Isobrassinin and its analogues: novel types of antiproliferative agents.

Isobrassinin (2-(S-methyldithiocarbamoylaminomethyl)indole (7a), a regioisomer of the cruciferous phytoalexin brassinin (1), exerted marked antiproliferative effects on the HeLa, A431 and MCF7 cell lines (>78.6% inhibition at 30muM). For structure-activity relationships, further analogues were synthesized. The highest cytotoxic effect was displayed by 2-phenylimino-1,3-thiazino[5,6-b]indole (10) (10 microM, 76.8%-HeLa and 46.3%-MCF7). The effect of the natural phytoalexin brassinin was also determined.

Different forms of antiparallel stacking of hydrogen-bonded antidromic rings in the solid state: polymorphism with virtually the same unit cell and two-dimensional isostructurality with alternating layers.

As a continuation of a systematic structural analysis of 2-hydroxycycloalkanecarboxylic acids and their carboxamide analogs, the effects of antidromic rings [Jeffrey & Saenger (1991). Hydrogen Bonding in Biological Structures. Berlin, Heidelberg: Springer Verlag] upon the layer stacking of cyclopentane and cycloheptane derivatives are compared. Determination of the structure of trans-2-hydroxycycloheptanecarboxylic acid (2) led to the discovery of two polymorphs with virtually the same unit cell [Kalman et al. (2003). J. Am. Chem. Soc. 125, 34-35]. (i) The layer stacking of the antidromic rings for the whole single crystal is antiparallel (2b). (ii) The antidromic rings and the 21 axis are parallel (2a), consequently the domains of the single crystal must be antiparallel. While their polymorphism is solvent-controlled, they illustrate a novel form of two-dimensional isostructurality. Antiparallel layer stacking is again demonstrated by trans-2-hydroxycycloheptanecarboxamide (3) (space group Pbca). It is built up from layers isostructural with those in the homologous trans-2-hydroxycyclopentanecarboxamide (4) [Kalman et al. (2001). Acta Cryst. B57, 539-550], but in this structure (space group Pca21) the layers are stacked in parallel mode. Similar to (2a) and (2b), the antiparallel layer stacking in (3) versus their parallel array in (4) illustrates the two-dimensional isostructurality with alternating layer orientations. Although (3) and (4) display isostructurality, they are not isomorphous.

Two polymorphs of a beta-lactam (trans-13-azabicyclo[10.2.0]tetradecan-14-one). Concomitant crystal polymorphism and isostructurality.

Two polymorphs of trans-13-azabicyclo[10.2.0]tetradecan-14-one display a unique example of isostructurality, differing only in the orientation of a given hydrogen bond with respect to the beta-lactam bond. This slight difference can be attributed to the twofold rotation of the carbocyclic macroring of C2 symmetry, which in the crystal structure is hardly noticeable.

Dipole-induced polymorphs of trans-2-hydroxycycloheptanecarboxylic acid with virtually the same unit cell.

The polymorphs of trans-2-hydroxycycloheptanecarboxylic acid have exactly the same lattice parameters and thus mimic isomorphism. They differ only in their space group: Pna21 versus Pn21a. In form II, the screw axes turn the 18-membered rings of hydrogen-bonded tetramers around the b axis. In this way, the stacking of the layers becomes antiparallel, which cancels out the dipoles within the unit cell. In form I, the same turn around the c axis leaves the stacking of the layers parallel. Thus, the dipoles are canceled out by antiparallel domains in the crystals. Between the antiparallel domains of I, each frontier is a double layer of II. This implies that (a) a pure form of I cannot be isolated and (b) the percentage of II in I may alter from crystal to crystal.

Predictable close-packing similarities between cis- and trans-2-hydroxy-1-cyclooctanecarboxylic acids and trans-2-hydroxy-1-cyclooctanecarboxamide.

In order to extend the experimental data already available on the close packing of cyclopentanes substituted with vicinal COX (X = OH, NH(2)) and OH groups to the analogous cyclohexanes, cycloheptanes and cyclooctanes, (1R*,2S*)-cis-2-hydroxy-1-cyclooctanecarboxylic acid (8C), (1R*,2R*)-trans-2-hydroxy-1-cyclooctanecarboxylic acid (8T) and (1R*,2R*)-trans-2-hydroxy-1-cyclooctanecarboxamide (8T*) were subjected to X-ray crystal structure analysis. In 8T and 8T*, the hydrogen bonds form infinite ribbons of dimers joined by R(2)(2)(12) rings with C(i) symmetry. Two types of dimer alternate along each ribbon. The dimers differ in the donor and acceptor roles of the functional groups. This pattern was previously deduced topologically among the possible forms of association for heterochiral dimers [Kálmán et al. (2002). Acta Cryst. B58, 494-501]. As they have the same pattern of hydrogen bonds, 8T and 8T* are isostructural. The additional donor (i.e. the second hydrogen of the NH(2) group) present in 8T* links the adjacent ribbons so as to form smaller R(2)(2)(8) rings between them. The crystals of the cis stereoisomer 8C are built up from antiparallel hydrogen-bonded helices. The topology and symmetry of this structure are the same as for the close packing of (1R*,2R*,4S*)-4-tert-butyl-2-hydroxy-1-cyclopentanecarboxamide [Kálmán et al. (2001). Acta Cryst. B57, 539-550]; only the hydrogen-bond donors and acceptors are interchanged, in the same way as in the two dimer types of 8T and 8T* ribbons. This analogy suggests that helices may originate as homochiral dimers with C(2) symmetry and polymerize into helices during crystal formation. The conformational characteristics of the heterochiral dimers observed in the title compounds and in closely related structures are discussed.

Novel, predicted patterns of supramolecular self-assembly, afforded by tetrameric R44(12) rings of C2 symmetry in the crystal structures of 2-hydroxy-1-cyclopentanecarboxylic acid, 2-hydroxy-1-cyclohexanecarboxylic acid and 2-hydroxy-1-cycloheptanecarboxylic acid.

Determination of the crystal structures of the homologous (1R*,2R*)-trans-2-hydroxy-1-cyclopentanecarboxylic acid (5T), (1R*,2S*)-cis-2-hydroxy-1-cyclohexanecarboxylic acid (6C) and (1R*,2S*)-cis-2-hydroxy-1-cycloheptanecarboxylic acid (7C) proved a predicted pattern of supramolecular close packing. The prediction was based on the common features observed in the crystal structures of six related 2-hydroxy-1-cyclopentanecarboxylic acids and analogous carboxamides [Kálmán et al. (2001). Acta Cryst. B57, 539-550]. This pattern is characterized by tetrameric R(4)(4)(12) rings of C(2) symmetry formed from dimeric R(2)(2)(12) rings. The C(2) symmetry of such tetramers is not common in the literature, usually they have C(i) symmetry. Both types of tetramers are formed from dimers with similar or opposite orientation. The R(2)(2)(12) dimers differ in their hydrogen bonds. In 5T the monomers are joined by a pair of O1[bond]H...O2[double bond]C bonds, whereas in 7C they are joined by a pair of O3[bond]H...O1-H bonds. In 6C 60% of the disordered R(2)(2)(12) dimers are similar to those in 7C, while 40% resemble those in 5T. Apart from these hydrogen-bonding differences and the ring-size differences, the three crystals exhibit isostructurality.

Structure of norbornene-fused 3,1-oxazine double cycloadducts.

Pentacyclic isoxazolines were obtained by the cycloaddition of benzonitrile oxide to norbornene-azetidinone-fused 3,1-oxazines. The constitutions of two of the isomers obtained, and the configurations and conformations of all products, were determined by means of 1 H and 13 C NMR spectroscopy and DNOE experiments.