Biomedical subjects
Publications and source records attributed to Ronald K Castellano.
The first discrete, self-complementary, quadruply hydrogen-bonded complexes based on the 2,6-diaminopurine (DAP) scaffold have been prepared; regioselective urea formation at the C2 amino group of the heterocycle allows intermolecular dimerization (K(dim) approximately 1-1.6 x 10(3) M(-1) in CDCl3) through a DADA hydrogen bonding motif.
Described are among the first highly diastereoselective, one-pot organometallic addition and hydride reduction reactions (>95% de) involving three symmetry-equivalent carbonyl centers, each that bears a 1,5-relationship to its nearest neighbor. Three-fold methyllithium addition to 2,4,6-trimethoxybenzene-1,3,5-tricarbaldehyde gives the anti,syn triol exclusively (by 1H NMR); addition of HMPA to the reaction or replacement of the substrate's methoxy groups with ethyl groups affords a statistical 3:1 (anti,syn:syn,syn) diastereomeric product ratio. Analogous asymmetric induction is found upon hydride reduction (using LiAlH4 or NaBH4) of the complementary triketone, 2,4,6-trimethoxybenzene-1,3,5-triethanone. Chelation and steric (gearing) effects about the crowded aromatic core contribute to the observed stereoselectivity.
[reaction: see text] Directional intramolecular interactions play a critical role in the self-assembly of donor-sigma-acceptor molecules in solution. Amide functions on the periphery of the tricyclic core stabilize a C3-symmetric monomer conformation by intramolecular hydrogen bonding and dipole-dipole interactions. The molecules are effective organogelators and show long-range ordering in the bulk.
[structure: see text] 3,5,7-Tris(arylmethyl)-1-aza-adamantanetrione donor-sigma-acceptor compounds have been synthesized in four steps. Computational and (1)H NMR analyses rationalize the solubility, gelation, and conformational properties of the C3-symmetric molecules toward employing sigma-coupled donor-acceptor interactions in molecular self-assembly.
A series of Rebek imide receptors with naphthalene or heteroaromatic platforms attached by amide or ester linkers have been prepared from the corresponding acyl chloride or anhydride; the X-ray crystal structure of the receptor-derived anhydride reveals a supramolecular H-bonded helix formation in the crystal; the complexes of adenine bound to the receptors by Hoogsteen H-bonding are found to be stabilised by stacking with a methylquinolinium ion, but destabilised by stacking with a perfluorinated naphthalene.
Intermolecular interactions involving aromatic rings are key processes in both chemical and biological recognition. Their understanding is essential for rational drug design and lead optimization in medicinal chemistry. Different approaches-biological studies, molecular recognition studies with artificial receptors, crystallographic database mining, gas-phase studies, and theoretical calculations-are pursued to generate a profound understanding of the structural and energetic parameters of individual recognition modes involving aromatic rings. This review attempts to combine and summarize the knowledge gained from these investigations. The review focuses mainly on examples with biological relevance since one of its aims it to enhance the knowledge of molecular recognition forces that is essential for drug development.
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Rebek imides (3), formed from Kemp's triacid, were developed in the mid-1980's as model receptors for adenine derivatives. We report here the first account of their hydrogen-bonding preferences upon binding 9-ethyladenine (1a) in the solid state. Structural analysis begins with simple imides 3a-e that form discrete dimers, while bis-imide 4 forms ribbon-like structures in the crystalline phase. The hydrogen-bonding interface within each of the representative assemblies features short intermolecular N(3)imide...O(8*)imide* distances (ca. 2.95 A), indicative of two-point hydrogen bonding. Imides 3f-h could be co-crystallized with 1a; single-crystal X-ray analysis of the resulting complexes reveals hydrogen-bonding geometries nearly identical to those observed in nucleobase complexes of adenine and pyrimidine derivatives. Imides 3f and 3g form 2:1 ternary assemblies with 1a; the complex of the former, (3f)2 x 1a, displays both Watson-Crick- and Hoogsteen-type hydrogen bonding, whereas the complex of the latter, (3g)2 x 1a, shows the Hoogsteen motif and imide hydrogen bonding to N(3) of the purine base (N(3)adenine...N(3'')imide = 3.07(1) A). Imide 3h forms a 1:1 complex with 1a (3h x 1a x CHCl3) and displays Hoogsteen binding exclusively. All of the 3 x 1a assemblies show C(adenine)...O(imide) distances (3.38-3.75 A) that are consistent with C-H...O hydrogen bonding. Base-pairing preferences for the Rebek imides are further explored in solution by 1H NMR one-dimensional NOE experiments and by computational means; in all cases the Hoogsteen motif is modestly favored relative to its Watson-Crick counterpart.