Linear and Branched Pyridyl–Oxazole Oligomers: Synthesis and Circular Dichroism Detectable Effect on c‐Myc G‐Quadruplex Helicity

Abstract

Five unprecedented pyridyl–oxazole oligomers exhibiting either linear or branched connectivity of their subunits were developed as a family of potential G‐quadruplex‐interacting ligands. Our synthesis employed variations of a key Pd/Cu‐mediated C–C cross‐coupling/C–H activation reaction to gain access to the oligomer products from a small set of substituted pyridine building blocks. The effect of the compounds on the conformation of a c‐myc oncogene promoter G‐quadruplex was investigated by circular dichroism under various conditions. Some or all of the compounds induced detectable helicity enhancement in low‐cation and Na+‐rich Tris‐HCl (pH 7.4) buffers, respectively, in which the helix was only partially prefolded.

Investigation of ‘Head-to-Tail’-Connected Oligoaryl N,O-Ligands as Recognition Motifs for Cancer-Relevant G-Quadruplexes

“…Recently developed synthetic methodologies, involving sp 2 C–H bond activation, combined with cross-coupling reactions [ 31 , 32 ], have potential to revolutionize the production of new and complex oligoaryl N , O -ligands in a limited number of steps. By employing variations of such methodologies previously described by us [ 33 ] and others [ 25 ] and compatible with the presence of N and O -heteroatoms, we have synthesized a small library of pyridyl-oxazole oligomers (with oligomer length varying from 2 to 7 rings) exhibiting a one-directional, ‘head-to-tail’ connectivity of alternating pyridine and oxazole units ( Figure 2 ) [ 34 ]. Oligomer directionality is a direct consequence of oxazole orientation within the structures.…”

“…These are equipped with either aldehyde or bromide functionalities or both, which are necessary for carrying out the desired reaction scheme. Our synthesis relied on two key chemical transformations to construct the oligomers’ skeleton: (I) The conversion of aldehyde moieties to oxazoles in MeOH under Van Leusen conditions ( p -toluenesulfonyl isocyanate or TOSMIC reagent, in the presence of base) [ 35 ] (condition set a in Scheme 1 ), and (II) A direct C–C cross-coupling to pair pyridine and oxazole, which proceeds via activation of the C–H bond of the 2-position of the oxazole and subsequent coupling to a bromo-substituted position of the pyridine, under Pd(OAc) 2 /CuI cocatalysis [ 25 , 33 , 34 ] (condition set c). To avoid side reactions during C–C cross-coupling steps, free aldehydes were protected with ethylene glycol as 1,3-dioxolanes [ 36 ] (condition set b) and deprotected later with LiCl [ 37 ] (condition set d), immediately prior to an oxazole formation step.…”

Design, Synthesis, Computational, and Preclinical Evaluation of natTi/45Ti-Labeled Urea-Based Glutamate PSMA Ligand

“…The synthesis of the chelating pharmacophore CA-PSMA (10) is presented in Scheme 2. The room temperature O-alkylation of the chelidamic acid diethyl ether (4) [19] with benzylic bromide (5) [20] yielded the corresponding isothiocyanate (6), which was coupled with (7) and synthesized as described by Maresca et al [21] to yield (8). The ethyl esters were saponified with LiOH in tetrahydrofuran (THF)/water, giving (9) followed by removal of the tert-butyl groups with trifluoroacetic acid (TFA) in dichloromethane (DCM) to give CA-PSMA (10).…”

“…Compound 4 was synthesized as described previously [19]. First, 12.6 mL (173 mmol) thionyl chloride was added to 50 mL of anhydrous ethanol in a round-bottom flask under argon flow cooled in an ice bath.…”

Five-Membered Ring Systems With O and N Atoms

“…An elegant synthesis of good candidates for G-quadruplex binding, such as the propeller-like oxazole-pyridine structure 87, together with similar linear structures, was reported in two different contributions (15SL489, 16EJO122). Continuing in the field of medicinal chemistry, two antimicrobial agents, among a library of binaphthyl-peptide-oxazoles, are the most active synthesized so far in this category (15OBC10813), while a series of diacylglycerol lipase α inhibitors, containing a benzoxazole unit, was screened in the search for a promising lead compound (15JMC9742).…”