Molecules 2013, 18(10), 11938-11963; doi:10.3390/molecules181011938
Article

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

1, 1,†, 1, 2,3, 2,3, 2,3, 1,3 and 1,3,* email
Received: 22 August 2013; in revised form: 10 September 2013 / Accepted: 17 September 2013 / Published: 26 September 2013
(This article belongs to the Special Issue G-Quadruplexes & i-Motif DNA)
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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 (DTtran 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.
Keywords: synthesis; macrocycle; G-quadruplex; G-quadruplex stabilizer; G-quadruplex ligands
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MDPI and ACS Style

Blankson, G.; Rzuczek, S.G.; Bishop, C.; Pilch, D.S.; Liu, A.; Liu, L.; LaVoie, E.J.; Rice, J.E. Macrocyclic Pyridyl Polyoxazoles: Structure-Activity Studies of the Aminoalkyl Side-Chain on G-Quadruplex Stabilization and Cytotoxic Activity. Molecules 2013, 18, 11938-11963.

AMA Style

Blankson G, Rzuczek SG, Bishop C, Pilch DS, Liu A, Liu L, LaVoie EJ, Rice JE. Macrocyclic Pyridyl Polyoxazoles: Structure-Activity Studies of the Aminoalkyl Side-Chain on G-Quadruplex Stabilization and Cytotoxic Activity. Molecules. 2013; 18(10):11938-11963.

Chicago/Turabian Style

Blankson, Gifty; Rzuczek, Suzanne G.; Bishop, Cody; Pilch, Daniel S.; Liu, Angela; Liu, Leroy; LaVoie, Edmond J.; Rice, Joseph E. 2013. "Macrocyclic Pyridyl Polyoxazoles: Structure-Activity Studies of the Aminoalkyl Side-Chain on G-Quadruplex Stabilization and Cytotoxic Activity." Molecules 18, no. 10: 11938-11963.

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