Progress in synthetic studies on 1-oxacephems is reviewed. Antibacterial activity of this new class of compounds is also discussed briefly. Earlier syntheses, rather lengthy but quite pioneering, provided us with valuable information of the interesting biological activity of 1-oxacephems. Several improved synthesis have appeared, enabling to prepare a variety of derivatives and examine their antibacterial activity. Thus, syntheses and antibacterial activity of some interesting 1-oxacephems and 7α-methoxy-1-oxacephems, such as, arylmalonamido-, α-acylureidophenylacetamido-, and α-aminothiazolyl-α-methoxyiminoacetamido derivatives with representative 3'-substituents are described. A compound 6059-S 98 discovered in Shionogi Research Laboratories, proved to have excellent antibacterial activity, spectrum, and other pharmacological properties and, therefore, is currently under clinical studies. An industrially feasible synthetic method for its nucleus 88 a as well as 7α-methoxy-1-oxacephem nuclei with a variety of substituents at the 3'-position in general was established after extensive studies.
Thienamycin, an exceptionally potent, broad spectrum β-lactam antibiotic, possesses a novel 1-carbapen-2-em structure. Total syntheses and synthetic approaches of thienamycin and its related compounds, which have been published before early in June of 1980, are summarized according to the manner for the formation of carbapenem and carbapenam ring systems.
This review, including two parts, deals with recent progress in the prostaglandin field. The first part is concerned with the synthetic studies of endoperoxides, thromboxanes, prostacyclins and leukotrienes. The second describes briefly the biological properties of various stable synthetic analogs.
This review describes the synthetic studies on mitomycins and the related compounds especially through 1-benzazocinone derivatives, which are proposed hypothetically as key intermediates of the biosynthesis. The articles of this paper are constructed as follows : i) biological activity, ii) biosynthetic studies, iii) total synthesis, iv) synthesis of eight-membered ring system.
Since the discovery of the antitumor activity of cis-dichlorodiammineplatinum (II) (=DDP) by B. Rosenberg et al. in 1969, various diamino Pt complexes have been synthesized and their antitumor activities were tested, in order to prepare more potent Pt complexes, with least toxicity. cis-DDP was found very effective and it had been approved by the Food and Drug Administration, U.S.A. in December, 1978 as an antitumor agent for the treatmet of bladder cancer, ovarian cancer, testis cancer and, head and neck cancer. The problem is the kidney toxicity and severe nausea and vomiting, when DDP was administered to the patients. Ototoxicity is also another problem. Various Pt complexes were synthesized by replacing carrier ligands, and mono- and bi-dentate leaving groups. 1, 2- Cyclohexanediamine (= dach) is considered to be one of the useful carrier ligands. Dach has two geometrical isomers, cis and trans, and the latter is resolved into two optical isomers, d and l.Among the Pt complexes prepared in my laboratory, D-glucuronato and D-gluconato Pt (II) complexes of trans-1-dach are water-soluble and potential antitumor agents. 2- (Aminomethyl) cyclohexylamine and stilbenediamine were synthesized. The former has two geometrical isomers, each of which has two optical isomers, while the latter has three isomers, meso, trans-d and trans-l. Preparation of their Pt (II) complexes and their antitumor activities are described.
In the course of screening of immunostimulator from microbial secondary metabolites, bestatin was isolated from the culture filtrate of Streptomyces olivoreticuli as an inhibitor of aminopeptidase B. The structure of bestatin was determined to be (2S, 3R) -3-amino-2-hydroxy-4-phenylbutanoyl-L-leucine. General synthetic methods of 3-amino-2-hydroxy acids from α-amino acids and α, β-unsaturated esters were established, and structure-activity relationships between bestatin analogues and inhibition of aminopeptidase B were discussed. Bestatin enhanced delayed- type hypersensitivity, and was found to be effective against experimented murine tumors by bestatin alone and also enhanced the therapeutic effect of antitumor agents such as bleomycin and adriamycin. Bestatin is well adsorbed by oral administration and excreted into urine. It does not show any toxic sign. Bestatin is now clinically tested as an immunotherapeutic agent against cancer.
Recent advances in the field of the chemistry and biology of thymic factors are reviewed, in which the following items are described. 1) Chemical structure and some bilogical properties of ubiquitin. 2) Structure, synthesis and biological properties of thymopoietin. 3) Chemical nature, syntheses and immunologic activities of serum thymic factor (FTS). 4) Chemical structure and syntheses of thymosin d1.
1 Discovery of 2-5 A 2.1.5 Methoxytetrahydopyranyl protection 2 Synthesis of 2-5 A 2.1.6 Metal catalyzed synthesis 2.1 Formation of 2'-5' internucletide linkages 2.2 Formation of 5'-triphsosphate (Synthesis of A 2' p 5' A 2' p5' A) 2. 2. 1 5'-Phosphorylation 2.1.1 Enzymatic synthesis 2.2.2 5'-Triphosphorylation with DCC 2.1.2 Chemical method using benzoyl protection2.2.3 Carbonylimidazolide method 2. 1. 3 o-Nitobenzyl protection 2.2. 4 Other methods 2. 1. 4 Silyl protection3 Biological activity of 2-5 A
History of angiotensin-converting enzyme (ACE) inhibitors, their therapeutic role in hypertension and the recent world development trends towards them were reviewed briefly, and our continuous investigations in this field, which led to the discovery of a new potent ACE inhibitor, (2R, 4R) -2- (2-hydroxyphenyl) -3- (3-mercaptopropionyl) -4-thiazolidinecarboxylic acid (SA 446), were disclosed in this paper.
This article reviews the syntheses of 1, 4-benzodiazepines with a nitrogen atom-containing five-membered ring fused to the 1, 2-position of the diazepine ring. Recent work on this class of compounds has yielded new synthetic methodologies and compounds (potentially) useful in medicine. Descriptions are arranged according to types of structures of target tricyclic diazepines and to types of approaches in the synthesis. The activity of the compounds on the central nervous system (CNS) is also mentioned. Contents : 1. Introduction, 2. 4H-pyrrolo [1, 2-a] [1, 4] benzodiazepines, 3. 4H-imidazo [1, 2-a] [1, 4] benzodiazepines, 4. 4H-imidazo [1, 5- a] [1, 4] benzodiazepines, 5. 4H-pyrazolo [1, 5- a] [1, 4] benzodiazepines, 6. 4H-s-triazolo [4, 3- a] [1, 4] benzodiazepines, 7. 4H-s-triazolo [1, 5-a] [1, 4] benzodiazepines, 8. 4H-υ-triazolo [1, 5-a] [1, 4] benzodiazepines, 9. 4 H-tetrazolo [1, 5-a] [1, 4] benzodiazepines, 10. CNS activity, 11. Closing comment.
First, characteristics of a carbon-fluorine bond from the biological point of view are summarized with some examples : mimic effect, protective fluorination, irreversible conjugation with enzyme, increased lipophilicity and so on are presented. Secondly, some approaches to biologically active compounds utilizing the above characteristics are shown by the examples of trifluoromethylated nucleoside derivatives and fluorinated vitamin D3 analogues.