Highly Antiproliferative Latonduine and Indolo[2,3-c]quinoline Derivatives: Complex Formation with Copper(II) Markedly Changes the Kinase Inhibitory Profile

Q1 · MEDICINE

Article

Author: Enyedy, Eva A. ; Dömötör, Orsolya ; Reynisson, Jóhannes ; Arion, Vladimir B. ; Spengler, Gabriella ; Madejski, Christian ; Bacher, Felix ; Wittmann, Christopher

A series of latonduine and indoloquinoline derivatives HL¹-HL⁸ and their copper(II) complexes (1-8) were synthesized and comprehensively characterized. The structures of five compounds (HL⁶, [CuCl(L¹)(DMF)]·DMF, [CuCl(L²)(CH₃OH)], [CuCl(L³)]·0.5H₂O, and [CuCl₂(H₂L⁵)]Cl·2DMF) were elucidated by single crystal X-ray diffraction. The copper(II) complexes revealed low micro- to sub-micromolar IC₅₀ values with promising selectivity toward human colon adenocarcinoma multidrug-resistant Colo320 cancer cells as compared to the doxorubicin-sensitive Colo205 cell line. The lead compounds HL⁴ and 4 as well as HL⁸ and 8 induced apoptosis efficiently in Colo320 cells. In addition, the copper(II) complexes had higher affinity to DNA than their metal-free ligands. HL⁸ showed selective inhibition for the PIM-1 enzyme, while 8 revealed strong inhibition of five other enzymes, i.e., SGK-1, PKA, CaMK-1, GSK3β, and MSK1, from a panel of 50 kinases. Furthermore, molecular modeling of the ligands and complexes showed a good fit to the binding pockets of these targets.

03 Jan 2022·Chemistry – A European JournalQ2 · CHEMISTRY

4‐Phosphoryl Pyrazolones for Highly Selective Lithium Separation from Alkali Metal Ions

Q2 · CHEMISTRY

Article

Author: Schaper, Gerrit ; Zheng, Shili ; Du, Hao ; Zhang, Jianfeng ; Steup, Johannes ; Wenzel, Marco ; Lindoy, Leonard F. ; Hennersdorf, Felix ; Weigand, Jan J.

AbstractEffective receptors for the separation of Li+ from a mixture with other alkali metal ions under mild conditions remains an important challenge that could benefit from new approaches. In this study, it is demonstrated that the 4‐phosphoryl pyrazolones, HL2‐HL4, in the presence of the typical industrial organophosphorus co‐ligands tributylphosphine oxide (TBPO), tributylphosphate (TBP) and trioctylphosphine oxide (TOPO), are able to selectively recognise and extract lithium ions from aqueous solution. Structural investigations in solution as well as in the solid state reveal the existence of a series of multinuclear Li+ complexes that include dimers (TBPO, TBP) as well as rarely observed trimers (TOPO) and represent the first clear evidence for the synergistic role of the co‐ligands in the extraction process. Our findings are supported by detailed NMR, MS and extraction studies. Liquid‐liquid extraction in the presence of TOPO revealed an unprecedented high Li+ extraction efficiency (78 %) for HL4 compared to the use of the industrially employed acylpyrazolone HL1 (15 %) and benzoyl‐1,1,1‐trifluoroacetone (52 %) extractants. In addition, a high selectivity for Li+ over Na+, K+ and Cs+ under mild conditions (pH ∼8.2) confirms that HL2‐HL4 represent a new class of ligands that are very effective extractants for use in lithium separation.

01 Sep 2002·Infection and ImmunityQ2 · MEDICINE

Macrophage Plasma Membrane Cholesterol Contributes to Brucella abortus Infection of Mice

Q2 · MEDICINE

Article

Author: Shirahata, Toshikazu ; Makino, Sou-ichi ; Watarai, Masahisa ; Michikawa, Makoto ; Yanagisawa, Katsuhiko ; Murakami, Shigeru

ABSTRACTBrucella abortus is a facultative intracellular bacterium capable of surviving inside macrophages. Intracellular replication of B. abortus requires the VirB complex, which is highly similar to conjugative DNA transfer systems. In this study, we show that plasma membrane cholesterol of macrophages is required for the VirB-dependent internalization of B. abortus and also contributes to the establishment of bacterial infection in mice. The internalization of B. abortus was accelerated by treating macrophages with acetylated low-density lipoprotein (acLDL). Treatment of acyl coenzyme A:cholesterol acyltransferase inhibitor, HL-004, to macrophages preloaded with acLDL accelerated the internalization of B. abortus . Ketoconazole, which inhibits cholesterol transport from lysosomes to the cell surface, inhibited the internalization and intracellular replication of B. abortus in macrophages. The Niemann-Pick C1 gene (NPC1), the gene for Niemann-Pick type C disease, characterized by an accumulation of cholesterol in most tissues, promoted B. abortus infection. NPC1-deficient mice were resistant to the bacterial infection. Molecules associated with cholesterol-rich microdomains, “lipid rafts,” accumulate in intracellular vesicles of macrophages isolated from NPC1-deficient mice, and the macrophages yielded no intracellular replication of B. abortus . Thus, trafficking of cholesterol-associated microdomains controlled by NPC1 is critical for the establishment of B. abortus infection.

100 Deals associated with HL-004

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Indication	Highest Phase	Country/Location	Organization	Date
Atherosclerosis	Phase 1	JP	Taisho Pharmaceutical Co., Ltd.	13 Aug 1999
Hypercholesterolemia	Phase 1	JP	Taisho Pharmaceutical Co., Ltd.	13 Aug 1999
Hyperlipidemias	Phase 1	-	Taisho Pharmaceutical Holdings Co., Ltd.	-

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