2- Formylpyridine thiosemicarbazone

Bis(thiosemicarbazones) [89-97] and AT-heterocyclic thiosemicarbazones comprise two interesting series of experimental chemotherapeutic agents. 2-formylpyridine thiosemicarbazone, the first of the latter series to be examined for biological activity, showed mild antileukemic activity against 1-1210 tumor in mice [98]. However, it was found to be toxic at the therapeutic dose levels which led to synthesis of other aromatic and heterocyclic thiosemicarbazones as potential agents [80, 99, 100]. However, the only active anticancer compounds besides glyoxal bis(thiosemicarbazones) were the iV-heterocyclic thiosemicarbazones [101], 2 formyl-3-hydroxypyridine thiosemicarbazone [102] and... 

The E and Z isomers of 2-formylpyridine thiosemicarbazone, 5a, and 5b, respectively [123], as well as those of other heterocyclic thiosemicarbazones [124], have been separated and characterized. The difierentiation of stereochem-... 

Iron(II) complexes are often included in studies when complexes are prepared from a large number of different metal ions. 2-formylpyridine thiosemicarbazone, 5, forms brown [Fe(5)2A2] (A = Cl, Br) when prepared in ethanol and [Fe(5-H)2] from aqueous alcohol solution [156], All of these complexes are diamagnetic. The resonance Raman and infrared spectra of [Fe(5-H)2] were examined in detail [130] and coordination occurs via the pyridyl nitrogen, azomethine nitrogen and thiol sulfur. There is appreciable d-d sulfur-to-iron(II) Jt-bonding. Solution studies of iron(II) complexes of some 5-substituted-2-formylpyridine thiosemicarbazones have been reported [157], but no solids... 

In aqueous solution the formation constants of Cu(5-H)", (5 is 2-formylpyridine thiosemicarbazone) have been studied in relation to the possible reaction of this ion with biological systems [166]. A pre-resonance Raman spectral study of... 

Two copper(II) complexes of 2-acetylpyridine thiosemicarbazone, 8, were included in a study of complexes of 2-formylpyridine thiosemicarbazone [169]. [Cu(8-H)OAc] has a magnetic moment consistent with a monomeric copperfll) center and both it and [Cu(8)Cl2] have d,2-y2 ground state ESR spectra (Table 2). A d-d envelope and a magnetic moment of 1.68 B.M. have led others [178] to propose a distorted tetrahedral environment with metal-metal interaction for the brown complex, [Cu(8)Cl2]. 

In a recent search for new antitumour chelates of thiosemicarbazones, Mohan et al.304 have examined the 4-(m-aminophenyl)-2-formylpyridine thiosemicarbazone chelates of cobalt(II), nickel(II), copper(II), zinc(II) and platinum(II) for antitumour properties but found antitumour activity absent. 

Monomethylated derivatives of 2-formylpyridine thiosemicarbazone have been synthesized to define molecular dimensions compatible with antineoplastic activity. These were the thiosemicarbazones of 3-, 4-, 5-, and 6-methylpyridine-2methylated pyridine derivatives were found to be active tumour-inhibitory agents, indicating that substitution of such alkyl groups did not interfere with biological potency. However, introduction of the methyl group in the 6 position of the pyridine ring resulted in a compound with no antineoplastic activity, suggesting an apparent intolerance to substitu-... 

A series of meta and para substituted 3- and 5-benzyloxy derivatives of 2-formylpyridine thiosemicarbazone has been synthesized both to explore and to utilize a hypothetical hydrophobic binding zone adjacent to the major inhibitor binding site of the target enzyme, ribonucleoside diphosphate reductase [20]. These agents were synthesized by condensing a nitrobenzyl bromide (19) with 3-or 5-hydroxy-2-hydroxymethylpyridine (18), followed by oxidation with MnOj... 

The synthesis of iron, cobalt and nickel complexes of 2-formylpyridine thiosemicarbazone has been reported [59]. The a-(AO-heterocyclic carboxaldehyde thlosemicarbazones strongly complex transition metals through their N -N -S ... 

The hydroxylated derivatives, 5-hydroxy-2-formylpyridine thiosemicarbazone and 3-hydroxy-2-formylpyridine thiosemicarbazone, show a different pattern of inhibition [74]. They appear competitive with iron and either non-competitive or uncompetitive with the dithiol substrate the imprecise nature of the assay does not allow a choice between these alternatives. The failure of the dithiol to reverse inhibition of ribonucleoside diphosphate reductase by the hydroxylated derivatives implies that the interaction of these inhibitors with the enzyme occurs at a site different from that involved in the action of (4) and (1). The impure nature of this complex enzyme system, however, makes it impossible to explain fully these differences and further advances will require the availability of a highly purified enzyme. 

Hydroxy-2-formylpyridine thiosemicarbazone is the only member of this series that has been administered to man as part of a Phase I study [55,56]. The selec-... 

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