Antitumor agents 288: Design, synthesis, SAR, and biological studies of novel heteroatom-incorporated antofine and cryptopleurine analogues as potent and selective antitumor agents
Journal
Journal of Medicinal Chemistry
Journal Volume
54
Journal Issue
14
Pages
5097-5107
Date Issued
2011
Author(s)
Yang X.
Shi Qian
Yang S.-C.
Chen C.-Y.
Bastow K.F.
Morris-Natschke S.L.
Wu P.-C.
Lai C.-Y.
Wu T.-S.
Pan S.-L.
Teng C.-M.
Lin J.-C.
Lee K.-H.
Abstract
Novel heteroatom-incorporated antofine and cryptopleurine analogues were designed, synthesized, and tested against a panel of five cancer cell lines. Two new S-13-oxo analogues (11 and 16) exhibited potent cell growth inhibition in vitro (GI 50: 9 nM and 20 nM). Interestingly, both compounds displayed improved selectivity among different cancer cell lines, in contrast to the natural products antofine and cryptopleurine. Mechanism of action (MOA) studies suggested that R-antofine promotes dysregulation of DNA replication during early S phase, while no similar effects were observed for 11 and 15 on corresponding replication initiation complexes. Compound 11 also showed greatly reduced cytotoxicity against normal cells and moderate antitumor activity against HT-29 human colorectal adenocarcinoma xenograft in mice without overt toxicity. ? 2011 American Chemical Society.
SDGs
Other Subjects
12 oxa cryptopleurine; 13 oxa cryptopleurine; 13n boc 11 oxo 13 aza cryptopleurine; 13n boc 13 aza cryptopleurine; 2 (6,7,10 trimethoxy 1,2,3,4 tetrahydrodibenzo[f,h]isoquinolin 3 yl)acetaldehyde; 6,7,10 trimethoxy 3 (2 methoxyvinyl) 1,2,3,4 tetrahydrodibenzo[f,h]isoquinoline; antineoplastic agent; antofine; cryptopleurine; natural product; unclassified drug; animal experiment; animal model; antineoplastic activity; article; cancer cell culture; cancer inhibition; cell cycle S phase; cell strain HT29; colorectal carcinoma; controlled study; cytotoxicity; DNA replication; drug design; drug mechanism; drug potency; drug selectivity; drug synthesis; human; human cell; in vitro study; male; mouse; nasopharynx cancer; nonhuman; prostate cancer; regulatory mechanism; structure activity relation; tumor xenograft; umbilical vein endothelial cell; Alkaloids; Animals; Antineoplastic Agents; Cell Line, Tumor; DNA Replication; Drug Design; Drug Screening Assays, Antitumor; Indoles; Mice; Neoplasm Transplantation; Phenanthrolines; S Phase; Stereoisomerism; Structure-Activity Relationship; Transplantation, Heterologous
Type
journal article