Macrocyclic hexaoxazoles: Influence of aminoalkyl substituents on RNA and DNA G-quadruplex stabilization and cytotoxicity

A series of macrocyclic biphenyl tetraoxazoles was synthesized. The latter stages of the synthetic approach allowed for the addition of varied N-protected α-amino acids, which were subsequently deprotected and condensed to provide the desired macrocycles. Improved yields could be realized in the macrocyclization step of their synthesis relative to other macrocyclic G-quadruplex stabilizers. These 24-membered macrocycles were evaluated for their ability to stabilize G-quadruplex DNA and for their relative cytotoxicity against human tumor cells. These biphenyl tetraoxazoles were not strong ligands for G-quadruplex DNA relative to other macrocyclic polyoxazoles. This reduced stabilizing potential did correlate with their comparatively lower cytotoxic activity as observed in the human tumor cell lines, RPMI 8402 and KB3-1. These studies provide useful insights into the conformational requirements for the development of selective and more potent G-quadruplex ligands.

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“…When evaluated in vivo, YAK-1-161 had a T/C value of 21.6% and was well tolerated at doses levels ≤45 mg/kg. 22 …”

Section: Introductionmentioning

confidence: 99%

Macrocyclic biphenyl tetraoxazoles: Synthesis, evaluation as G-quadruplex stabilizers and cytotoxic activity

Blankson

Pilch²,

Liu³

et al. 2013

Bioorganic & Medicinal Chemistry

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“…Moving the side-chain away from the phenyl ring and onto an oxazole ring also fails to improve cytotoxic activity. As we have noted previously, a compound having a single water-solubilizing 2-(dimethylamino)ethyl chain 36 is superior to an analog having two such substituents 37 [22,36]. While 36 has reasonable cytotoxic potency and good water-solubility, the synthesis of this analog was considerably more involved than compound 2 .…”

Section: Resultsmentioning

confidence: 96%

“…While the propyl (n = 3) analog was a slightly more efficient G-quadruplex stabilizer than the ethyl analog, the 2-(dimethylamino)ethyl analog was more cytotoxic. A lysinyl (n = 4) analog was neither stabilizing towards G-quadruplexes not cytotoxic (IC 50 > 3 µM) [22]. The aryl amine analogs 8 and 19 and the 2-(dimethylamino)ethyl analogs 11 and 2 are strongly cytotoxic with excellent G-quadruplex stabilization.…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2013

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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 (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.

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“…Both of these molecules were reported to stabilize G-quadruplex DNA [70]. Due to the importance of cationic residue in the stabilization of G-quadruplex DNA, Rice developed Telomestatin analogues by examining the effect of the alkylamino chain length on two structures (Structure A and B, Table 5) [71].…”

Section: Telomestatinmentioning

confidence: 99%

Predicting the unpredictable: Recent structure–activity studies on peptide-based macrocycles

Wahyudi

McAlpine

2015

Bioorganic Chemistry

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Macrocyclic hexaoxazoles: Influence of aminoalkyl substituents on RNA and DNA G-quadruplex stabilization and cytotoxicity

Cited by 27 publications

References 31 publications

Macrocyclic biphenyl tetraoxazoles: Synthesis, evaluation as G-quadruplex stabilizers and cytotoxic activity

Macrocyclic biphenyl tetraoxazoles: Synthesis, evaluation as G-quadruplex stabilizers and cytotoxic activity

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

Predicting the unpredictable: Recent structure–activity studies on peptide-based macrocycles

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