Trevor J. Petcher

Design, synthesis, and binding affinity of a nonpeptide mimic of somatostatin

Abstract The tetrasubstituted xylofuranose 4 was synthesized as a potential nonpeptide mimic of somatostatin, based on conformational analysis of the endogenous ligand and molecular modelling studies. It displaced the radioligand [ 125 I-Tyr 3 ]-octreotide with an IC 50 of 23 μM. The tetrasubstituted xylose derivative 4 (Ic 50 =23μM) was synthesised as SRIF mimetic, based on conformational analysis of SRIF and molecular modelling studies.

Neuromuscular blocking agents: Structure and activity

Abstract Correlation of crystal structure analyses and model building of rigid molecules indicate the structural requirements for curariform activity and the structural differences between depolarizing and non-depolarizing neuromuscular blocking agents.

Crystal structure and absolute configuration of 2′-bromopodophyllotoxin–0.5 ethyl acetate

The crystal structure of the title compound (I; R = Br) has been determined in order to provide conclusive evidence for the absolute configuration of podophyllotoxin (I; R = H) and related lignans. The structure was determined from diffractometer data by the heavy-atom method and refined by least-squares techniques to R 0·098 for 2043 observed reflections. Crystals are monoclinic, space group P21, with Z= 4 in a unit cell of dimensions a= 1321(4), b= 1558(2), c= 1168(5) pm, β= 102·0(2)°.

The crystal structure of (–)-(S)-hyoscine hydrobromide

The structure of (–)-(S)-hyoscine hydrobromide (scopolamine hydrobromide) has been determined.

X-Ray crystal structure and absolute configuration of p-bromophenacylseptamycin monohydrate, a polyether antibiotic

The constitution and absolute configuration of the polyether antibiotic C48H81O16–Na+ has been established by X-ray crystal structure analysis of the p-bromophenacyl derivative.

Conformations of some semi-rigid neuroleptic drugs. Part 1. Crystal structures of loxapine, clozapine, and HUF-2046 monohydrate {2-chloro-11-(4-methylpiperazin-1-yl)dibenzo[b,f][1,4]oxazepine, 8-chloro-11-(4-methylpiperazin-1-yl)dibenzo[b,e][1,4]diazepine, and 2-chloro-11(4-methylpiperazin-1-yl)dibenzo[b,e][1,4]diazepine monohydrate}

The crystal structures of three closely related rigid neuroleptic drugs have been determined from diffractometer data. Crystals of Loxapine (II) are orthorhombic, space group Pbca, with a= 1 796(5), b= 1 413(4), c= 1 301 (3) pm, Z= 8. Crystals of Clozapine (III) are also orthorhombic, space group P212121, with a= 1 804(3), b= 957(1), c= 950(1) pm, Z= 4. Crystals of HUF-2046 (IV) are monoclinic, space group P21/n, with a= 936(2), b= 1 717(4), c= 1 102(3) pm, β= 102.61(1)°, Z= 4. All three structures were solved by direct methods and refined by block-diagonal least squares to the following R and R′(no. of significant reflections and total no. of observations respectively in parentheses) : (II) 0.064 (1 657), 0.081 (2 410) : (III) 0.036 (1 295), 0.043 (1 468); (IV) 0.068 (2 469), 0.073 (2 843). Hydrogen atoms were located and their positions were refined in all structures.The molecular conformations of all three molecules are practically identical, despite the differing substitutions. The dihedral angle between the planes of the two benzene rings is (II) 114, (III) 115, and (IV) 117.5° and a partial double bond between the piperazine ring and the bicyclic system effectively prevents rotation of this former moiety.

Crystal structures of the Teonanácatl hallucinogens. Part I. Psilocybin C12H17N2O4P

The crystal structure of psilocybin, the major hallucinogenic component of Teonanacatl, the sacred mushroom of Mexico, has been determined in crystals of the monomethanolate. Crystals are monoclinic, space group P21/c, a= 1264(1), b= 2911(2), c= 884·7(6) pm, β= 107·37(2)°, and contain two molecules of psilocybin and two molecules of methanol of solvation per asymmetric unit. Data were collected on a four-circle diffractometer; the structure was solved by direct methods and refined by block-diagonal least squares to R 0·049 over 4217 significant reflections. The two independent molecules are both zwitterions, have different conformations, and are involved in a complex hydrogen-bonding scheme in which there are very short phosphate–phosphate hydrogen bonds, and in which the methanol of solution also takes part. Significant deviations of the substituents from the indole plane are apparent. Bond lengths have been determined to a precision of 0·5 pm.

X-Ray determination of the molecular structure and absolute configuration of vincamine and of its hydrobromide methanolate

The structure and absolute configuration of the indole alkaloid vincamine (I) have been determined by X-ray analysis of the natural product and of its hydrobromide methanolate (II). A comparison of both molecular structures shows that protonation and different crystal packing have no measurable effect on bond lengths and bond angles, but noticeable differences in torsion angles and consequently in the finer details of the conformation are observed. Crystal data: (I), space group P212121, Z= 4, a= 7·708(4), b= 14·527(7), c= 16·776(6)A; (II), space group P21, Z= 2, a= 7·390(2), b= 17·843(3), c= 9·437(4)A, β= 115·69(2)°. The structures were solved from diffractometer data by the multi-solution (I) and heavy-atom methods (II), and refined by least-squares techniques to R 0·042 [(I), 1341 reflections] and 0·045 [(II), 2033 reflections].

Crystal structure of oxotremorine sesquioxalate, 1-[4-(2-oxopyrrolidin-1-yl)but-2-ynyl]pyrrolidinium sesquioxalate

The crystal structure of the title compound (I) has been determined from X-ray diffraction data. Crystals are triclinic, a= 8·183(4), b= 14·449(6), c= 8·879(4)A, α= 125·00(3), β= 89·32(3), γ= 98·30(3)°, Z= 2, space group P. The structure was solved by direct methods and refined by full-matrix least-squares to R 0·104 for 1895 three-dimensional diffractometer data. There is considerable disorder in the positions of the oxalic acid and oxalate anion. The pyrrolidine ring adopts the envelope conformation with the nitrogen 0·54 A out of the plane of the carbon atoms, and the nitrogen substituent in the pseudo-equatorial position. The pyrrolidone ring is almost planar. The structure is linked by a series of hydrogen bonds between the oxotremorine cation and the oxalic acid and oxalate moieties.

Conformations of some semi-rigid neuroleptic drugs. Part 2. Crystal structures of racemic and of (+)-(S)-octoclothepin{2-chloro-10,11-dihydro-11-(4-methylpiperazin-1-yl)dibenzo[b,f]thiepin} and the absolute configuration of the latter

The crystal structures of racemic and of dextrorotatory Octoclothepin, a neuroleptic drug, have been determined from diffractometer data, as has the absolute configuration of the latter. Crystals of racemic Octoclothepin are orthorhombic, space group Pna21, a= 1 265(4), b= 1 008(2), c= 1 412(5) pm. The structure was solved by Patterson convolution methods and refined by block-diagonal least-squares to R 0.040 (1 083 significant reflections). Crystals of (+)-Octoclothepin are orthorhombic, space group P212121, a= 1 758(5), b= 1 260(4), c= 787(2) pm. The structure was solved by multisolution direct methods and refined by block-diagonal leastsquares to R 0.039 (1 079 significant data). The absolute configuration was determined to be S by means of an R-factor ratio test at termination of refinement (significant at <0.005 probability level) and confirmed by measurement of 50 Friedel pairs with Cu-Kα radiation.The conformations of racemic and dextrorotatory molecules are practically identical despite different crystal packings. The central seven-membered ring folds about a line through S(5) and C(12), whereby atoms C(12) and C(13) are almost coplanar with the chlorine-substituted benzene ring. Despite removal of the constraint of a 10,11-double bond in the seven-membered heterocycle, the overall molecular conformation bears a strong resemblance to those of Loxapine, Clozapine, and HUF-2046, in that the mean plane of the piperazine ring lies roughly parallel to the plane of one of the benzene rings.