Antitumour activities

The AMAPs (2-[ arylmethyl amino]-l,3-propanediols) are a class of planar polycyclic aromatic derivatives, which contain polar side-chains. They are known to be DNA intercalators and possess broad spectrum antitumour activity. An approach to C-radiolabelled AMAP derivative 40 used the Bucherer reaction as an initial starting reaction. 2-Naphthol was reacted with 4-bromophenylhydrazine 38 in the presence of sodium metabisulfite and HCl to afford 39. Subsequent derivatisation of 39 afforded 40. 

The synthesis of the naphthalene rings found in the gilvocarcin group and in the rubromycin class of natural products via benzannulation was also reported. Both classes show promising antitumour activity [67,68]. 

One of the pectic fractions from Angelica acutiloba showed potent antitumour activity, and this polymer was rich in the AG-I type structure, indicating that the 4-linked galactose units are important for this activity [40]. 

Antitumour activity has been reported for alkyltins, particularly dibutyltin. The effect in mouse skin initiation/promotion protocols showed dibutyltin inhibiting the promotion stage (Arakawa Wada,... 

The pyrrolopyrimidines 100 react with chloroamines to yield cyclic products 101 which are being investigated for antitumour activity <95MI08 96CA(124)117234>. 

Schein, P.S., Cooney, D.A. and Veron, M.L. (1967). The use of nicotinamide to modify the toxicity of streptozotocin diabetes without loss of antitumour activity Cancer Res. 27, 2324-2332. 

In total the analysis of protein complexes indicates that methionine is the most likely group to bind to [PtCU]2 and [PtenClfc] probably by a displacement reaction. However a specific attachment to another residue such as histidine or sulphydryl can not be ruled out. Furthermore the antitumour activity is that of cis- [Pt (NH 3) 2CI2] and the di-functional character of this reagent has not been revealed so far by the above studies. In fact no attempt has been made to uncover the difference between [PtCl2(NH3)2] in its cis and fraMS-forms. 

Metabolites of marine sponges such as dibromophakellstatin 362 <2002TL5135> have been shown to possess potent antitumour activity in a number of different human cell-lines. 

Since plants used as herb medicines contain high amounts of germanium compounds, the latter have been regarded as having immunopotentiation and antitumour activities. At present, organogermanium compounds are mainly used for medical applications. For example, Ge-132 is well known to have not only an antitumour effect, but also to induce interferon (IFN) production in vivo8. 

Horgan K, Cooke E, HallettMB,Mansel RE (1986) Inhibition of protein kinase C mediated signal transduction by tamoxifen importance for antitumour activity. Biochem Pharmacol 35(24) 4463-4465... 

An excellent antineoplastic potency against the murine neoplasm Sarcoma 180 has been observed with arylsulphonylhydrazones derived from pyridazine-3-carboxaldehyde 2-oxide (85) [298]. These compounds were prepared in the U.S.A. in order to investigate the effect of the incorporation of an additional nitrogen atom into antitumour active pyridine 1-oxide congeners. Interestingly, the pyridazine-derived compounds (85, R = H, Me, MeO) proved to be superior to the corresponding pyridine derivatives, whereas the analogous pyrimidine-4-carboxaldehyde 3-oxide derivatives were found to be devoid of activity. 

Finally, several patents claiming antitumour-active pyridazine derivatives are to be mentioned [273, 274, 303-305]. Thus for instance, numerous... 

Keppler et al. have shown that the introduction of heterocyclic ligands into Ru(III) complexes such as 28 (163) and 29 (164) can improve the solubility and retain the antitumour activity, especially... 

Mayer LD, Nayar R, Thies RL, Boman NL, Cullis PR, Bally MB. Identification of vesicle properties that enhance the antitumour activity of liposomal vincristine against murine L1210 leukemia. Cancer Chemother Pharmacol 1993 33 17. 

Thus in this example the tetramer serves as both the donor and the acceptor. Usui et al, (43) propose this reaction for the synthesis of hexa-N-acetylchitohexaose, an oligosaccharide with reported antitumour activity (24), They dso observed formation of heptamer by incubating the pentamer wiA the Nocardia enzyme, but no chain elongation was observed with tiie hexamer as initial substrate. Similar activities with the formation of chitin oligosaccharides have also been observed for... 

Although tumour growth inhibition by 6-mercaptopurine has been attributed to the inhibition of the conversion of inosinic acid to adenylic acid [309, 310, 312], probably at the first step, this conversion by cell-free extracts from the exquisitely sensitive tumour adenocarcinoma 755 was inhibited only at high levels of 6-mercaptopurine ribonucleotide [313]. Furthermore, hadacidin (A -formylhydroxyaminoacetic acid) is an excellent inhibitor of adenylosuccinate synthetase [314, 315], and yet it has little antitumour activity and is not cytotoxic, showing that this inhibition may be relatively unimportant to cells. 

Another guanine analogue, thioguanine, is also incorporated into both DNA and RNA of mammalian cells [198], and a correlation between its antitumour activity and the extent of its incorporation into DNA has been observed [339,340], although some investigators feel that the metabolic effects of thioguanylic acid may be more universally important [13, 91, 341]. The incorporation of a- and... 

The condensation product of 6-uracilylhydrazine and 2-pyridinecarboxaldehyde (LVIll), shows a pronounced in vitro antitumour activity in the Miyamura test [409]. 

Ikegami Y, Yano S, Nakao K, Fujita F, Fujita M, Sakamoto Y, Murata N, Isowa K (1995) Antitumour activity of the new selective protdn kinase C inhibitor 4 -N-benzoyl staurosporine on murine and human tumour models. Arzneim Forsch 45 1225-1230... 

Ferlini C, Distefano M, Pignatelli F, et al. Antitumour activity of novel taxanes that act at the same time as cytotoxic agents and P-glycoprotein inhibitors. BrJ Cancer 2000 83(12) 1762-1768. 

Many other sydnones have been tested for antioxidant activity <95JPP623>, antitumour activity <94MI 403-06), antifungal activity <95IJC(B)346>, and analgesic activity <95EJM64l>. 

Peroxy derivatives of steroids have been isolated from both marine and terrestrial sources. They are most commonly 5a, 8a-endoperoxides with variations in the side-chains. The ergosterol peroxide 102 is the most ubiquitous endoperoxide-containing natural product and is isolated from a large number of sources. Ergosterol peroxide 102 was found to have antitumour activity against breast cancer and carcinosarcoma cell lines. A number of other steroidal endoperoxides have been reported which differ in the nature of the side-chain. Compound 103 was found to be an inhibitor of tumour promotion in mouse studies . 

Posner and coworkers have prepared a series of semi-synthetic and synthetic ether and ester-linked dimers that were found to have potent anti-proliferative and antitumour activities in vitro. Some of these trioxane dimers were found to be as antiproliferative as calcitriol, the hormonally active form of vitamin D, which is used to treat psoriasis, a skin disorder characterized by uncontrolled cell prohferation. Of the semi synthetic dimers, a polyethylene glycol-linked dimer 107, with S-stereochemistry at both of the lactol acetal positions, was found to be very anti-proliferative and showed activity against leukaemia and colon cancer cell hues in the National Cancer Institute (NCI), USA 60-cell line assay. 

O Neill and coworkers have also sought to address the problem of the metabolically susceptible CIO acetal linkage . A series of CIO carba dimers were prepared and assayed for antitumour activity. The two most potent compounds that were prepared are two phosphate ester finked dimers 115 and 116 (Scheme 40). They are principally active against leukaemia, colon and certain melanoma and breast cancer cell lines in the NCI 60-cell line assay. 

The dimers were studied more closely in HL-60 leukaemia and Jurkat cell lines, and it was found that they have activities comparable to the clinically nsed anticancer drng doxorubicin. In terms of general toxicity to normal cells, it was observed that dimers 115 and 116 were not toxic to lymphocytes at doses approaching 100 p,M. In preliminary studies, apoptotic cell death was observed on exposnre to these componnds and further studies are ongoing to elucidate the underlying mechanism of apoptosis. For purposes of comparison, the corresponding phosphate ester monomers 117 and 118 were prepared and proved to have no antitumour activity in the cell lines examined. This result is important, because it rules out any role of the phosphate ester functionality in mediating the observed cytotoxic effects and emphasizes the necessity for a bivalent unit. 

Antiproliferative trioxane dimers, 283 Antitumour active trioxane dimers, 283 Antitumour endoperoxides, 1333-41 AN02, 1335... 

PfATP6 enzyme inhibihon, 1313, 1320 antitumour activity, 1336-41 biosynthesis, 133-4 chemistry, 1314-17 extraction, 1280-1... 

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