Antitumor agents 283. Further elaboration of Desmosdumotin C analogs as potent antitumor agents: Activation of spindle assembly checkpoint as possible mode of action
Journal
Bioorganic and Medicinal Chemistry
Journal Volume
19
Journal Issue
5
Pages
1816-1822
Date Issued
2011
Author(s)
Nakagawa-Goto K.
Wu P.-C.
Bastow K.F.
Yang S.-C.
Chen H.-Y.
Lin J.-C.
Goto M.
Morris-Natschke S.L.
Lee K.-H.
Abstract
In our ongoing study of the desmosdumotin C (1) series, twelve new analogues, 21-32, mainly with structural modifications in ring-A, were prepared and evaluated for in vitro antiproliferative activity against several human tumor cell lines. Among them, the 4′-iodo-3,3,5-tripropyl-4-methoxy analogue (31) showed significant antiproliferative activity against multiple human tumor cell lines with ED 50 values of 1.1-2.8 μM. Elongation of the C-3 and C-5 carbon chains reduced activity relative to propyl substituted analogues; however, activity was still better than that of natural compound 1. Among analogues with various ether groups on C-4, compounds with methyl (2) and propyl (26) ethers inhibited cell growth of multiple tumor cells lines, while 28 with an isobutyl ether showed selective antiproliferative activity against lung cancer A549 cells (ED 50 1.7 μM). The gene expression profiles showed that 3 may modulate the spindle assembly checkpoint (SAC) and chromosome separation, and thus, arrest cells at the G2/M-phase. ? 2011 Elsevier Ltd. All rights reserved.
SDGs
Other Subjects
3,3,5 tripropyl 5 prenyldesmosdumotin C; 4 isobutoxy 3,3,5 tripropyldesmosdumotin C; 4 propoxy 3,3,5 tripropyldesmosdumotin C; antineoplastic agent; carbon; desmosdumotin C derivative; methyl group; natural product; paclitaxel; propane; unclassified drug; vincristine; antineoplastic activity; article; cancer cell culture; cell cycle arrest; cell cycle G2 phase; cell cycle M phase; cell proliferation; chromosome; controlled study; drug mechanism; drug potency; drug screening; drug selectivity; gene expression profiling; human; human cell; in vitro study; mitosis spindle; structure activity relation; Alkenes; Antineoplastic Agents; Cell Line, Tumor; Drug Screening Assays, Antitumor; Humans; Ketones; Mitotic Spindle Apparatus; Models, Biological; Molecular Structure; Neoplasms
Type
journal article