit cell parameters a = 7.894(1), b = 58.454(6), c = 8.161(1) angstroms, beta = 102.04(1) degrees, and V = 3682.9(8) angstroms3. Polymorph II crystallizes in space group P2(1)/n, Z = 4, with unit cell parameters a = 13.999(2), b = 10.714(1), c = 12.465(2) angstroms, beta = 98.76(5) degrees, and V = 1847.9(3) angstroms3. Polymorph III crystallizes in space group P2(1)/c, Z = 4, with unit cell parameters a = 3.0751(4), b = 4.0487(4), c = 14.956(2) angstroms, beta = 100.41(7) degrees, and V = 1831.3(4) angstroms3. Polymorph I, found to be identical with that deposited in the European Pharmacopeia, shows four crystallographically independent Acitretin molecules, arranged in pairs through conventional hydrogen-bonded carboxylic dimers; also in form II, carboxylic dimers are observed, located on crystallographic inversion centres, while in form III, a catameric arrangement of the carboxylic residues, winding up about the rather short monoclinic axis, generates one-dimensional chains of hydrogen-bonded Acitretin molecules. Thermal analysis showed that form I can be quantitatively transformed into form II by moderate heating near 200 degrees C, under vacuum. These results show that ab initio structural studies from conventional laboratory X-ray powder diffraction (XRPD) data are fully providing the opportunity to investigate the structural aspects of moderately complex substances also in the absence of single crystals, disclosing the crystal chemistry of a few polymorphs of pharmaceutically relevant species.

Crystal architecture and conformational properties of the inclusion complex, neohesperidin dihydrochalcone-cyclomaltoheptaose (beta-cyclodextrin), by X-ray diffraction.

The crystal structure of the host-guest noncovalent complex of cyclomaltoheptaose (beta-cyclodextrin, betaCD) with the O-diglycosyl flavonoid neohesperidin dihydrochalcone [(3,5-dihydroxy-4-(3-hydroxy-4-methoxyhydrocinnamoyl)phenyl-2-O-(alpha-L-rhamnopyranosyl)-beta-D-glucopyranoside, NDC] has been determined from single-crystal X-ray diffraction data collected at low temperature (130 K), using synchrotron radiation. The crystal data are as follows: a =15.125(5), b =30.523(5), c =41.332(5) Angstroms, orthorhombic, space group C222(1). The structure contains 19 molecules of water, of which 11 appeared well positioned, whereas 9 are disordered over 23-positions. The betaCD-NDC complex is characterized by one aromatic part of NDC deeply inserted into the hydrophobic cavity of the betaCD through the primary OH rim, and it is present in the crystal as a dimer. The dimeric units, formed by head-to-head assemblies of CD molecules, each with its guest, are self-assembled in columns. The stability of the columns is provided by host-guest and guest-guest attractive interactions, thus showing a key role of the guest molecules in the crystal architecture. The guest conformation in the complex is different from that reported in the literature for uncomplexed NDC. The host-induced conformational changes on NDC provide the optimum geometry requirements for the assembly of the dimeric units.

Structural and energetic aspects of a new bupropion hydrochloride polymorph.

Crystalline bupropion hydrochloride [(±)1-(3-chlorophenyl)-2-[(1,1-dimethylethyl)amino]-1-propanone hydrochloride], recently characterized as form 1, was found to undergo, upon storage at RT within months, a solid-solid conversion to a new polymorphic form, hereafter named form 2, containing a markedly different molecular conformer in the solid state. This new form, available only as a polycrystalline material, has been fully characterized using structural X-ray powder diffraction methods, coupled to thermoanalytical analyses. The relative stability of the two crystalline phases (forms 1 and 2) was compared by quantum mechanics calculations including density functional methods specific for solid state molecular systems. Bupropion hydrochloride form 2 crystallizes in the orthorhombic space group Pbca with Z=8, a=27.2853(5)Å, b=8.7184(3)Å, c=12.0422(3)Å, V=2864.7(1)ų, as centrosymmetric dimers, thanks to the presence of N-H…Cl interactions, and µ2-bridging chloride ions, each connected to two protonated amine moieties.

Pressure-temperature state diagram for the phase relationships between benfluorex hydrochloride forms I and II: a case of enantiotropic behavior.

The active pharmaceutical ingredient racemic benfluorex hydrochloride (benfluorex-HCl) has an interesting phase behavior due to an elusive solid-solid phase transition. The stability hierarchy between different phases is often determined based on heat-related experiments only or slurry interconversion. It is shown that if pressure and volume are taken into account, not only the phase equilibria are correctly positioned in the pressure-temperature phase diagram, but the experimental data also improves. Thus, it has been found that the racemic benfluorex-HCl is enantiotropic under "ordinary conditions" with polymorph II and polymorph I, respectively, being the low- and the high-temperature phases. Above ∼ 151 MPa, the system becomes monotropic and polymorph II is the single stable phase.

Thermal and X-ray powder diffraction structural characterization of two benfluorex hydrochloride polymorphs.

Two polymorphic forms of benfluorex hydrochloride, phases I and II, were isolated as monophasic polycrystalline samples, and structurally characterized using ab initio X-ray powder diffraction methods and a global optimization strategy (simulated annealing). Form I crystallizes in monoclinic system, space group P2(1)/n, with Z=4, a=21.0719(10)A, b=7.0563(4)A, c=14.8684(7)A, beta=116.998(3) degrees , V=1969.8(2)A(3), while Form II crystallizes in the orthorhombic space group Pbca, with Z=8, a=33.8031(2)A, b=15.1451(8)A, c=7.6138(6)A, V=3897.9(4)A(3). Crystals of Form I and Form II of benfluorex hydrochloride are based upon an ionic packing of protonated benfluorex molecules at the most basic site, the N1 atoms, and chloride anions. Form I shows the presence of mu-Cl ions, generating centrosymmetric dimers with a N(2)Cl(2) moiety, while Form II contains antiparallel chains of C-H...O hydrogen-bonded molecules running along c axis. DSC and thermodiffractometric measurements showed that heating progressively Form II from ambient temperature to 160 degrees C causes a phase transition to the thermodynamically stable Form I, immediately followed by the sample melting, near 165 degrees C. Recrystallization directly to Form I is observed when the melt is cooled back to ambient temperature, with a significant hysteresis (this event being centered near 130 degrees C).

Structures from powders: bupropion hydrochloride.

The crystal structure of bupropion hydrochloride, 1, was fully characterized from powdered crystalline samples, using the ab-initio XRPD technique and a global optimization strategy (simulated annealing), adopting, as starting model, the already known molecular structure of its ethanol solvate, 2. Bupropion hydrochloride crystallizes as a racemate in monoclinic system, space group P2(1)/c with Z=4, a=14.3406(3)A, b=8.7564(2)A, c=11.8801(2)A, beta=78.025(2) degrees , V=1459.34(5)A(3). In the crystals of 1 the molecules interact via strong NH[...]Cl contacts, generating dimeric entities with mu-Cl ions. Further stabilizing contacts, of the CH[...]O are at work, but differently organized in the 1 and 2 phases. The thermal behaviour of the product was assessed by differential scanning calorimetry.