660395-39-1Relevant articles and documents
Facile Conversion of Molecularly Complex (Hetero)aryl Carboxylic Acids into Alkynes for Accelerated SAR Exploration
Lutter, Ferdinand H.,Jouffroy, Matthieu
supporting information, p. 14816 - 14820 (2021/10/08)
1,2,3-Triazoles are well-established bioisosteres for amides, often installed as a result of structure?activity-relationship (SAR) exploration. A straightforward approach to assess the effect of the replacement of an amide by a triazole would start from the carboxylic acid and the amine used for the formation of a given amide and convert them into the corresponding alkyne and azide for cyclization by copper-catalyzed alkyne?azide cycloaddition (CuAAC). Herein, we report a functional-group-tolerant and operationally simple decarbonylative alkynylation that allows the conversion of complex (hetero)aryl carboxylic acids into alkynes. Furthermore, the utility of this method was demonstrated in the preparation of a triazolo analog of the commercial drug moclobemide. Lastly, mechanistic investigations using labeled carboxylic acid derivatives clearly show the decarbonylative nature of this transformation.
Water-soluble inhibitors of ABCG2 (BCRP) – A fragment-based and computational approach
Antoni, Frauke,Wifling, David,Bernhardt, Günther
supporting information, (2020/11/20)
A good balance between hydrophilicity and lipophilicity is a prerequisite for all bioactive compounds. If the hydrophilicity of a compound is low, its solubility in water will be meager. Many drug development failures have been attributed to poor aqueous solubility. ABCG2 inhibitors are especially prone to be insoluble since they have to address the extremely large and hydrophobic multidrug binding site in ABCG2. For instance, our previous, tariquidar-related ABCG2 inhibitor UR-MB108 (1) showed high potency (79 nM), but very low aqueous solubility (78 nM). To discover novel potent ABCG2 inhibitors with improved solubility we pursued a fragment-based approach. Substructures of 1 were optimized and the fragments ‘enlarged’ to obtain inhibitors, supported by molecular docking studies. Synthesis was achieved, i.a., via Sonogashira coupling, click chemistry and amide coupling. A kinetic solubility assay revealed that 1 and most novel inhibitors did not precipitate during the short time period of the applied biological assays. The solubility of the compounds in aqueous media at equilibrium was investigated in a thermodynamic solubility assay, where UR-Ant116 (40), UR-Ant121 (41), UR-Ant131 (48) and UR-Ant132 (49) excelled with solubilities between 1 μM and 1.5 μM – an up to 19-fold improvement compared to 1. Moreover, these novel N-phenyl-chromone-2-carboxamides inhibited ABCG2 in a Hoechst 33342 transport assay with potencies in the low three-digit nanomolar range, reversed MDR in cancer cells, were non-toxic and proved stable in blood plasma. All properties make them attractive candidates for in vitro assays requiring long-term incubation and in vivo studies, both needing sufficient solubility at equilibrium. 41 and 49 were highly ABCG2-selective, a precondition for developing PET tracers. The triple ABCB1/C1/G2 inhibitor 40 qualifies for potential therapeutic applications, given the concerted role of the three transporter subtypes at many tissue barriers, e.g. the BBB.
COMPOUNDS AND METHODS FOR TREATING CANCER
-
Paragraph 0190; 0393, (2020/12/19)
Substituted cinnamamide compounds and analogs, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds to treat, prevent or ameliorate cancer are provided.
