Macrocyclic Pyridyl Polyoxazoles: Structure-Activity Studies of the Aminoalkyl Side-Chain on G-Quadruplex Stabilization and Cytotoxic Activity

Abstract

Pyridyl polyoxazoles are 24-membered macrocyclic lactams comprised of a pyridine, four oxazoles and a phenyl ring. A derivative having a 2-(dimethylamino)ethyl chain attached to the 5-position of the phenyl ring was recently identified as a selective G-quadruplex stabilizer with excellent cytotoxic activity, and good in vivo anticancer activity against a human breast cancer xenograft in mice. Here we detail the synthesis of eight new dimethylamino-substituted pyridyl polyoxazoles in which the point of attachment to the macrocycle, as well as the distance between the amine and the macrocycle are varied. Each compound was evaluated for selective G-quadruplex stabilization and cytotoxic activity. The more active analogs have the amine either directly attached to, or separated from the phenyl ring by two methylene groups. There is a correlation between those macrocycles that are effective ligands for the stabilization of G-quadruplex DNA (ΔTtran 15.5–24.6 °C) and cytotoxicity as observed in the human tumor cell lines, RPMI 8402 (IC50 0.06–0.50 µM) and KB3-1 (IC50 0.03–0.07 µM). These are highly selective G-quadruplex stabilizers, which should prove especially useful for evaluating both in vitro and in vivo mechanism(s) of biological activity associated with G-quaqdruplex ligands.

Insights on Structure–Passive Permeability Relationship in Pyrrole and Furan-Containing Macrocycles

“…Aromatic heterocycles are often considered as an interesting moiety not only for their prevalence in nature but also because of their potential to modulate physicochemical properties, biological activities, and conformations. − The impact of a heterocycle moiety in a macrocycle’s skeletal flexibility may help chameleonism . In macrocyclic peptides, replacing amino acids with heterocycles not only diversifies the structure but may also lead to increased membrane permeability.…”

A Three-Step Method for the Preparation of N-Substituted 3,4-Dihydroisoquinolin-1(2H)-ones and Heteroaryl-Fused 3,4-Dihydropyridin-2(1H)-ones from 2-Bromobenzoate Precursors

“…We initiated our investigation by preparing a number of aryl-substituted N -Boc-phenethylamines 2a – i from various aryl-substituted ethyl 2-bromobenzoates 1a – i and commercially available potassium {2-[( tert -butoxycarbonyl)­amino]­ethyl}­trifluoroborate using the protocol reported by the Molander group when developing this reagent for cross-coupling reactions . This reagent has been used on a number of occasions for cross-coupling chemistry, including in approaches toward new molecules in discovery programs Table displays the best outcomes from using both of the two palladium-catalyzed procedures described in the original publications.…”

“…Scheme depicts results from the cross-coupling of ethyl 2-bromobenzoate ( 1a ) with the commercially available potassium {2-[(phenylmethoxycarbonyl)­amino]­ethyl}­trifluoroborate, another reagent developed by the Molander group for cross-coupling chemistry. , The Cbz-protected phenethylamine ethyl ester 2j was isolated in good isolated yield. Subjection of 2j to the one-step protocol with 1.2 equiv of sodium hydride as a base provided the N -benzyl 3,4-tetrahydroisoquinolin-1­(2 H )-one 3a in good yield and with only a trace of byproducts.…”