Matthew Lam

Design and synthesis of highly constrained factor Xa inhibitors: amidine-Substituted bis(benzoyl)-[1,3]-diazepan-2-ones and bis(benzylidene)-bis(gem-dimethyl)cycloketones

Two conformationally constrained templates have been designed to provide selective inhibitors of the coagulation cascade serine protease, Factor Xa (FXa). The most active inhibitor, 2,7-bis[(Z)-p-amidinobenzylidene)]-3,3,6,6-tetramethylcycloheptanone, exhibits a K(i) of 42 nM against FXa, with strong selectivity against thrombin (1000-fold), trypsin (300-fold) and plasmin (900-fold). With only two freely rotatable bonds, molecular modeling suggests that one amidine group is positioned into the S1 pocket, forming hydrogen bonds with the side chain of Asp189, similar to other amidine-based inhibitors, with the second benzamidine positioned into the S4 pocket in a position to form strong cation-pi bonding with the S4 aryl cage. We suggest that this interaction plays an important role in the specificity of these inhibitors against other serine proteases.

Bimetallic reactivity. Preparations, properties and structures of complexes formed by unsymmetrical binucleating ligands bearing 4- and 6-coordinate sites supported by alkoxide bridges

Four binucleating ligands which potentially could provide bimetallic complexes bearing 5- and 6-coordinate sites have been prepared. These ligands, which have alkoxide bridging groups, can be regarded as more elaborate versions of binucleating ligands which have tridentate chelates on each side of the alkoxy bridge. Unlike these previous, less complex ligands, the present series of binucleating ligands have a strong tendency to form oligomers. This has been demonstrated with a series of crystal structures of copper(II) complexes of these ligands. It is probable that oligomers are formed because of the high flexibility of the present ligands. The work serves to illustrate the limits of binuclear ligand design and suggests that, with alkoxide ligand bridges, rigidity is necessary in order to obtain bimetallic complexes with extended multidentate binucleating ligands. One of the ligands gives a mixed valence Mn(II)–Mn(IV) complex after O2 oxidation of a di-Mn(II) precursor.

Anhydrides of real and hypothetical [hydroxy(R-O)iodo]benzenes.

The anhydrides of [hydroxy(methanesulfonato-O)]iodobenzene (HMIB) and [hydroxy(toluenesulfonato-O)]iodobenzene (HTIB) were prepared by drying acetonitrile solutions of the compounds. The anhydrides of the hypothetical compounds [hydroxy(chloroacetato)-O]iodobenzene and [hydroxy(iodoacetato)-O]iodobenzene were obtained from aqueous solutions. Crystallographic structures were obtained for the anhydrides, except that of HTIB. The electron-domain geometries of the I atoms vis-a-vis secondary I...O bonds were explored. The presence of delocalized bonding in groupings of O and I atoms was suggested. A linear relationship between the C-I-O angles and the I-O bond orders was observed.

Promotion of host folding during the formation of a taco complex

Host folding for the formation of taco complexes can be promoted by introduction of additional interactions between the host and guest as shown by enhanced associations and X-ray crystal structures.