John N. Lisgarten

The antimalarial and cytotoxic drug cryptolepine intercalates into DNA at cytosine-cytosine sites.

Cryptolepine, a naturally occurring indoloquinoline alkaloid used as an antimalarial drug in Central and Western Africa, has been found to bind to DNA in a formerly unknown intercalation mode. Evidence from competition dialysis assays demonstrates that cryptolepine is able to bind CG-rich sequences containing nonalternating CC sites. Here we show that cryptolepine interacts with the CC sites of the DNA fragment d(CCTAGG)2 in a base-stacking intercalation mode. This is the first DNA intercalator complex, from ∼90 solved by X-ray crystallography, to bind a nonalternating (pyrimidine-pyrimidine) DNA sequence. The asymmetry of the drug induces a perfect stacking with the asymmetric site, allowing for the stability of the complex in the absence of hydrogen bonding interactions. The crystal structure of this antimalarial drug–DNA complex provides evidence for the first nonalternating intercalation and, as such, provides a basis for the design of new anticancer or antimalarial drugs.

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.]

Crystal and molecular structure of 5-carbamyl-5H-dibenzo[b,f] azepine

The structure of the title compound has been determined by direct methods from diffractometer data, and refined by full-matrix least squares. Crystals are monoclinicP21/n,a=7.534(1),b=11.150(2),c=13.917(3) Å,β=92.94(4)°,Z=4,Dx=1.34 (3) g cm−3,R=0.084 for 1259 observed reflections. The azepine ring has a boat conformation. The fused benzene rings are planar. Molecules are packed as hydrogen-bonded dimers through the carboxamide groups. The atomic charge distribution over the fused ring system is approximately symmetrical.

Crystallization and preliminary X-ray analysis of the antimalarial and cytotoxic alkaloid cryptolepine complexed with the DNA fragment d(CCTAGG)2

Crystals of the indoloquinoline alkaloid cryptolepine complexed with the DNA fragment d(CCTAGG)(2) have been grown by the hanging-drop technique at 293 K using ammonium sulfate as the precipitating agent. Over a period of three weeks, yellow tapering bullet-shaped crystals grew to maximum dimensions of 0.2 x 0.1 x 0.1 mm. The crystals belong to space group P6(4), with unit-cell parameters a = b = 29.960, c = 39.64 A, alpha = beta = 90, gamma = 120 degrees, and diffract to 1.4 A.

Crystallization of Pleurotus ostreatus (oyster mushroom) lectin.

Crystals of Pleurotus ostreatus (oyster mushroom) lectin have been grown by the hanging-drop technique using ammonium sulfate as the precipitant at 293 K. Over a period of between two and three weeks, crystals of hexagonal bipyramidal morphology grew to maximum dimensions of 0.2 x 0.2 x 0.5 mm. The crystals belong to space group P6(1)22 or P6(5)22, with unit-cell parameters a = b = 155.9, c = 149. 8 A, V = 3153078 A(3), Z = 12 (assuming 50% solvent), and diffract to 4.1 A at 293 K.

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).

Structure of the tetraphenyl borate complex of the indoloquinoline alkaloid cryptolepine

The crystal and molecular structure of the complex, cryptolepine-tetraphenylborate, C16H13N2+·(C6H5)4B−, has been determined by direct methods. The pale yellow crystals are monoclinic, P21/n, a = 11.039(5), b = 16.4918(7), c = 16.404(2) Å, β = 95.70(1)°, V = 2968.75 Å3, and Z = 4. The structure exhibits an unusual form of static disorder with the planar cryptolepine molecules occupying a cleft between tetraphenyl borate molecules. The disorder involves essentially planar cryptolepine molecules packed in one of two orientations in the cleft, related by an almost exact noncrystallographic twofold rotation axis passing through the molecules. The tetraphenyl borate cation, on the other hand, shows no disorder. The distribution of bonds around the boron atom is essentially tetrahedral and the four phenyl rings are planar within experimental error.

Crystallization and preliminary X-ray analysis of the DNA decamers d(CCGGATCCGG) and d(CCGGCGCCGG)

The DNA decamers d(CCGGATCCGG) and d(CCGGCGCCGG) have been crystallized for X-ray analysis in order to investigate the effects of changing the two central base pairs of the DNA fragment d(CCGGGACCGG). Previous studies have already demonstrated that the structure of the former DNA fragment contains a DNA Holliday junction. Crystals were obtained at 293 K by the hanging-drop vapour-diffusion technique using the Nucleic Acid Mini Screen. Over a period of two weeks, hexagonal plates appeared. For the DNA fragment d(CCGGATCCGG), the crystals belong to space group P3(1), with unit-cell parameters a = b = 33.54, c = 46.39 A, alpha = beta = 90, gamma = 120 degrees, and diffract to 2.2 A. In the case of the DNA fragment d(CCGGCGCCGG) the crystals belong to the space group C2, with unit-cell parameters a = 65.35, b = 24.07, c = 37.34 A, beta = 109.97 degrees, and diffract to 2.0 A.

X-ray and neutron structure of 1,8-(3,6,9-trioxaundecane-1,11-diyldioxy)-9,10-dihydro-10,10-dimethylanthracene-9-ol (P326); some pitfalls of automatic data collection

The structure of the crown ether 1,8-(3,6,9-trioxaundecane-1,11-diyldioxy)-9,10-dihydro-10,10-dimethylanthracene-9-ol, C(24)H(30)O(6).H(2)O (1), code name P326, the parent compound for a series of derivatives, has been determined by both X-ray diffraction at room temperature and neutron diffraction at very low temperature. The unit cells are very similar at both temperatures and in both cases the crystals exhibit P2(1) symmetry with Z = 4 (two molecules, A and B, respectively, per asymmetric unit) and pseudosymmetry P2(1)/c. The higher symmetry is broken mainly by the two independent water molecules in the unit cell, some reflections which would be absent in P2(1)/c having strong intensities in both the X-ray and neutron data. In both molecules A and B hydrogen bonds involving the water molecule stabilize the macrocyclic ring structure, one involving the macrocyclic O(9) as a donor. Close contacts between the water and macrocyclic O atoms in each molecule also suggest the presence of two bifurcated hydrogen bonds, involving water HW2 to both O(16) and O(18), and water HW1 to both O(18) and O(20), respectively, with considerable variation in the geometry being present. Both molecules A and B exhibit very close pseudosymmetry across a plane perpendicular to the molecular plane and through atoms C(9) and O(18), and in addition are predominantly planar structures. The X-ray analysis failed to reveal one H atom per water molecule, each being subsequently included after location and refinement in the neutron analysis.