Macrocyclic pyridyl polyoxazoles: selective RNA and DNA G-quadruplex ligands as antitumor agents.
The synthesis of a series of 24-membered pyridine-containing polyoxazole macrocycles is described. Seventeen new macrocycles were evaluated for cytotoxic activity against RPMI 8402, KB-3, and KB-3 cell lines that overexpress the efflux transporters MDR1 (KBV-1) and BCRP (KBH5.0). Macrocycles in which the pyridyl-polyoxazole moiety is linked by a 1,3-bis(aminomethyl)phenyl group with a 5-(2-aminoethyl)- (18) or a 5-(2-dimethylaminoethyl)- substituent (19) displayed the greatest cytotoxic potency. These compounds exhibit exquisite selectivity for stabilizing G-quadruplex DNA with no stabilization of duplex DNA or RNA. Compound 19 stabilizes quadruplex mRNA that encodes the cell-cycle checkpoint protein kinase Aurora A to a greater extent than the quadruplex DNA of a human telomeric sequence. These data may suggest a role for G-quadruplex ligands interacting with mRNA being associated with the biological activity of macrocyclic polyoxazoles. Compound 19 has significant in vivo anticancer activity against a human breast cancer xenograft (MDA-MB-435) in athymic nude mice.
Rzuczek
Suzanne G
SG
Department of Medicinal Chemistry, Ernest Mario School of Pharmacy, Rutgers-The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, New Jersey 08854-8020, USA.
Pilch
Daniel S
DS
Liu
Angela
A
Liu
Leroy
L
LaVoie
Edmond J
EJ
Rice
Joseph E
JE
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy; D002352:Carrier Proteins; D045744:Cell Line, Tumor; D004247:DNA; D004354:Drug Screening Assays, Antitumor; D054856:G-Quadruplexes / Q000187:drug effects*; D006801:Humans; D008024:Ligands; D047028:Macrocyclic Compounds / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins; D010080:Oxazoles / Q000737:chemistry / Q000494:pharmacology*; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D012313:RNA; D023041:Xenograft Model Antitumor Assays
C513055:ABCB1 protein, human; C116614:ABCG2 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D002352:Carrier Proteins; D008024:Ligands; D047028:Macrocyclic Compounds; D009363:Neoplasm Proteins; D010080:Oxazoles; D011725:Pyridines; D012313:RNA; D004247:DNA