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.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3141083 | PMC |
| http://dx.doi.org/10.1021/jm200330s | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Design, Synthesis, and Biological Activity of Sulfonamide Analogues of Antofine and Cryptopleurine as Potent and Orally Active Antitumor Agents.
J Med Chem
October 2015
Research Institute of Pharmaceutical Science, College of Pharmacy, Seoul National University, Seoul 151-742, Korea.
Due to their profound antiproliferative activity and unique mode of action, phenanthroindolizidine and phenanthroquinolizidine alkaloids, represented by antofine and cryptopleurine, have attracted attention recently as potential therapeutic agents. We have designed, synthesized, and evaluated the methanesulfonamide analogues of these natural alkaloids with the hope of improving their druglikeness. The analogues showed enhanced growth inhibition of human cancer cells compared with the parent natural products.
View Article and Find Full Text PDFCollective asymmetric synthesis of (-)-antofine, (-)-cryptopleurine, (-)-tylophorine, and (-)-tylocrebrine with tert-butanesulfinamide as a chiral auxiliary.
J Org Chem
April 2014
State Key Laboratory of Elemento-Organic Chemistry, Research Institute of Elemento-Organic Chemistry, Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Nankai University, Tianjin 300071, People's Republic of China.
A collective asymmetric synthesis of phenanthroindolizidine and phenanthroquinolizidine alkaloids (-)-antofine, (-)-cryptopleurine, (-)-tylophorine, and (-)-tylocrebrine was achieved by means of a reaction sequence involving efficient generation of chiral homoallylic amine intermediates by asymmetric allylation of the corresponding tert-butanesulfinyl imine. From these intermediates, the pyrrolidine and piperidine rings were constructed by means of an intramolecular SN2 substitution reaction and a ring-closing metathesis reaction, respectively. The unusual C5-methoxy-substituted phenanthrene moiety of (-)-tylocrebrine was generated by means of an InCl3-catalyzed cycloisomerization reaction of an o-propargylbiaryl compound.
View Article and Find Full Text PDFTotal synthesis of (+)-antofine and (-)-cryptopleurine.
European J Org Chem
May 2013
Department of Chemistry and Biochemistry, New Mexico State University, MSC 3C, Las Cruces, NM 88003 USA.
The tylophorine alkaloid anticancer compounds antofine and cryptopleurine have been synthesized in optically active form. Both syntheses employ optically pure α-amino acids as the starting materials, require only seven steps from known 2-ethynylpyrrolidine or 2-ethynylpiperidine derivatives, and are free of protecting groups. Key steps include an alkyne hydration and a chromium carbene complex based net [5+5]-cycloaddition step.
View Article and Find Full Text PDFAntitumor agents 295. E-ring hydroxylated antofine and cryptopleurine analogues as antiproliferative agents: design, synthesis, and mechanistic studies.
J Med Chem
August 2012
Natural Products Research Laboratories and ‡Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599-7568, United States.
Various E-ring hydroxylated antofine and cryptopleurine analogues were designed, synthesized, and tested against five human cancer cell lines. Interesting structure-activity relationship (SAR) correlations were found among these new compounds. The most potent compound 13b was further tested against a series of nonsmall cell lung cancer (NSCLC) cell lines in which it showed impressive antiproliferative activity.
View Article and Find Full Text PDFAntitumor agents 288: design, synthesis, SAR, and biological studies of novel heteroatom-incorporated antofine and cryptopleurine analogues as potent and selective antitumor agents.
J Med Chem
July 2011
Natural Products Research Laboratories, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599-7568, USA.
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.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!