Macrocyclic pyridyl polyoxazoles: structure-activity studies of the aminoalkyl side-chain on G-quadruplex stabilization and cytotoxic activity.
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 (DT(tran) 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.
Department of Medicinal Chemistry, Ernest Mario School of Pharmacy, Rutgers-The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ 08854, USA. jrice@rci.rutgers.edu.
Gifty
G
Blankson
Suzanne G
SG
Rzuczek
Cody
C
Bishop
Daniel S
DS
Pilch
Angela
A
Liu
Leroy
L
Liu
Edmond J
EJ
Lavoie
Joseph E
JE
Rice
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003500:Cyclization; D004247:DNA / Q000737:chemistry; D004354:Drug Screening Assays, Antitumor; D054856:G-Quadruplexes; D006801:Humans; D020128:Inhibitory Concentration 50; D047028:Macrocyclic Compounds / Q000138:chemical synthesis; D010080:Oxazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D047028:Macrocyclic Compounds; D010080:Oxazoles; D011725:Pyridines; D004247:DNA