High-content analysis of cancer-cell-specific apoptosis and inhibition of in vivo angiogenesis by synthetic (-)-pironetin and analogs.
The natural product (-)-pironetin is a structurally simple small molecule microtubule-perturbing agent whose biological activities appear to be exquisitely dependent on defined stereochemistry and the presence of an eletrophilic alpha,beta-unsaturated lactone moiety. We used alkaloid-catalyzed acyl halide-aldehyde cyclocondensation reactions in asymmetric total syntheses of (-)-pironetin and three synthetic analogs, and evaluated their biological activities by high-content analysis in cell culture and in a zebrafish model. Synthetic (-)-pironetin and 2,3-dihydro-3-hydroxypironetin caused mitotic arrest and programmed cell death in human lung cancer cells but not in normal lung fibroblasts, had nanomolar growth inhibitory activity in multi-drug resistant cells, and inhibited neovascularization in zebrafish embryos. Synthetic (-)-pironetin delayed the onset but increased the extent of tubulin assembly in vitro. The data illustrate the power of acyl halide-aldehyde cyclocondensation to generate biologically active synthetic analogs of stereochemically complex targets and suggest that (-)-pironetin and 2,3-dihydro-3-hydroxypironetin possess unique properties that may bestow them with advantages over existing microtubule-perturbing agents in the context of a whole organism or under conditions of multi-drug resistance.
Vogt
Andreas
A
Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15260, USA. avogt@pitt.edu
McPherson
Peter A
PA
Shen
Xiaoqiang
X
Balachandran
Raghavan
R
Zhu
Guangyu
G
Raccor
Brianne S
BS
Nelson
Scott G
SG
Tsang
Michael
M
Day
Billy W
BW
D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D016466:CHO Cells; D045744:Cell Line, Tumor; D006224:Cricetinae; D003412:Cricetulus; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008870:Microtubules / Q000378:metabolism; D008938:Mitosis / Q000187:drug effects; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D011753:Pyrones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D050257:Tubulin Modulators / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D015027:Zebrafish
D020533:Angiogenesis Inhibitors; D011753:Pyrones; D050257:Tubulin Modulators; C088446:pironetin
J Biomol Screen. 2003 Apr;8(2):125-35
12844433
Org Lett. 2001 Mar 8;3(5):707-10
11259042
Dev Dyn. 2009 Mar;238(3):656-63
19235725
Chem Biol. 2004 Jun;11(6):799-806
15217613
Dev Biol. 2002 Aug 15;248(2):307-18
12167406
Nat Rev Cancer. 2002 Oct;2(10):727-39
12360276
Dev Dyn. 1995 Jul;203(3):253-310
8589427
Arterioscler Thromb Vasc Biol. 2003 May 1;23(5):911-2
12740225
Chem Biol Drug Des. 2007 Aug;70(2):75-86
17683369
Proc Natl Acad Sci U S A. 1998 Dec 22;95(26):15798-802
9861050
J Antibiot (Tokyo). 2000 May;53(5):540-5
10908119
Curr Med Chem Anticancer Agents. 2002 Jan;2(1):19-53
12678750
Nat Rev Cancer. 2004 Apr;4(4):253-65
15057285
Cancer Res. 2003 Aug 15;63(16):5054-9
12941834
J Antibiot (Tokyo). 1994 Jun;47(6):697-702
8040075
J Am Chem Soc. 2006 Jun 14;128(23):7438-9
16756287
Nat Rev Drug Discov. 2006 Mar;5(3):219-34
16518375
Anticancer Res. 2007 Mar-Apr;27(2):729-36
17465195
Blood. 1999 Dec 15;94(12):4143-55
10590059
Mol Pharmacol. 2003 Jun;63(6):1349-55
12761345
Proc Natl Acad Sci U S A. 1980 Jan;77(1):467-71
6928639
Org Lett. 2003 Feb 6;5(3):265-8
12556168
Eur J Biochem. 2003 Sep;270(18):3822-8
12950266
Science. 1977 Apr 1;196(4285):60-3
841339
Biochem J. 1999 Jun 1;340 ( Pt 2):411-6
10333483
Clin Cancer Res. 1996 Nov;2(11):1843-9
9816139
BMC Dev Biol. 2007 Jun 06;7:62
17553162
J Pharmacol Toxicol Methods. 2000 Jul-Aug;44(1):235-49
11274893
Anal Biochem. 1985 Oct;150(1):76-85
3843705
Dev Biol. 2001 Feb 15;230(2):278-301
11161578
Oncol Res. 2004;14(6):305-14
15206493
Nat Rev Drug Discov. 2007 Apr;6(4):273-86
17396134
Cancer Lett. 1998 Apr 10;126(1):29-32
9563645
Nat Rev Genet. 2002 Sep;3(9):674-82
12209142
Cancer Res. 1983 Jan;43(1):222-8
6847771
Chem Biol Drug Des. 2006 Jan;67(1):66-73
16492150