Synthetic analogues of marine sponge guanidine alkaloids showed in vitro antiparasitic activity against Leishmania (L.) infantum and Trypanosoma cruzi. Guanidines 10 and 11 presented the highest selectivity index when tested against Leishmania. The antiparasitic activity of 10 and 11 was investigated in host cells and in parasites. Both compounds induced depolarization of mitochondrial membrane potential, upregulation of reactive oxygen species levels, and increased plasma membrane permeability in Leishmania parasites. Immunomodulatory assays suggested an NO-independent effect of guanidines 10 and 11 on macrophages. The same compounds also promoted anti-inflammatory activity in L. (L.) infantum-infected macrophages cocultived with splenocytes, reducing the production of cytokines MCP-1 and IFN-γ. Guanidines 10 and 11 affect the bioenergetic metabolism of Leishmania, with selective elimination of parasites via a host-independent mechanism.
Structural features associated with the antimalarial activity of the marine natural product crambescidin 800 were studied using synthetic analogues of the related compound ptilomycalin A. The study suggests that the guanidine moiety is cytotoxic, whereas the spermidine-containing aliphatic chain increases activity. The most active analogue, compound 11, had in vitro activity against Plasmodium falciparum strain 3D7 (IC 50 ϭ490 nM) that was stronger than the in vitro activity against murine L5178Y cells (IC 50 ϭ8.5ϳ59 mM). In vitro growth inhibition of liver stages of P. yoelii yoelii in mouse hepatocytes was observed (IC 50 ϭ9.2 mM). The compound did not significantly prolong median survival time after a single subcutaneous administration of 80 mg/kg in P. berghei-infected mice. Compound 11 did not cause DNA fragmentation in an in vitro micronucleus assay.
Keywords malaria, natural product, crambescidin, Plasmodium
DescriptionCrambescidin 800 was isolated from a Mycophora sp. sponge. The methanol extract was partitioned with hexane, dichloromethane (DCM) and chloroform. The DCM fraction was chromatographed successively on Sephadex LH20 (101.6ϫ2.5 cm, 100% methanol, 2 ml/minute, elution volume (V e )ϭ280 ml) and C18 columns (gravity column, 50.8ϫ2.5 cm, methanol/water 9 : 1, 1 ml/minute, V e ϭ33 ml) yielding a bioactive fraction (55.4 mg) whose 1 H-and 13 C-NMR shifts and mass spectrum data matched previously reported values for crambescidin 800 [1].Analogues had been synthesized as described and were provided (by P. J. Murphy) as pure crystalline solids [2ϳ5]. The structures are shown in Fig. 1.The structures of crambescidin 800, ptilomycalin A, and the synthetic compound 11 are shown in Fig. 2.
PalladiumII and nickelII halide complexes of the ferrocenyl polyphosphines 1,1',2,3-tetrakis(diphenylphosphino)ferrocene (1), and 1,1',2-tris(diphenylphosphino)-4-tert-butylferrocene (5) were prepared and characterized by multinuclear NMR. The metallo-ligand 1, the palladium [Pd2Cl4(1)] (3b) and nickel [NiCl2(5)] (6) coordination complexes were additionally characterized by X-ray diffraction crystallography. The behavior of 1 toward coordination to nickel and palladium was surprisingly different because the coordination of a second metal center after the initial 1,2-phosphorus-bonding of nickel was markedly difficult. The preference of nickel for 1,2-P coordination on 1,1'-bonding was confirmed by the exclusive formation of 6 from 5. The changes noted between the solid state structure of the ligand 1 and the structure obtained for the dinuclear palladium complex 3b reveal the rotational flexibility of this tetraphosphine. This flexibility is at the origin of the unique framework for a metallocenic dinuclear metal complex in which both coexist a 1,1'-heteroannular chelating P-bonding and a 2,3-homoannular chelating P-bonding with two palladium centers. Some reported specimens of ferrocenyl polyphosphines of constrained geometry have previously revealed that phosphorus lone pair overlap can lead to very intense "through-space" 31P31P nuclear spin-spin coupling constants (JPP) ( J. Am. Chem. Soc. 2004, 126 (35), 11077-11087] in solution phase. In these cases, an internuclear distance between heteroannular phosphorus atoms below 4.9 A, with an adequate orientation of the lone-pairs in the solid state and in solution, was a necessary parameter. The flexibility of the new polyphosphines 1 and 5 does not allow that spatial proximity (internuclear distances between heteroannular phosphorus above 5.2 A in the solid state); accordingly the expected through-space nuclear spin-spin coupling constants were not detected in any of their coordination complexes nor in 1.
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