Tumour-associated compound

A nonasaccharide corresponding to compound (19) with ct-L-fucopyranosyl units bonded to Q-2 of the terminal -D-galactosyl moiety and to g-3 of the neighbouring unit has been isolated from human milk, and the tumour-associated compound (21) has been synthesised. ... 

It should be noted, however, that mechanisms of action of most anti-angiogenic compounds are not well understood at present. For example, trombospondrn-1 (TSP-1) is able to inhibit tumour-associated angiogenesis, but when TSP-1 pellets were implanted into the ankles of AIA rats, it enhanced joint swelling and body weight loss in a dose- and time-dependent manner. These, possibly indirect, effects may be due to the involvement of TSP-1 in cell adhesion, as well as to its interactions with other adhesion molecules and inflammatory mediators [125]. 

In addition to the well-characterized role of iron in catalysing redox interactions, other metallic contaminants, for example, nickel, may also contribute. In vivo toxicity studies have demonstrated the capacity of nickel particulate compounds to induce tumours following intraperitoneal injection (Pott etal., 1987). Such activity is proportional to their phagocytic uptake, and to the associated respiratory burst and generation of PMN-derived reactive oxygen metabolites (ROMs), a proposed pathogenic mechanism (Evans et al., 1992a). 

Optical activity in metal complexes may also arise either if one of the ligands bound to the metal in the first co-ordination sphere is itself optically active or if the complex as a whole lacks a centre of inversion and a plane of symmetry. Thus all octahedral cts-complexes of the tris-or bis-chelate type have two isomeric forms related by a mirror plane, the d- and /-forms. These species have circular dichroism spectra of identical intensities but opposite in sign. The bands in the circular dichroism spectrum are, of course, modified if ligand exchange occurs but they are also exceedingly sensitive to the environment beyond the first co-ordination sphere. This effect has been used to obtain association constants for ion-pair formation. There also exists the possibility that, if such compounds display anti-tumour activity, only one of the mirror isomers will be effective. 

Deoxoartemisinin and carboxypropyldeoxoartimisinin have also been shown to have anti-tumour activity and, NMR studies on solution conformations have been reported <00BBR359>. One of the problems with artemisinin use is its poor water solubility characteristics. An attempt to rectify this, and to overcome stability problems associated with sodium artesunate in solution, has involved the introduction of amino group functionality as in 127 (eg. R = 0(CH2)3NR r2 where NR r2 = morpholine). The maleate salt of this compound has reasonable water solubility and aqueous solutions are stable at room temperature for an extended time. However activity against Plasmodium knowlesi in rhesus monkeys after oral administration was poorer compared with artesunic acid <00JMC1635>. 

A few examples to render tetrapyrrolic compounds less phototoxic can be found in the hterature. In one approach, carotenoid structures were employed for the synthesis of some carotenoporphyrin derivatives [92-94]. Figure 8 shows two stuctures by way of example. Due to similar photophysical properties of the two structural components, the excited triplet state of the porphyrin is quenched by the carotenoid moiety, thus inhibiting the formation of singlet oxygen, while its fluorescence capabilities are still preserved. Biodistribution studies revealed enhanced uptake into tumour tissue [39,93,95]. However, microscopy studies have shown that such compounds are associated with connective tissues in the tumors rather than with cancerous cells indicating low specificities for mahgnant transformation [96]. 

Siastatin B (40), the first natural inhibitor of neuraminidase and a compound that also inhibits -D-glucuronidase, was discovered in 1974 [139]. Two total syntheses of this compound have been published to date [140,141]. Due to the fact that recent studies have shown that human tumours are associated with... 

The N-oxide of indicine (49) exhibits anti-tumour activity in experimental tumour systems, without some of the toxic effects associated with other pyrrolizidine alkaloids. The N-oxides of echinatine and europine show similar anti-tumour activity against P 388 lymphocytic leukaemia tumours.23 Indicine N-oxide is metabolized to the free base in rabbits and humans,62 although the N-oxide is the more active anti-tumour agent. It has been suggested that the conversion of indicine N-oxide into indicine is not essential for its anti-tumour activity.63 Indicine N-oxide is the first pyrrolizidine alkaloid to be tested as an anti-tumour agent in humans. The toxicity and pharmacokinetics of this compound have been studied in 29 patients with advanced cancers.64 The major toxic effect was myelosuppression, but acute liver damage was not observed. 

For the tumour-inhibiting activity of amides from Piper novaehollandiae (Piperaceae) see ref. 128. Tumour-inhibiting extracts have also been obtained from Brugueria spp. (Rhizophoraceae), but it is not clear whether this activity is partly associated with tannins or with tannin-free compounds. 

LPM appears to be a more permanent indicator that has correlated strongly with renal tumour development associated with all other compounds suggested so far to act through the o 2u-globulin pathway. The evidence therefore is in support of the o 2u-globulin nephropathy-based MOA for both MTBE and TBA, but there is, in addition, evidence for CPN involvement in the MTBE tumours. 

Substances that have been associated with increases in Leydig cell tumours in mice are mainly chemicals with clear oestrogenic properties, e.g., diethylstilboestrol, methoxychlor, tri-p-anisylchloroethylene, stilboestrol, 17/3-oestradiol, oestradiol ester, tamoxifen and triphenylethylene [171-179]. Other compounds active in mice are finasteride, a 5a-reductase inhibitor that also induces Leydig cell hyperplasia, but not adenomas, in Sprague-Dawley rats [170,180] and M-nitrosodiethylamine [181]. In contrast to its effects in mice and Syrian and European hamsters [182], 17)d-oestradiol treatment of rats does not induce Leydig cell tumours and inhibits the appearance of the spontaneous tumours in the F344 strain [184]. 

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