Aya Tanatani

Boron Cluster-based Development of Potent Nonsecosteroidal Vitamin D Receptor Ligands: Direct Observation of Hydrophobic Interaction between Protein Surface and Carborane

We report here the design and synthesis of a novel vitamin D receptor (VDR) agonist whose hydrophobic core structure is p-carborane (1,12-dicarba-closo-dodecaborane, an icosahedral carbon-containing boron cluster having remarkable thermal and chemical stability and a characteristically hydrophobic B-H surface). This carborane-based VDR ligand exhibited moderate vitamin D activity, comparable to that of the natural hormone, despite its simple and flexible structure. X-ray structure analysis provided direct evidence that the carborane cage binds to the hydrophobic surface of the ligand-binding pocket of the receptor, promoting transition to the active conformation. These results indicate that the spherical B-H surface of carborane can function efficiently as a hydrophobic anchor in binding to the receptor surface, thereby allowing induced fitting of the three essential hydroxyl groups on the alkyl chains to the appropriate positions for interaction with the VDR binding site, despite the entropic disadvantage of the flexible structure. We suggest that carborane structure is a promising option in the design of novel drug candidates.

Anti-androgens with full antagonistic activity toward human prostate tumor LNCaP cells with mutated androgen receptor.

Anti-androgens were designed based on the principle of inhibiting the folding of helix 12 of the nuclear androgen receptor. The prepared anti-androgens exhibited full antagonistic activity toward human prostate tumor LNCaP cells with T877A point-mutated nuclear androgen receptor, as far as examined, towards which other known anti-androgens, including hydroxyflutamide, are inactive or act as androgen agonists.

Folding of a Linear Array of α‑Amino Acids within a Helical Aromatic Oligoamide Frame

Control of the spatial organization of proteinogenic side chains is critical for the development of protein mimics with selective recognition properties toward target protein surfaces. We present a novel methodology for producing a linear array of proteinogenic residues based on the incorporation of α-amino acids into sequences of rigid, helically folded oligoamides of 8-amino-2-quinolinecarboxylic acid (Q). When L-leucine (L) was alternated with dimer Q2, the resulting sequence adopted a right-handed helical conformation, as deduced in solution from the CD spectra of L-(LQ2)n (n = 2, 4) and in the solid state from X-ray crystallographic analysis of (±)-(LQ2)4. Each LQ2 segment spanned just one helix turn (pitch of 3.5 Å), and consequently, the four leucine side chains of (LQ2)4 formed a linear array. In solution, NMR analysis showed that both L-(LQ2)2 and L-(LQ2)4 exist as a mixture of two slowly equilibrating folded conformers, the proportion of which strongly varies with the solvent.

Helical aromatic urea and guanidine

N , N ′-Dimethyl- N , N ′-dipheylurea ( 1 ) and N , N ′-Dimethyl- N , N ′-diphenyl-guanidinium bromide ( 2 ) each have folded structures with the two phenyl groups located face-to-face. Oligomeric compounds 3 and 4 , having five benzene rings connected at the meta positions by cis -urea or guanidino groups, form aromatic layered helices in the crystal state. The crystals are racemic with a 1:1 enantiomer ratio. They exhibit stacked ( 3 ) or zigzag chain ( 4 ) packing, reflecting displaced parallel structure for the terminal phenyl groups of neighboring molecules of 3 and tilted T-shaped structure for those of 4 , respectively.

Identification of Absolute Helical Structures of Aromatic Multilayered Oligo(m-phenylurea)s in Solution

The oligomeric aromatic ureas bearing N,N-dimethylated urea bonds such as 3 have aromatic multilayered structure, based on the (cis,cis)-urea structure, and also have dynamic helical structure (all-R or all-S axis chirality) when the benzene rings are connected at the meta positions. The absolute helical structure of oligo(m-phenylurea)s were identified by the empirical and theoretical studies on the CD and vibrational CD (VCD) spectra. Thus, each enantiomer of the oligo(m-phenylurea)s 4 bearing a chiral N-2-(methoxyethoxyethoxy)propyl group were synthesized. Intense dispersion-type CD spectra of 4 were observed, which indicated the induction of handedness in the helical structure. In the VCD spectra of 4 in the film state, the signals due to the carbonyl and aromatic ring vibrations were seen with negative and positive values for compounds 4a and 4b, respectively. The calculations of both CD and VCD spectra of oligo(m-phenylurea)s 3 without any chiral N-substituent gave the same assignment about the axis chirality of 4. Thus, the absolute configurations of 4a and 4b are all-R and all-S structures, respectively.

A chiral N-methylbenzamide: Spontaneous generation of optical activity

Abstract 1,2-Bis(N-benzoyl-N-methylamino)benzene (1) was crystallized from distilled ethyl acetate as chiral crystals belonging to space group P212121. The optically active crystals of the two enantiomers were distinguishable morphologically, and their CD spectra in KBr were mirror images. In solution, several conformational isomers due to rotations of the Arue5f8N bonds and the amide bonds were observed. The major conformer corresponds to the crystal structure in which the two N-benzoyl groups exist on opposite sides of the central benzene ring (anti conformation) and the amide bonds are both cis. The enantiomers in solution could be distinguished from each other by 1H-NMR measurements in the presence of chiral 1,1′-bi-2-naphthol. Mixed crystals of 1 and (R)-1,1′-bi-2-naphthol were obtained from their 1:1 mixed solution in MeOH. An X-ray crystallographical analysis showed that the configuration of 1 in the mixed crystals was (R,R). 1H-NMR measurements of the mixed crystals at 178 K in CD2Cl2 showed the absolute configuration of 1 in the CD260-(+)-crystal to be (R,R).

6-Arylcoumarins as Novel Nonsteroidal Type Progesterone Antagonists: An Example with Receptor-Binding-Dependent Fluorescence

Various 6-arylcoumarin derivatives were designed and synthesized as candidate nonsteroidal type progesterone antagonists. 6-Bromocoumarin derivatives were prepared from the corresponding 4-substituted 2-acetoxy-5-bromobenzaldehyde by employing the Still-Gennari modification of the Horner-Wadsworth-Emmons olefination reaction and were converted to 6-arylcoumarins by means of Suzuki-Miyaura cross-coupling reactions. The biological activities of these coumarin derivatives were evaluated by means of alkaline phosphatase assay in the T47D human breast carcinoma cell line. Among the synthesized compounds, 36 (IC(50) = 0.12 μM) and 38 (IC(50) = 0.065 μM), bearing a five-membered heterocycle, showed potent PR antagonist activity. Competitive binding assay showed that compounds 8 and 34 have potent PR binding affinity. The fluorescence of compound 8 was dependent on the solvent properties and was increased in the presence of PR ligand binding domain. This property might be applicable to the development of fluorescence probes for studies on PR.

Molecular construction based on icosahedral carboranes and aromatic N,N′-dimethylurea groups. Aromatic layered molecules and a transition metal complex

Abstract cis-Preference of N-methyl aromatic ureas in combination with regulation of the C-substituent on an o-carborane cage is applicable to construct structurally unique macromolecules. Aromatic ureas with multilayer structure (5–12) and an aromatic urea containing an intramolecular nido-carborane–cobalt complex (13) were synthesized and their structures were determined by X-ray crystallography.

4-(Anilino)pyrrole-2-carboxamides : Novel non-steroidal/non-anilide type androgen antagonists effective upon human prostate tumor LNCaP cells with mutated nuclear androgen receptor

Various 4-(anilino)pyrrole-2-carboxamides were designed and synthesized as novel androgen receptor (AR) antagonists without steroidal or anilide structure, based on our strategy for developing full antagonists of nuclear receptors. Introduction of a bulky N-alkyl group, such as a cyclohexylmethyl or benzyl group, increased the binding affinity for wild-type AR and the potency for growth inhibition of androgen-dependent SC-3 cells. Among the compounds obtained, N-[4-[(benzyl)(4-nitrophenyl)amino]-1-methylpyrrole-2-carbonyl]pyrrolidine (22) is as potent an AR antagonist as the typical anilide-type AR antagonists hydroxyflutamide and bicalutamide. Further, compound 22 had potent binding affinity for T877A mutated AR, and dose-dependently inhibited the testosterone-induced production of prostate-specific antigen in LNCaP cells bearing T877A AR.

Aromatic layered guanidines bind sequence-specifically to DNA minor groove with precise fit

Abstract Tetraguanidines ( 1 and 2 ) with an aromatic multilayered structure exhibit potent binding to a specific site of DNAs with binding constants of the order of 10 7 M −1 as deduced from Scatchard analysis of ultrafiltration data and simulation of CD titration curves. NMR spectra of the complexes indicated that 1 and 2 bind DNAs sequence-specifically at the minor groove, as predicted by computational docking studies.