日本抗生素研究动向

本文对1987年日本国内发表的抗生素论文183篇和专利112份进行综述。β-内酰胺抗生素类从约氏纤维粘细菌PB-5266的培养液,用色层分离技术分离到新型的单环β-内酰胺PB-5266A、B和C。它们与以前报道过的单环β内酰胺不同,有脱氢天冬酰胺基。它们对β-内酰胺抗生素敏感的大肠杆菌变株的抗菌活性弱。它们的结构式见图1所示。氨基糖苷抗生素类从产生SporaricinA糖多孢菌(S.hirsta subsp.kobensis)分离到新的类似物2″-N-甲亚胺氧基sporaricin A。它对包括氨基糖苷耐药菌在内的革蓝氏阳性和阴性菌有强的抗菌活性。     

β-内酰胺环的合成方法

继青霉素、头孢菌素以后在七十年代又发现了棒酸、诺卡菌素和硫霉素等具有β-内酰胺环结构的抗生素或β-内酰胺酶抑制剂。近几年来,又发现了一些单环S-内酰胺抗生素并合成了氨噻羧单胺菌素(Azthreonam,SQ26,776)等许多抗菌作用强的单环β-内酰胺类化合物。这些发现引起人们对β-内酰胺类化合物的极大兴趣。现在有关     

P-(3-酰氨基-4-取代苯基-2-吖丁啶酮基-1)-苯乙酸和P-(3-酰氨基-4-取代苯基-2-吖丁啶酮基-1)-苯乙酮的合成及抑制β-内酰胺酶作用

为研究吸电子基团远离环氮的单环β-内酰胺类化合物对β-内酰胺酶的抑制作用,设计与合成了21个新的p-(3-酰氨基-4-取代苯基-2-吖丁啶酮基-1)苯乙酸和p-(3-酰氨基-4-取代苯基-2-吖丁啶酮基-1)苯乙酮类化合物,经元素分析、红外光谱、核磁共振氢谱和质谱证实。生物活性测定表明,其中15个具有游离羧基的水溶性化合物对试验的腊样芽胞杆菌和绿脓杆菌产生的β-内酰胺酶有抑制作用。     

P-(3-酰氨基-4-取代苯基-2-吖丁啶酮基-1)-苯乙酸和P-(3-酰氨基-4-取代苯基-2-吖丁啶酮基-1)-苯乙酮的合成及抑制β-内酰胺酶作用

为研究吸电子基团远离环氮的单环β-内酰胺类化合物对β-内酰胺酶的抑制作用,设计与合成了21个新的p-(3-酰氨基-4-取代苯基-2-吖丁啶酮基-1)苯乙酸和p-(3-酰氨基-4-取代苯基-2-吖丁啶酮基-1)苯乙酮类化合物,经元素分析、红外光谱、核磁共振氢谱和质谱证实。生物活性测定表明,其中15个具有游离羧基的水溶性化合物对试验的腊样芽胞杆菌和绿脓杆菌产生的β-内酰胺酶有抑制作用。     

单环β—内酰胺环合成化学（1）：由单一分子的化学转化合成环的方法

本世纪八十年代初,在抗生素的研究领域里,出现了一类具有β-内酰胺单环母核的新型化学物质,即单环β-内酰胺抗生素。它们的出现标志着β-内酰胺抗生素药物研究的新突破。 由于单环β-内酰胺的结构新颖简单,并且这类抗生素具有广泛的抗菌谱和很高的抗菌活性。因而立即引起了人们的重视,许多研究机构均涉足于此领域。从而使得这类化合物成了八十年代合成β-内酰胺类抗生素的重点对象之一。人们围绕着它展开了     

4-无取代单环β-内酰胺抗生素合成方法的研究

本文报道了用L(+)—天门冬氨酸为原料,经Schmidt重排反应得到L(+)-2,3-二氨基丙酸,再在Ph₃P—(PyS)₂—CH₃CN系统中环合得到4-无取代单环β-内酰胺抗生素的关键中间体,N-苄氧甲酰基-3 S-氨基-2-氧吖丁啶(Ⅲ)的方法。研究了用2,2′-二苯并噻唑二硫醚代替(PyS)₂作为环合氧化剂;以(Ⅲ)制备了三个新的单环β-内酰胺抗生素衍生物(Ⅷa),(Ⅷb)和(Ⅷc)。     

科研技术简讯

S039 从L-α-氨基-β-羟基酸合成(S)-3-氨基-1-磺酸氮杂环丁酮-2 Floyd D M等[J.O.C.47(26):5160～5167,1982] 新型单环类β-内酰胺抗生素-单环磺酸类(Monobactams)(1),可从丝氨酸类合成。已进入临床的阿苏胺(Azthreonam,即SQ26776)(2)的主环(3),可从L-苏氨酸合成。在用叔丁氧羰基保护氨基之后,即与O-甲羟胺及水溶性碳二亚胺一锅煮得O-甲基羟肟酸酯,羟基经甲磺酰化,在碳酸钾作用下,环合成β-内酰胺(4)。再用钠氨去除氮上的甲氧基,经N磺化及去除3位氨基保护基后,即得(3)。总收率可达45％,较前此的文献高,且方法上也有较大的改进。     

日本抗生素研究动向

本文对1988年日本国内发表的抗生素论文225篇进行综述。β-内酰胺类抗生素由假单孢菌(P.cocovenenans 326-32B)培养液分离到单环内酰胺抗生素MM42842和bulgecins。MM42842的化学结构与Sulfazecin相似(图1)。北里孢菌(Kitasatosporic papulosaAB-110)产生表硫霉素A、B、E和F的同时,还产生一种新抗生素AB-110-D(图2),它对革兰氏阳性和阴性菌都有很强的抗菌活性,对β-内酰胺酶也有很强的抑制活性。从沙雷氏菌和欧文氏菌培养液分离到两种β-内酰胺,即(3R,5R)-和(3S,5R)-碳     

一种口服用单菌霉素泰基莫喃

泰基莫喃(Tigemonam)是一种新合成的单环β-内酰胺类抗生素,其口服效果较其他单环β-内酰胺类抗生素为优.作者采用体外试验方法,测定了对临床分离菌株的敏感性,影响抗菌活性的诸因素,并     

顺-4-羟甲基-3-苄氧羰酰胺基-2-吖丁啶酮的新合成方法

报道单环β-内酰胺抗生素重要中间体4-羟甲基-β-内酰胺(2)的新合成方法。用 Dane 盐(3)与Schiff 碱(4)加成环合法先制得4-苯乙烯基-β-内酰胺(5),再经四氧化锇-高碘酸钠氧化断裂双键,继经硼氢化钠还原而得4-羟甲基-β-内酰胺(2)。本文对环合、脱保护等各步反应条件进行了改进。总收率以 Schiff 碱计算为12%。     

Synthesis and antimicrobial properties of substituted 3-aminoxypropionyl and 3-aminoxy-(E)-2-methoxyiminopropionyl monobactams

The substituted 3-aminoxyproprionyl (VII) and 3-aminoxy-(E)-2-methoxyiminopropionyl monobactams (VIII) which possess the monocyclic beta-lactam nucleus of aztreonam (IX) were synthesized by reaction of triethylammonium (3S, 4S)-3-amino-4-methyl-2-oxo-1-azetidinsulfonate with the aminoxy acids X and XI, respectively. Compounds VII and VIII were assayed in vitro for their antimicrobial properties against Gram-positive and Gram-negative bacteria, whether producers of beta-lactamases or otherwise. Both types of compounds (VII and VIII) exhibited a poor antibacterial activity towards Gram-positive bacteria, comparable to that of aztreonam. On the contrary VII and VIII proved to be practically inactive against Gram-negative microorganisms, towards which aztreonam exhibits a high degree of activity.     

Synthesis and in vitro antibacterial activity of a new series of monobactam derivatives

Using as a model monobactams with a substituted alpha-oxyimino moiety in the side chain (aztreonam), a series of 2-(2-aminothiazol-4-yl)-2-hydrazono-acetamido monobactam (II a, f) were prepared by condensation of the hydrazones (I a, e) (Z form) with tetrabutylammonium 3-amino-4-methyl-2-oxo-1-azetidin-sulphonate. Isomerization occurred during this synthesis and gave the E form of all compounds. Monobactams (II a, f) showed no significant in vitro antibacterial activity when compared with aztreonam and with some cephalosporins bearing the same E-hydrazono side chain.     

New constituents of Leontopodium alpinum and their in vitro leukotriene biosynthesis inhibitory activity

Phytochemical investigations of the roots of Leontopodium alpinum Cass. resulted in the isolation and structure elucidation of six novel compounds and two known compounds. Novel constituents could be identified as the polyacetylenes 1-acetoxy-3-angeloyloxy-(4 E,6 E)-tetradeca-4,6-diene-8,10,12-triyne and its (6 Z)-isomer, the kaurenic acid derivative methyl ent-7alpha,9alpha-dihydroxy-15beta-[(2 Z)-2-methyl-but-2-enoyloxy]kaur-16-en-19-oate, the bisabolane derivative (1 R*,3 S*,4 R*,6 S*)-9-(acetoxy)-4-hydroxy-1-[(2Z)-2-methylbut-2-enoyloxy]bisabol-10(11)-ene and the lignans [(2 S,3 R,4 R)-4-(3,4-dimethoxybenzyl)-2-(3,4,5-trimethoxyphenyl)-tetrahydrofuran-3-yl]-methyl-(2 Z)-2-methylbut-2-enoate and its 3,4,5-trimethoxybenzyl derivative. Known compounds, reported here for the first time for the genus Leontopodium, were identified as ent-kaur-16-en-19-oic acid and T-cadinol. The obtained compounds were tested together with 15 previously described compounds of L. alpinum in an ex vivo leukotriene biosynthesis inhibition assay. The highest activities were determined for the bisabolane derivates (IC50: 7.7 to 11.4 microM), one lignan (IC50: 10.7 microM) and the ent-kaurenoate (IC50: 10.4 microM).     

Phenolic compounds from the aqueous extract of Acacia catechu

Two new phenolic compounds, 5-hydroxy-2-[2-(4-hydroxyphenyl) acetyl]-3-methoxylbenzoic acid (1) and (2S,3S)-3,7,8,3',4'-pentahydroxyflavane (2), were obtained from the aqueous extract of Acacia catechu, along with four known compounds identified as rhamnetin (3), 4-hydroxyphenyl ethanol (4), 3,3',5,5',7-pentahydroxyflavane (5), and fisetinidol (6). Their structures were determined on the basis of spectroscopic analysis. Free radical-scavenging activities of the new compounds were evaluated.     

Taraxasterane-type triterpene and neolignans from Geum japonicum Thunb. var. chinense F. Bolle

The phytochemical investigation of the ethanolic extract of the whole plants of Geum japonicum Thunb. var. chinense F. Bolle yielded four new compounds: 20 β,28-epoxy-28-hydroxytaraxasteran-3 β-ol (1), (7R,8R)-4-hydroxy-9'-O-(α-L-rhamnopyranosyl)-3,3',5'-trimethoxy-8-O-4'-neolignan (2), (7R,8S)-4-hydroxy-9'-O-(α-L-rhamnopyranosyl)-3,3',5'-trimethoxy-8-O-4'-neolignan (3), and (7S,8S)-5-methoxycupressoside A (4), as well as 40 other known compounds. Structures were elucidated by physical, chemical, and spectroscopic methods, including 1D and 2D NMR, HRESIMS, and CD experiments. The taraxasterane-type triterpene (1) and lignans (2- 6) are reported for the first time from the GEUM genus. Moreover, all compounds were evaluated for anti-inflammatory activities against NO production in RAW264.7 macrophages, and only moderate activities were detected.     

Inhibitory effects of various sulfur compounds on the activity of bovine erythrocyte enzymes

Studies were conducted to assess the in vitro effects of selected sulfur compounds on the activities of superoxide dismutase (SOD), catalase, glutathione peroxidase (GSHPX), and glucose-6-phosphate dehydrogenase (G6PDH) in hemolyzates of bovine erythrocytes. All sulfur compounds produced concentration-dependent inhibition in the activities of these enzymes, but their effects on each enzyme were different. SOD and catalase activities were most sensitive to sulfide (S2-), followed by sulfite (SO3(2-)) and sulfate (SO4(2-)). GSHPX activity was most sensitive to SO3(2-), followed by S2-, cysteine and SO4(2-). The activity of G6PDH, however, was maximally inhibited by reduced glutathione (GSH), followed by SO3(2-) and SO4(2-); S2- was inhibitory only at high concentrations. Dialysis of the S2- and SO3(2-)-inhibited enzymes resulted in complete or partial reversal of inhibitory effects. The biochemical significance of these effects in relation to erythrocyte physiology is discussed.     

Synthesis and antimicrobial activities of some new tetrahydro-2H-1,3,5-thiadiazine-2-thione derivatives of cephalexin

In this study, compounds with a 7-[2-(dihydro-5-substituted 6-thioxo-2H-1,3,5-thiadiazine-3[4H]-yl)-2-phenyl]acetamido-3 -methyl-3- cephem-4-carboxylic acid structure were synthesized by reacting cephalexin monohydrate with formaldehyde and dithiocarbamic acid salts prepared from some primary amines. The structure of the compounds was confirmed by spectral data and elementary analysis. The antimicrobial activities of the compounds were investigated against some bacteria (Staphylococcus aureus, Streptococcus faecalis, Escherichia coli and Pseudomonas aeruginosa) and some Candida sp. (C. albicans, C. parapsilosis, C. stellatoidea and C. pseudotropicalis) by using tube dilution method. In microbiological studies, cephalexin monohydrate was used as reference standard. Both compounds were synthesized and cephalexin monohydrate was found ineffective against S. faecalis and P. aeruginosa in the concentrations studied. While most of the compounds showed bacteriostatic activity against S. aureus, compounds 1, 3 and 7 showed the same activity against E. coli. On the other hand, compound 3, 5, 6, 7 and 10 showed anticandidal activity, whereas cephalexin monohydrate was not active against any Candida sp. Compound 11 was found effective against C. stellatoidea and C. pseudotropicalis.     

A new para-quinone-type flavan from the leaves of Ilex centrochinensis and its anti-inflammatory activities

A new para-quinone-type flavan, (2S)-7-methoxy-3′,4′-dihydroxy-5,8-quinoflavan (1), together with three known compounds, were isolated from the leaves of Ilex centrochinensis. Their structures were elucidated by detailed spectroscopic analyses for new structure and in comparison with published data for known compounds. Moreover, the new compound was evaluated its cytotoxic and anti-inflammatory activities in vitro on LPS induced RAW 264.7 cells and the results showed that 1 has promising anti-inflammatory activities.     

7-[(1S,5R)-2-苄基-2,6二氮杂环(3.2.1)辛烷-6-基]喹诺酮类化合物的合成与抗菌作用

以 ( 4R) 羟基 L 脯氨酸为原料 ,经十三步反应得 ( 1S ,5R) 2 苄基 2 ,6 二氮杂二环 ( 3.2 .1)辛烷二氢溴酸盐 ,以此化合物作为 7位侧链 ,合成了四个喹诺酮类化合物 ,并测定了它们对 10株革兰氏阳性菌和 6株革兰氏阴性菌的MIC值 ,结果表明 ,它们的体外抗菌作用均低于对照药加替沙星和环丙沙星。本文共合成了 2 0个化合物 ,除 2、3、4外 ,其余均为文献未见报道的新化合物 ,其结构经NMR和MS所确证。     

Novel diarylheptanoids of Alpinia blepharocalyx

The seeds of Alpinia blepharocalyx K. Schum. (Zingiberaceae) is used in Chinese traditional medicine for the treatment of stomach disorders. From the ether fraction of a 95% ethanolic extract, which showed hepatoprotective and antiproliferative activities, we isolated 16 novel diarylheptanoids bearing a chalcone or a flavanone moiety [calyxins A-H; epicalyxins B-D, G, and H; 6-hydroxycalyxin F; and blepharocalyxins A and B] together with seven known compounds, while the residual fraction of the ethanolic extract gave 32 novel diarylheptanoids namely, calyxins A, E-G, and I-M; epicalyxins B, F, I-K, and M; deoxycalyxin A; blepharocalyxins C-E; neocalyxins A and B; (3S,5S)- and (3S,5R)-3-hydroxy-1-(4-hydroxyphenyl)-5-methoxy-7-phenyl-6E-heptene, (3S,5S)- and (3S,5R)-3-hydroxy-1-(4-hydroxyphenyl)-5-ethoxy-7-phenyl-6E-heptene, (3S)-3-methoxy-1,7-bis(4-hydroxyphenyl)-6E-hepten-5-one, 1,7-bis(4-hydroxyphenyl)-hepta-4E,6E-dien-3-one, (3S,7R)-5,6-dehydro-1,7-bis(4-hydroxy-phenyl)-4"-de-O-methyl-centrolobine, (3S,5S,6S,7R)-5,6-dihydroxy-1,7-bis(4-hydroxyphenyl)-4"-de-O-me-thylcentrolobine, (3S,5R,6S,7R)- and (3S,5S,6R,7R)-5,6-dihydroxy-1,7-bis(4-hydroxyphenyl)-4"-de-O-methyl-centrolobine, 1,2- dihydro-bis(de-O-methyl)curcumin, and (3S,7S)-5,6-dehydro-4"-de-O-methylcentrolobine, and one known diarylheptanoid [(3S,5S)-3,5-dihydroxy-1,7-bis(4-hydroxyphenyl)heptane] together with 12 other known phenolic compounds. Moreover, in vitro NO inhibitory and antiproliferative activities of the isolated compounds were also tested and the active constituents identified.