Bisphosphines related to bis(diphenylphosphino)ethane (dppe) and their gold complexes are described that are active in a spectrum of transplantable tumor models. When administered ip on days 1-5 at its maximally tolerated dose (MTD) of 40 mumol/kg, dppe reproducibly gives 100% increase in life span (ILS) in mice bearing ip P388 leukemia. Coordination of chlorogold(I) to each phosphine in dppe gave a complex that had similar activity but at a much lower dose level than dppe; the MTD for the gold(I) complex was 7 mumol/kg. Among other metal complexes of dppe, the Au(III) complex was active (greater than 50% ILS) whereas Ag(I), Ni(II), Pt(II), Pd(II), and Rh(I) complexes were inactive. Among dppe analogues, replacement of phenyl groups with ethyl or benzyl groups resulted in inactivity for both ligands and the corresponding gold complexes whereas substitution with cyclohexyl or heterocyclic ring systems yielded ligands and/or gold complexes with antitumor activity. Among substituted-phenyl dppe and dppe(AuCl)2 analogues, 3-fluoro, 4-fluoro, perdeuterio, 4-methylthio, and 2-methylthio analogues were active; 4-methyl, 3-methyl, 4-methoxy, 4-dimethylamino, and 4-trifluoromethyl analogues were marginal or inactive. Analogues in which the ethane bridge of dppe or dppe(AuCl)2 was varied between one and six carbons, unsaturated or substituted, revealed that activity was maximal with ethane or cis-ethylene. Compounds with good P388 activity were also active in other animal tumor models.

Isomeric 5( 6)-(4-pyridyl)-and 6( 5)-(4-substituted-phenyl)-2,3-dihydroimidazo[2,l-6]thiazoles were prepared by a mixed benzoin-imidazothione route, and their structures were assigned by spectral comparison to compounds of established substitution pattern. The structural assignment was confirmed by X-ray analysis. Examination of the compounds for antiinflammatory activity by an adjuvant arthritic rat assay revealed strikingly higher potencies for one analogous series than for their isomers. This selectivity was paralleled in the ability to stimulate cell-mediated immunity, as reflected in an oxazolone-induced contact sensitivity model. A drug-receptor complex is proposed that requires at least three sites of interactions.

The cytotoxicity of many nitroaromatic compounds is mediated by bioreduction. There is a correlation between the one-electron-reduction potentials and cytotoxic potencies of simple nitroheterocycles such as nitroimidazoles, but no such correlation is observed with DNA-binding nitroacridines related to the drug nitracrine. A study of the reduction of 1-nitroacridines by the enzyme xanthine oxidase and by reduced flavin mononucleotide, FMNH, (as a model of the enzyme's active site) has been undertaken to explore the redox dependence in this series. The values of V,,,,,/K,,, for reduction by xanthine oxidase, XOD, and the second-order rate constants of reduction by F M N H, , analysed using Marcus electron-transfer theory, indicate a correlation between reduction potential and the rate of reduction, but suggest that the potential-energy barrier for electron transfer is small relative to that imposed by requirements for association, orientation and desolvation of the reactants. The close similarity in Marcus parameters for reduction by FMNH, and by XOD suggests that reduction occurs by a similar mechanism in each case. The free-energy change for electron transfer, AG:, is only 1-2 kJ mot-'. It appears that the rate of reduction is unlikely to be the only determinant of hypoxic cytotoxicity for the nitroacridines, although the applicability of findings with XOD t o other nitroreductases is uncertain.

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Consistent with previous studies IVF pregnancies had significantly lower PAPP-A levels supporting the need to appropriately adjust the combined first-trimester screening (cFTS) risk algorithm for IVF conceptions. The Brahms Kryptor and Immulite 2000 platforms are significantly different; however, the universally lower PAPP-A findings support the hypothesis that the lower PAPP-A is due to a biological cause.