Journal of medicinal chemistry
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Preclinical and clinical research findings have revealed that the hormone progesterone, when acutely administered, can dramatically reduce cerebral edema, inflammation, tissue necrosis, and programmed cell death following traumatic brain injury (TBI). The poor aqueous solubility of progesterone, however, limits its potential use as a therapeutic. Several chemically novel analogues of progesterone and its natural metabolite allopregnanolone have been synthesized and screened using both in vitro and whole animal models of TBI. The new derivatives demonstrated greatly improved solubility and select compounds have shown equivalent effectiveness to progesterone in reducing cerebral edema after TBI.
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The first metal complexes of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (Triapine) were synthesized. Triapine was prepared by a novel three-step procedure in 64% overall yield. In addition, a series of related ligands, namely, 2-formylpyridine thiosemicarbazone, 2-acetylpyridine thiosemicarbazone, 2-pyridineformamide thiosemicarbazone, and their N(4)-dimethylated derivatives (including the N(4)-dimethylated analogue of Triapine) were prepared, along with their corresponding gallium(III) and iron(III) complexes with the general formula [M(L)(2)](+), where HL is the respective thiosemicarbazone. ⋯ All ligands and complexes were tested for their in vitro antiproliferative activity in two human cancer cell lines (41M and SK-BR-3), and structure-activity relationships were established. In general, the coordination to gallium(III) increased the cytotoxicity while the iron(III) complexes show reduced cytotoxic activity compared to the metal-free thiosemicarbazones. Selected compounds were investigated for the capacity of inhibiting ribonucleotide reductase by incorporation of (3)H-cytidine into DNA.
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Inhibition of tumor angiogenesis through blockade of the vascular endothelial growth factor (VEGF) signaling pathway is a new treatment modality in oncology. Preclinical findings suggest that blockade of additional pro-angiogenic kinases, such as fibroblast and platelet-derived growth factor receptors (FGFR and PDGFR), may improve the efficacy of pharmacological cancer treatment. Indolinones substituted in position 6 were identified as selective inhibitors of VEGF-, PDGF-, and FGF-receptor kinases. ⋯ In contrast, no direct inhibition of tumor cell proliferation was observed. Compounds 2 (BIBF 1000) and 3 (BIBF 1120) are orally available and display encouraging efficacy in in vivo tumor models while being well tolerated. The triple angiokinase inhibitor 3 is currently in phase III clinical trials for the treatment of nonsmall cell lung cancer.
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Through systematic structure-activity studies of the 2-benzoylpyridine thiosemicarbazone (HBpT), 2-(3-nitrobenzoyl)pyridine thiosemicarbazone (HNBpT) and dipyridylketone thiosemicarbazone (HDpT) series of iron (Fe) chelators, we identified structural features necessary to form Fe complexes with potent anticancer activity (J. Med. Chem. 2007, 50, 3716-3729). ⋯ Four of the six HApT chelators had potent antitumor activity (IC(50): 0.001-0.002 microM) and Fe chelation efficacy that was similar to the most effective HBpT and HDpT ligands. The HApT Fe complexes had the lowest Fe(III/II) redox potentials of any thiosemicarbazone series we have generated. This property, in combination with their ability to effectively chelate cellular Fe, make the HApT series one of the most potent antiproliferative agents developed by our group.