Malcolm Sainsbury

New antioxidants incorporating indole and indoline chromophores

Abstract Syntheses of potent antioxidants utilising indenoindole or indenoindoline pharmacophores are described. The antioxidant behaviour and the oxidation potentials of these compounds are correlated, and some of their reactions with radicals are noted.

Characterization of novel indenoindoles. Part I. Structure-activity relationships in different model systems of lipid peroxidation.

Structure-activity relationships are presented for some representative compounds from a novel series of potent inhibitors of lipid peroxidation. The compounds are indenoindole derivatives with oxidation potentials in organic solvents of between 0.2 and 1.5 V. Two of these compounds, cis-5,5a,6,10b-tetrahydro-9-methoxy-7-methylindeno[2,1-b]indole (H 290/51) with an oxidation potential of 0.32 V and cis-4b,5,9b,10- tetrahydro-8-methoxy-6-methylindeno[1,2-b]indole (H 290/30) with an oxidation potential of 0.30 V, have been tested more extensively and compared with reference compounds in several pharmacological models of lipid peroxidation. The inhibitory potencies (pIC50) of the compounds in respect to Fe/Ascorbate-induced production of thiobarbituric acid-reactive substances (TBARS) in a suspension of purified soybean lecithin were calculated. These data are 8.2 for H 290/51; 8.0 for H 290/30; 5.6 for vitamin E; and 6.6 for butylated hydroxytoluene (BHT). In isolated rat renal tissue subjected to hypoxia and reoxygenation, the potency for inhibition of TBARS formation is 6.9 for H 290/51, 6.9 for H 290/30, and <5 for vitamin E. In oxidative modification of low-density lipoproteins (LDL) induced by mouse peritoneal macrophages, the corresponding pIC50 values for TBARS inhibition for each compound are: 8.7, 8.3, <5, and 6.9, respectively. It is concluded that the synthetic indenoindoles are potent antioxidants. The results suggest that indenoindoles such as H 290/51 and H 290/30 could be useful as therapeutic agents in pathophysiological situations where lipid peroxidation plays an important role.

The synthesis of dendrodoine, 5-[3-(N,N-dimethylamino- 1,2,4-thiadiazolyl]-3-indolylmethanone, a metabolite of the marine tunicate dendroda grossular

Abstract The cytotoxic natural product dendrodoine has been synthesised by a 1,3-dipolar addition reaction between indolyl-3-carbonyl nitrile and N,N-dimethylaminonitrile sulphide generated in situ through the thermolysis of 5-(N,N-dimethylamino)-1,3,4-oxathiazol-2-one.

An improved synthesis of noroxymorphone

Abstract A brief synthesis of noroxymorphone is described which involves the oxidation of 3-O-tbutyldimethylsilylmorphine by manganese dioxide. The initial product is the corresponding morphinone which is further oxidised to the 14-hydroxymorphinone. After hydrogenation the 7,8-dihydro-14-hydroxymorphinone is acetylated and N-demethylation of the 14-O-acetylated product is achieved using vinyl chloroformate as the reagent. The overall yield from morphine is 40–45%.

1,2-dihydroisoquinolines—XI: Further berbine syntheses

Abstract New syntheses of tetrahydroberberine and tetrahydropalmatine are described and some other potential routes to the berbine skeleton are explored.

1,2-dihydroisoquinolines—VII : New syntheses of avicine and nitidine derivatives☆

Abstract Synthetic routes to the benzo[c]phenanthridine ring system have been investigated, and new syntheses of oxyavicine ( 2a ), 2,3-dimethoxy-8,9-methylenedioxybenzo[c]phenanthridine ( 5c ) and 2,3,8,9-tetramethoxybenzo[c]phenanthridine ( 5a ) are described.

Inhibition of phospholipase A2; a molecular recognition study

A model of the enzyme PLA2 with a phospholipid substrate bound in the active site was derived using molecular graphics and molecular mechanics modelling techniques, and its ability to account for competitive inhibition tested by modelling the analogous complex of the enzyme and a known inhibitor; the model was then applied to the study of the binding of a new inhibitor, 3-arachidonyl-4(O-phosphoethanolamino)-methyltetrahydrofuran-2-one and the absolute stereochemistry for active site binding of this inhibitor predicted to be (3S,4R).

1,2-Dihydroisoquinolines X : The cyclization of benzylaminoacetaldehyde dialkylacetals

Abstract The cyclization of some benzylaminoacetaldehyde dialkyl acetals has been examined and their utilization for the preparation of various isoquinoline derivatives studied. Some observations on the mechanism of cyclization of these acetals have also been made.

The synthesis of 5-hydroxyberbine derivatives

Abstract The syntheses of 5-hydroxy-2,3,10,11-tetramethoxyberbine (4, R1 = OMe; R2 = OH) and 5-hydroxy-2,3-methylenedioxy-10,11-dimethoxyberbine(4, R1 + R1 = CH2O2R; = OH)aredescribed. The structures have been established by chemical and spectral methods and, in the former case, the relative stereochemistry has been elucidated. These are the first examples of 5-hydroxyberbine derivatives to be prepared.

Pyridine and piperidine alkaloids

The compounds of pyridine and piperidine alkaloids are plant bases and are being isolated from insects and from amphibians and marine animals. They are widely distributed in nature and they perform a number of different functions in nature, such as train pheromones and defense mechanisms in insects. In many cases, the stereochemistry is complex and the syntheses require sophisticated asymmetric methods. This chapter discusses these compounds for their synthesis and derivatives, and their applications. The section on terpenoid piperidine alkaloids found in plants is used for the treatment of rheumatism and is discussed as an analgesic in the chapter. A number of polyhydroxypiperidines (azahexoses) are known for creating much interest, as they show glycosidase inhibitory activity. The benefits and applications of spiropiperidine alkaloids are explained for their chemical methods and resulting compounds. The perhydroquinoline alkaloids—such as lepadin A (103), a cis-decahydroquinoline alkaloid, can be obtained from the north-sea tunicate clavelinia lepadiformis. The different types of pyridine alkaloids are presented for the reader. The compounds pyridine, dihydropyridone and tetrahydropiperidone alkaloids are briefly discussed.