Strong potassium channel-activating effects were found among a series of novel 4-substituted 3,4-dihydro-2H-1,4-benzoxazine derivatives. The key step in preparation was the nucleophilic substitution of 3,4-dihydro-2H-1,4-benzoxazine (3) with activated halogenopyridines, such as halogenopyridine N-oxides (15a--c) and the borane adduct (15d) of 4-bromopyridine. Structure-activity relationship studies identified 2-(3,4-dihydro-2,2-dimethyl-6-nitro-2H-1,4-benzoxazin-4-yl)pyridin e-1-oxide (16a: YM934) as the optimal compound. This compound (16a) showed a more potent oral antihypertensive effect than cromakalim in conscious spontaneously hypertensive rats.

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In terms of molecular symmetry and bioactivity, new C 3 -and C S -symmetrical derivatives based on the tris(2-aminoethyl)amine scaffold were designed and synthesized. The synthesized compounds were evaluated for antiviral activity with herpes simplex virus type 1 (HSV-1) by a plaque reduction assay and for cytotoxic activity with Vero cells. Most of the compounds showed no significant anti-HSV-1 activity, but some of the symmetrical derivatives showed high levels of cytotoxic activitiy.Key words tris(2-aminoethyl)amine; tripodal; anti-herpes simplex virus type 1; C 3 symmetry; C S symmetry; plaque reduction assay There have been many reports on the molecular recognition properties of symmetrical molecules, 1) and it is known that the symmetrical feature is frequently observed in many biological stages. Two-fold and three-fold symmetrical macromolecular structures are common features in specialized biological functions.2-4) Regarding the molecular symmetry, small symmetrical molecules with a C 2 -symmetrical or C 3 -symmetrical structure have often been found in various synthetic biologically active compounds. 5-7)In the course of our work on new antiviral compounds, we have presented a new class of antiviral candidates. For example, we have already reported that most of the triarylmethane derivatives showed a wide range of antiviral activities against herpes simplex virus type 1 (HSV-1). 8,9) In continuation with our work for finding potent antiviral derivatives, synthetic molecular modifications directed our attention to the molecular symmetry for the biological activity. Our recent studies on heteroaryl-substituted triarylmethane derivatives indicated that compounds bearing a prochiral symmetric feature (possessing C S symmetry) showed a higher level of antiviral activity than that of the corresponding C 3 -symmetrical molecules 9,10)

Optimal conditions for inversion of the chirality at 2-position of the 2-alkyllactone(5) have been established. By utitizing the inversion method developed, three indole alkaloids, (+)-velbanamine(16), (−)-isovelbanamine(17), and (+)-cleavamine(18), have been synthesized from the chiral lactone(1) which has been previously used for the syntheses of the enantiomers of these alkaloids.

A boronic acid-appended γ-cyclodextrin (BA-CyD) was synthesized as a hybrid cross-linker of polyvinyl alcohol (PVA) to form a new type of hydrogel. The CyD moiety of BA-CyD forms an inclusion complex with the PVA chain to produce a mechanically interlocking structure. At the same time, the BA moiety of BA-CyD forms covalent bonds with the 1,3-diol moieties of PVA. On the basis of these two modes of interaction, the hybrid cross-linker connects two PVA chains, thus resulting in the formation of a hydrogel. To investigate the possibility of this hydrogel becoming the basis for an intelligent material for drug delivery, sugar-responsive drug release from the hydrogel was demonstrated.

A new series of 3,4-dihydro-2H-1,4-benzoxazine derivatives, where various substituents were introduced into one of the geminal dimethyl groups at the 2 position, were synthesized and their potassium channel-activating activity was evaluated. Introduction of a hydroxyl group, as in compound 5, resulted in good solubility in water and a long duration of action compared with the parent compound 1. Introduction of a nitrato group, as in compound 8, produced typical nitrate activity such as exhibited by nitroglycerine in addition to potassium channel-activating activity. X-ray structural analysis of compound 5 showed that the sum of the bond angles around the N atom at the 4 position was 357.8 degrees, suggesting that the N atom had an approximately sp2-like planar bond configuration.

We prepared polypseudorotaxanes (PPRXs) composed of cyclodextrin (CyD) and polyethylene glycol (PEG) inside microspheres (MSs) by an emulsifying process using polypropylene glycol (PPG) that shows temperature-dependent hydrophilicity changes; PPG is hydrophobic at high temperatures but hydrophilic at low temperatures. An aqueous solution of CyD and PEG was dispersed as droplets in PPG at 60°C then cooled to 0°C to allow water of droplets to transfer into PPG. On removal of water in the droplets, CyD and PEG were left behind as a CyD/PEG PPRX inside the solid-state MSs. Examination of α-, β-, and γ-CyD revealed that α-CyD was suitable for the formation of PPRX containing PEG in this MS preparation procedure. Interestingly, a new PPRX composed of α-CyD and PPG was formed in the α-CyD MSs when they were prepared in the absence of PEG from the aqueous solution of α-CyD. This MS fabrication procedure can control the size and shape of PPRX particles, and will contribute to the production of new types of CyD inclusion complexes. Key words cyclodextrin (CyD); microsphere (MS); polyethylene glycol (PEG); polypropylene glycol (PPG); polypseudorotaxane (PPRX)Cyclodextrins (CyDs) are cyclic oligosaccharides composed of 6, 7, or 8 glucopyranoside units, which are named α-, β-, and γ-CyD, respectively. CyDs consist of a hydrophobic cavity in which hydrophobic molecules are enclosed to form an inclusion complex. CyDs are widely used as a pharmaceutical additive for their ability to improve the solubility and stability of drugs via CyD complexation.

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