Macrocyclic biphenyl tetraoxazoles: Synthesis,evaluation as G-quadruplex stabilizers and cytotoxic activity |
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Authors: | Gifty A. Blankson Daniel S. Pilch Angela A. Liu Leroy F. Liu Joseph E. Rice Edmond J. LaVoie |
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Affiliation: | 1. Department of Medicinal Chemistry, Ernest Mario School of Pharmacy, Rutgers—The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ 08854-8020, USA;2. Department of Pharmacology, The University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, NJ 08854-5635, USA;3. The Cancer Institute of New Jersey, New Brunswick, NJ 08901, USA |
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Abstract: | 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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Keywords: | G-quadruplex Biphenyl Macrocycle Oxazoles Cytotoxicity G-quadruplex ligand |
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