Indolizine-Based Scaffolds as Efficient and Versatile Tools: Application to the Synthesis of Biotin-Tagged Antiangiogenic Drugs

Abstract

We describe the design and optimization of polyfunctional scaffolds based on a fluorescent indolizine core derivatized with various orthogonal groups (amines, esters, oximes, alkynes, etc.). To show one application as tools in biology, the scaffold was used to prepare drug–biotin conjugates that were then immobilized onto avidin-agarose for affinity chromatography. More specifically, the antiangiogenic drug COB223, whose mechanism of action remained unclear, was chosen as a proof-of-concept drug. The drug-selective discrimination of proteins observed after elution of the cell lysates through the affinity columns, functionalized either with the biologically active COB223 or a structurally related inactive analogue (COB236), is a clear indication that the presence of the indolizine core does not limit drug–protein interaction and confirms the usefulness of the indolizine scaffold. Furthermore, the separation of COB223-interacting proteins from human placental extracts unveiled unanticipated protein targets belonging to the family of regulatory RNA-binding proteins, which opens the way to new hypotheses on the mode of action of this antiangiogenic drug.

Interest of novel N-alkylpyridinium-indolizine hybrids in the field of Alzheimer's disease: Synthesis, characterization and evaluation of antioxidant activity, cholinesterase inhibition, and amyloid fibrillation interference

“…Three of the pyridine-indolizine intermediates, 6 and 11 and 12, were selected for biological evaluation as neutral analogs. Four bis-pyridinium salts (17)(18)(19)(20) were also prepared by controlled mono N-alkylation with methyl iodide, followed by the reaction with bromoacetophenone (the structures are depicted in Table 1).…”

“…Both heterocycles possess a wide variety of interesting properties that have been reviewed recently [17][18][19] (for examples of active molecules, see Figure 1). It is worth highlighting the fluorescence properties of the indolizine nucleus which has been used in the design of fluorescent tags or markers [20][21][22] . Interestingly in the field of AD, several pyridinium salts have been designed to interfere with ChE activity as mentioned above 9,10,14,15 and it is worth citing methoxime and obidoxime that are potent agents against nerve toxin action 23 .…”

Whole-Cells of Yarrowia lipolytica Applied in “One Pot” Indolizine Biosynthesis

“…The indolizine core is present in many biologically active compounds and can be considered an important scaffold for the preparation of new pharmaceuticals [20,21]. These class of compounds holds valuable biologic activities [21], such as antimicrobial [22,23], antioxidant [24,25], anticancer [26][27][28], enzyme inhibitors [29,30], anti-inflammatory [21] and anti-HIV-1 [31].…”

“…The basic medium for yeasts cultivation was YPD broth containing (g L −1 ): peptone (20), yeast extract (10), glucose (10), pH = 5.5. YPD with 20 g L −1 agar was also used for pure culture preservation and multiplication.…”

Estudos sintéticos visando à preparação de novas indolizinas aromáticas

“…Além disso, compostos fluorescentes também são afetados pelos ambientes em que estão inseridos, de maneira que características como o pH do meio, polaridade, lipofilicidade, influência de solventes próticos ou apróticos, entre outros aspectos, devem ser considerados quando novos fluoróforos forem estudados (PAVIA et al, 2009). Nesse contexto, a fluorescência tem aplicações diversas e compostos fluorescentes que contém a indolizina podem ser empregados como biossensores (KIM et al, 2015), sondas de pH (KIM et al, 2008;GE et al, 2017), diodo orgânico emissor de luz (OLED) (KIM et al, 2015), marcadores de drogas (ARVIN-BEROD et al, 2017) e carreadores de substâncias biologicamente ativas (SURPATEANU et al, 2007) (Figura 7).…”