Brian S. Potter

Structure, absolute configuration, and conformation of the antimalarial compound, Artemisinin

The crystal and molecular structure of the antimalarial compound Artemisinin (formerly known as Qinghaosu), C15H22O5 has been determined by direct methods. Crystals are orthorhombic colorless needles, space group P212121, Z = 4. Dc = 1.299 g cm −3, with unit cell parameters a = 6.3543(9), b = 9.439(3), c= 24.066(4) Å. The molecule incorporates a fused ring system containing a six-membered ring C which includes an oxygen bridge and a peroxy-bridge. The ring C has a distorted boat conformation and the C - O - O - C torsion angle is 47.8(2)°. Rings A and D have symmetrical chair and distorted chair conformations, repectively. Ring junctions A/B, A/D, and C/D are cis, junction B/D is trans. All inter-molecular contacts are van der Waals. The absolute configuration of Artemisinin was determined from the refined value of the Flack x parameter. [The atomic coordinates given in a previous structure analysis, “Crystal Structure and Absolute Configuration of Qinghaosu,” Qinghaosu Research Group, Institute of Biophysics, Academica Sinica, Scientia Sinica, Vol. XXIII No. 3, 380 (1980), do not display the molecule in its absolute configuration.]

Structure of 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine isethionate solvate (lamotrigine isethionate)

The crystal and molecular structure of lamotrigine isethionate, C9H8Cl2N5+ .HOC2H4SO3− has been determined by direct methods. The compound crystallizes in the tetragonal space group I41/a. The isethionate moiety forms multiple hydrogen bonds to the lamotrigine nucleus, three from one isethionate, two from a symmetry related isethionate and a further two from two different symmetry related molecules. Protonation of N(2′) in the triazine ring, not observed in the native lamotrigine structure is presumably associated with the interaction of the isethionate moiety. Both rings in the lamotrigine moiety are essentially planar, with a dihedral angle of 66.08(7)° compared to 80.70° in native lamotrigine. The connecting bond length C(1)—C(6′) = 1.493(3) Å also correlates well with values in related compounds (1.480(3) Å) in the native structures.

Conformational flexibility within the chelate rings of [Pt(en)(CBDCA-O,O′)], an analogue of the antitumour drug carboplatin: X-ray crystallographic and solid-state NMR studies

The X-ray crystal structure of [Pt(en)(CBDCA-O,O′)] 1, an analogue of the anticancer drug carboplatin, shows that platinum has an approximate square-planar coordination. The crystals are orthorhombic with space group Pnma. The Pt-CBDCA chelate ring adopts a flattened-boat conformation, similar to that found for carboplatin, and the Pt-ethylenediamine chelate ring exhibits both δ and λ conformations with equal populations. Ethylenediamine chelate ring inversion was observed by 13C CP/MAS NMR spectroscopy. The exchange rate and the activation free energy (ΔG‡) at 317 K were determined to be ca. 415 s-1 and 62 kJ mol-1, respectively. The CBDCA ligand appears to have a direct effect on the dynamics of the en ring. Conformational flexibility of the CBDCA ring is also discussed. Such dynamic processes within chelated platinum complexes could play a role in the biological recognition of anticancer complexes.

Aza analogues of nucleic acid bases: experimental determination and computational prediction of the crystal structure of anhydrous 5-azauracil

The crystal and molecular structure of 5-azauracil, C3H3O2N3 M-r = 1 13.07 Da, was determined from X-ray diffraction data. The material crystallizes in the orthorhombic space group Pbca with eight molecules of 5-azauracil in a cell of dimensions a = 6.5135(3), b = 13,5217(4), c = 6.5824(4) Angstrom, crystal density D-c = 1.779 g cm(-3). The structure was determined using direct methods and refined by full-matrix least-squares to a conventional R index of 0.0337 for 763 observed reflections and 86 parameters. Two strong hydrogen bonds, N1H1...O4 and N3H3...N5, and several weaker intermolecular interactions produce a crinkled sheet structure. This crystal structure was independently predicted by a search for minima in the lattice energy, as calculated using an ab initio optimised molecular structure and a distributed multipole model for the electrostatic interactions. Indeed, the global minimum in the search corresponded to the same Pbca space group, with rms errors in the cell lengths of 3.7%. There is a larger energy gap separating the observed hydrogen bonding motif structure from alternative structures, with different hydrogen bonds and connectivity, for 5-azauracil than for 6-azauracil and uracil

Research Article: A comparative study of the single crystal X-ray determination and molecular modelling of the binding of oligomycin to ATP Synthase

Recently published X-ray structures of three common forms, A, B and C, of oligomycin, including absolute configurations, are investigated to examine their binding to ATP Synthase. The X-ray studies reveal regions with differences in three-dimensional structure and hydrogen bonding propensity between the oligomycins, which may be associated with their potential to bind to sites on ATP Synthase. Computational docking studies carried out using MOE with the X-ray structures and an homology model of the F(O) domain of ATP Synthase from Escherichia coli, are used to derive an induced fit pocket. Docking of all oligomycins to this pocket indicate that the B and C forms bind more tightly than the A form. Consideration of the single crystal X-ray data alone indicate the B form may be the best inhibitor and that O(24) is the most important ligating group for binding, this is supported by the docking data. The latter reveals Asn214 and other key proton translocating residues to be the main residues contacted by the inhibitor. These data allow the binding modes of different forms of oligomycin to be deduced from X-ray single crystal data supported by molecular modelling and computational docking studies.

Antagonist binding in the rat muscarinic receptor

A series of agonists to the rat muscarinic receptor have been docked computationally to the active site of a homology model of rat M1 muscarinic receptor. The agonists were modelled on the X-ray crystal structure of atropine, which is reported here and the docking studies are shown to reproduce correctly the order of experimental binding affinities for the agonists as well as indicate where there appear to be inconsistencies in the experimental data. The crystal and molecular structure of atropine (tropine tropate; alpha-[hydroxymethyl]benzeneacetic acid 8-methyl[3.2.1]oct-3-yl ester C17H23NO3) has been determined by X-ray crystallography using an automated Patterson search method, and refined by full-matrix least-squares to a final R of 0.0452 for 2701 independent observed reflections and 192 parameters using Mo Kalpha radiation, lambda=0.71073A at 150K. The compound crystallises in space group Fdd2 with Z=16 molecules per unit cell.

Two new cyclosporin folds observed in the structures of the immunosuppressant cyclosporin G and the formyl peptide receptor antagonist cyclosporin H at ultra-high resolution

Cyclosporins are cyclic undecapeptides of fungal origin the best known of which, CsA, is a lead clinical immunosuppressant; CsG is a potential clinical immunosuppressant differing from CsA in residue 2 (L-alpha-amino-butyric acid in CsA, L-norvaline in CsG); and CsH is an inverse formyl peptide receptor agonist, differing from CsA in the chiral inversion of MeVal-11 from L to D. Crystal structure determinations of CsG and CsH were undertaken to identify structural and surface features important for biological activity and the future design of new cyclosporin derivatives. Ultra-high resolution X-ray structures (0.80 to 0.87 A resolution) determined for two crystal forms of both CsH and CsG in the presence and absence of Mg2+ are described. A major outcome of this study is the observation that the local change in chirality between CsA and CsH is associated with a major structural transformation from open beta-sheet in CsA to a highly convoluted conformation in CsH. CsG also possesses a completely novel cloverleaf motif with no H-bonded secondary structure features in spite of the minimal chemical difference with CsA. Unlike CsA, the structures of both CsH and CsG are heavily solvated. This study therefore shows that the chemical differences between the three cyclosporins, CsA, CsG and CsH can invoke unpredictably major differences in their 3D structures. The 9-11 cis-peptide bond in CsA moves to 11-1 in CsG, influencing the overall molecular conformation, while the peptide bonds in the highly convoluted loop conformation of CsH are all trans.

Structure, absolute configuration, and conformation of the antimalarial drug artesunate

The crystal and molecular structure of the antimalarial compound artesunate has been determined by direct methods. Crystals are orthorhombic, P212121, a = 9.8371(12), b = 10.517(2), c = 18.7594(5) Å, Z = 4, Dc = 1.316 mg/mL. The molecule is comprised of a fused ring system containing a six-membered ring C which includes an oxygen bridge and a peroxy bridge. The 9-atom oxygen–carbon chain from O(5)—C(12)... to ... O(2)—C(6) displays a striking sequence of short, long, short, long ... bonds while these distances are all within the ranges of a normal single bond or partial double bond. It is proposed that this pattern is caused by the delocalization of the lone pair electrons on the oxygen atoms. The ring C has a distorted boat conformation and the C—O—O—C torsion angle is 46.3(2)°. Rings A and D have ideal chair conformations. Ring junctions A/B and A/D are cis junctions, B/D and C/D are trans. Packing of the molecules is stabilized by one strong hydrogen bond involving the hydroxyl group on the ester linkage and the oxygen atom of the lactone ring.

Crystal structure and conformation of the antimalarial drug 5,7-methoxy-8-(3-methyl-1-buten-3-ol)-coumarin

The crystal and molecular structure of the antimalarial compound 5,7-methoxy-8-(3-methyl-1-buten-3-ol)-coumarin, C16H18O5, Mr = 290.3 Da, has been determined from X-ray diffraction data. The material crystallizes in the monoclinic space group P21/c with 4 molecules per unit cell of dimensions a = 8.9044(9), b = 17.623(1), c = 10.175(1) Å, β = 113.97(1)°, crystal density Dc = 1.322 g/cm3. The structure was determined using direct methods and refined by full-matrix least squares to a conventional R index of 0.066 for 2416 measured reflections and 206 parameters.The coumarin ring system is almost planar with the methoxy C atoms rotated slightly out of the coumarin mean plane. Apart from the terminal CH3 groups C(12) and C(13), which are 1.184(3) Å above and −1.315(3) Å below the plane, the 3-methyl-1-buten-3-ol substituent is planar (rms deviation 0.009 Å) making an angle of 6.31(7)° with the phenyl ring. One intermolecular hydrogen bond is present in the crystal structure between O(5)–HO(5) and the symmetry related O(2′) oxygen, generated by the symmetry operation (x, 1/2 – y, −1/2 + z).

Aza analogs of nucleic acid bases: infrared and Raman spectra of 5-azauracil and crystal structure of 5-azauracil monohydrate

The X-ray crystal structure of 5-azauracil monohydrate (C3H3O2N3·H2O, Mr=131.10 Da) has been determined from X-ray diffraction data. In the crystal structure all atoms of the 5-azauracil molecule and the solvated water, including hydrogens, lie exactly in the mirror plane perpendicular to b at y=1/4 in the monoclinic space group P21/m and therefore exhibit symmetry m (Cs). The crystal structure comprises solvate-promoted hydrogen-bonded layers in the ac plane, separated by b/2=3.1054 A. The X-ray structure of 5-azauracil monohydrate is compared with the previously reported data for uracil, 6-azauracil and a complex of 5-azauracil with its own hydrolysis product. The presence of bands due to CO stretching vibrations in the infrared and Raman spectra confirms that 5-azauracil exists in its dioxo tautomeric form in both the anhydrous and hydrated crystal forms. The position of a strong Raman band due to the ring breathing vibration is found to be a marker for the state of hydration of 5-azauracil; it appears at 804 cm-1 in the solid state Raman spectrum of 5-azauracil and shifts upwards in wavenumber to 816 cm-1 in the spectrum of 5-azauracil monohydrate.