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

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,*
1 Department of Medicinal Chemistry, Ernest Mario School of Pharmacy, Rutgers–The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ 08854, USA 2 Department of Pharmacology, Rutgers Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA 3 The Cancer Institute of New Jersey, Rutgers–The State University of New Jersey, New Brunswick, NJ 08901, USA Current Address: Department of Chemistry, the Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, USA
* Author to whom correspondence should be addressed.
Received: 22 August 2013 / Revised: 10 September 2013 / Accepted: 17 September 2013 / Published: 26 September 2013
(This article belongs to the Special Issue G-Quadruplexes & i-Motif DNA)
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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 synthesis; macrocycle; G-quadruplex; G-quadruplex stabilizer; G-quadruplex ligands
This is an open access article distributed under the Creative Commons Attribution License (CC BY) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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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.

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