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

• Published in: Bioorganic & medicinal chemistry letters Vol. 20; no. 10; pp. 3150 - 3154
• Main Authors: Satyanarayana, Mavurapu, Kim, Young-Ah, Rzuczek, Suzanne G., Pilch, Daniel S., Liu, Angela A., Liu, Leroy F., Rice, Joseph E., LaVoie, Edmond J.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 15.05.2010; Elsevier
• Subjects: Animals; Antineoplastic agents; Antitumor; Athymic nude mice; Biological and medical sciences; Cell Line, Tumor; Cytotoxicity; G-quadruplex DNA; G-quadruplex ligands; G-quadruplex RNA; G-Quadruplexes; General aspects; Hexaoxazoles; Humans; Macrocycles; MDA-MB-435 xenograft; Medical sciences; Mice; Mice, Nude; Oxazoles - chemical synthesis; Oxazoles - chemistry; Oxazoles - toxicity; Pharmacology. Drug treatments; RNA - chemistry; Xenograft Model Antitumor Assays; G-quadruplex DNA; G-quadruplex RNA; Antitumor; Hexaoxazoles; MDA-MB-435 xenograft; Cytotoxicity; Macrocycles; Athymic nude mice; G-quadruplex ligands; Antineoplastic agent; Intraperitoneal administration; RNA; Lactam; Myeloma; Telomere; Guanine; Thermal stability; Macrocycle; Structure activity relation; Mammary gland; Chemical synthesis; Tumor cell; Oxygen nitrogen heterocycle; Human; Sequence specificity; Squamous cell carcinoma; Nucleotide sequence; Rodentia; Polycyclic compound; Malignant tumor; In vitro; In vivo; Vertebrata; Chemotherapy; Mammalia; Treatment; Cell line; Mouse; Animal; DNA; Cancer
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2010.03.086

Several monoaminoalkyl derivatives with R′′ being isopropyl and various bis-aminoalkyl substituted hexaoxazoles derivatives were evaluated for cytotoxicity and stabilization of G-quadruplex RNA and DNA. One of the more cytotoxic analogs (where n = 1, R′′ is isopropyl and both R and R′ are methyl substituents) inhibits human tumor growth in the athymic nude mouse xenograft model. A series of 24-membered macrocyclic hexaoxazoles containing one or two aminoalkyl substituents was synthesized and evaluated for cytotoxicity and for their ability to selectively stabilize G-quadruplex DNA and RNA. The most cytotoxic analog 4a, with IC 50 values of 25 and 130 nM using KB3-1 and RPMI 8402 cells, is efficacious in vivo in athymic nude mice with a human tumor xenograft from the breast cancer cell line MDA-MB-435.