Structural simplification of bioactive natural products with multicomponent synthesis. 2. antiproliferative and antitubulin activities of pyrano[3,2-c]pyridones and pyrano[3,2-c]quinolones.
Pyrano[3,2- c]pyridone and pyrano[3,2- c]quinolone structural motifs are commonly found in alkaloids manifesting diverse biological activities. As part of a program aimed at structural simplification of bioactive natural products utilizing multicomponent synthetic processes, we developed compound libraries based on these privileged heterocyclic scaffolds. The selected library members display low nanomolar antiproliferative activity and induce apoptosis in human cancer cell lines. Mechanistic studies reveal that these compounds induce cell cycle arrest in the G2/M phase and block in vitro tubulin polymerization. Because of the successful clinical use of microtubule-targeting agents, these heterocyclic libraries are expected to provide promising new leads in anticancer drug design.
Magedov
Igor V
IV
Department of Chemistry, New Mexico Institute of Mining and Technology, Socorro, New Mexico 87801, USA. imagedov@gmail.com
Manpadi
Madhuri
M
Ogasawara
Marcia A
MA
Dhawan
Adriana S
AS
Rogelj
Snezna
S
Van Slambrouck
Severine
S
Steelant
Wim F A
WF
Evdokimov
Nikolai M
NM
Uglinskii
Pavel Y
PY
Elias
Eerik M
EM
Knee
Erica J
EJ
Tongwa
Paul
P
Antipin
Mikhail Yu
MY
Kornienko
Alexander
A
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001688:Biological Products / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D011728:Pyridones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015363:Quinolones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D021241:Spectrometry, Mass, Electrospray Ionization; D014404:Tubulin / Q000187:drug effects*
D000970:Antineoplastic Agents; D001688:Biological Products; D011728:Pyridones; D015363:Quinolones; D014404:Tubulin