A pioneering work in the field of oxacephem antibiotics which had been carried out in our research laboratories is reviewed. Our research of β-lactam antibiotics was started in 1974 with the policy to make chemical modification at the nuclei but not the side chain of the existing β-lactam antibiotics, with an expectation to discover a new type of antibiotics. After the success in establishing an efficient synthetic method for 3'-nor-cephalosporin, we started oxacephem research in 1975. We succeeded in developing three synthetic methods starting from penicillins which efficiently served to prepare numerous oxacephem (1-oxa-1-dethia-cephalosporin) derivatives. It turned out that the oxacephem nucleus was much more distorted with an increased ring strain, resulting in reduction of the β-lactam amide resonance to a greater extent than the cephalosporin nucleus. This physicochemical properties conferred an increased chemical reactivity on the nucleus as evidenced by an increased hydrolysis rate as compared with the corresponding 1-thia counterpart. This increased chemical reactivity coupled with the reduced hydrophobicity of the oxacephem nucleus as evidenced by the lower distribution constant in a water-octanol system, characterized unique biological properties of oxacephem derivatives. These include (1) 2-16 times increase in antibacterial activity with emphasis against gram-negative bacteria ; (2) increased protecting effect in vivo parallel to the increased in vitro activity ; (3) reduction of the stability to β-lactamases leading to decreased antibacterial activity against the β-lactamase producing strains ; (4) 1.6-3.2 times increase in penetrability through the outer membrane of certain gram-negative bacteria, the increase being due to the increased hydrophilicity of the oxacephem nucleus ; (5) remarkably reduced binding to human serum albumin improving the efficacy of the oxacephems in the blood ; (6) a remarkable change in the excretion pattern, i.e. recovery in the bile reduced and that in the urine increased. These biological characteristics are generally favorable for antibacterial agents against pathogenic diseases except for the reduced stability to β-lactamases. This unfavorable property of the oxacephem nucleus was the only barrier for developing a new agent of the oxacephem nucleus. However, this problem was relatively easily solved by introduction of (1) the methoxy group at 7α and (2) appropriately α-substituted acyl amide side chain at 7β ; the former and the latter substituent effectively stabilized the oxacephems to various kinds of penicillinases and cephalosporinases, respectively. It turned out that both effects were complementary and, thus, combination of both substituents produced perfect stabilization of the oxacephems to β-lactamases, and brought about the complete recovery of the activity against resistant strains. Extensive studies were performed to obtain deep and broad knowledge in structureactivity relationships in the field of the newly explored oxacephems. As the results of these efforts we succeeded in obtaining two important and useful oxacephem compounds, i.e. latamoxef 18 and flomoxef 19. Latamoxef 18 is a very potent and broadly active third generation β-lactam antibiotic, and perfectly stable to various kinds of β-lactamases showing efficacy against most of the resistant bacteria. Moreover, it has very favorable pharmacological properties, such as a high blood level and a long half-life, which are essential for efficacy in human body. One of the drawback of this antibiotic, as commonly observed in the third generation antibiotics, was the rather weak activity against grampositive bacteria, especially against Staphylococcus aureus. This weak point was basically improved by introducing a new 7β-acylamido side chain and by a minor structural change in the N-methyl-tetrazol part, as seen in structure 19. [the rest omitted]

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The following species ; superoxide (O₂^⨪), hydrogen peroxide (H₂O₂), hydroxyl radical (·OH) and singlet oxygen (¹O₂), are generally called as reactive oxygen species (ROS). These species have been suggested to play important roles in various diseases caused by oxygen toxicity such as ischemia, carcinogenesis, inflammation, diabetes and aging. During the past two decades, considerable interests have been focused on chemical and biological research of ROS. We have also reported about the research results on ROS, which can be classified as following below ; 1) chemical reactivities of O₂^⨪, 2) formation and toxicity of ¹O₂, 3) chemical reactivities of ·OH, 4) enzyme mechanism of xanthine oxidase, 5) development of the compounds which induce the formation of O₂^⨪ and H₂O₂ in living cells and 6) development of superoxide dismutase mimics. These studies are reviewed from the standpoint of both chemical and biological interests.

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From the dried rhizomes of Oleandra wallichii, six hydrocarbons [hop-22 (29)-ene, neohop-13 (18)-ene, fern-7-ene, fern-8-ene, fern-9 (11)-ene and adian-5-ene], an ozonide (adian-5-ene ozonide, a new compound), three acetates (dryocrassyl acetate, neriifolyl acetate and tetrahymanyl acetate), a lactone (hopan-28, 22-olide), three mono-ols (hydroxyhopane, tetrahymanol and neriifoliol) and a diol (hopan-22, 28-diol, the first example from nature) with cycloartanoid alcohol mixture, sterol mixture and a mixture of fatty acid esters of cycloartanoid alcohols, neriifoliol, dryocrassol and sterols were detected as pentacyclic triterpenoids. The occurrence of various kinds of hopane and migrated hopane group hydrocarbons and their oxygenated compounds suggests that this fern is related to Adiantum (Pteridaceae) from a chemotaxonomical point of view. Especially, adian-5-ene ozonide, has been found only in O. wallichii and Adiantum monochlamys.

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In screening of new antifungal agents, bis (naphthalenemethyl) amines were found to have more potent antifungal activity than clotrimazole. Studies on their structure-activity relationships indicated that benzylamines had potent antifungal activity. Among them, butenafine hydrochloride (N-p-tert-butylbenzyl-N-methyl-1-naphthalenemethylamine hydrochloride, KP-363) has proved to show the strongest activity. It exhibits a wide spectrum activity in vitro against particularly dermatophytes (87 strains ; minimal inhibitory concentration (MIC) range, 0.0015 to 0.05μg/ml), and also against Aspergillus (15 strains ; MIC range, 0.025 to 0.78μg/ml), Cryptococcus neoformans (4 strains ; MICs 0.78 and 1.56μg/ml) and yeasts of genus Candida (67 strains ; MIC range, 3.13 to >100μg/ml).

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In the folk-medicine, several kinds of crude drugs are used as diuretics. Twenty three kinds of diuretic drugs were chosen, and examined for their effects on the horse kidney (Na⁺+K⁺)-adenosine triphosphatase (ATPase), which is an intrinsic enzyme of the plasma membrane and responsible for the active transport of Na⁺ and K⁺ across the membrane. Twenty one out of twenty three kinds of ethanol extracts of diuretic drugs inhibited the kidney (Na⁺+K⁺)-ATPase activity. The intensity of the inhibition of these drugs was compared by estimating the amounts of their ethanol extracts which inhibited the (Na⁺+K⁺)-ATPase activity by 50% (I₅₀, μg/ml). Among these drugs, Atractylodis Lanceae Rhizoma ( ?? ??, I₅₀=12.8) Atractylodis Rhizoma ( ?? ??, I₅₀=15.2), Plantaginis Semen ( ?? ?? ??, I₅₀=16.0), Plantaginis Herba ( ?? ?? ??, I₅₀=16.0) and Alismatis Rhizoma ( ?? ??, I₅₀=22.0), have strong inhibitory effects on the kidney (Na⁺+K⁺)-ATPase activity. The ethanol extracts of the rhizomes of Atractylodes lancea DE CANDOLLE ( ?? ?? ?? ?? ) and Atractylodis japonica KITAMURA ( ?? ?? ?? ) were examined with varying concentrations of ATP and ouabain. The mode of inhibition of these two extracts on the (Na⁺+K⁺)-ATPase activity appeared to be uncompetitive with respect to ATP as judged from Line-weaver-Burk plot. The ethanol extract of Atractylodes japonica KITAMURA decreased the I₅₀ for ouabain from 1.6×10^-7 to 7.0×10^-9M, while that of Atractylodes lancea DE CANDOLLE did not change the I₅₀ for ouabain.

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