Antimitotic and vascular disrupting agents: 2-hydroxy-3,4,5-trimethoxybenzophenones
- Eur J Med Chem. 2014 Apr 22:77:306-14. doi: 10.1016/j.ejmech.2014.02.061.
- 1. School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan, ROC.
- 2. Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli 350, Taiwan, ROC.
- 3. National Institute of Cancer Research, National Health Research Institutes, Tainan 70456, Taiwan, ROC.
- 4. National Institute of Cancer Research, National Health Research Institutes, Tainan 70456, Taiwan, ROC; Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC. Electronic address: [email protected].
- 5. School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan, ROC; School of Pharmacy, National Defense Medical Center, 161 Minchuan East Road, Section 6, Taipei 114, Taiwan, ROC. Electronic address: [email protected].
2-Hydroxy-3,4,5-trimethoxybenzophenones (8-16) manifest pseudo-ring formation involving intramolecular hydrogen bonding of the 2-OH and the carbonyl group. Among the synthetic products described in this report, (3-hydroxy-4-methoxyphenyl)(2-hydroxy-3,4,5-trimethoxyphenyl)-methanone (14) and (3-amino-4-methoxyphenyl)(2-hydroxy-3,4,5-trimethoxy-phenyl)methanone (16) exhibit significant antiproliferative activity against KB cells with IC50 values of 11.1 and 11.3 nM, respectively. These two compounds also displayed tubulin affinity comparable to that of combretastatin A-4. In studies with human umbilical vein endothelial cells, compounds 14 and 16 revealed concentration-dependent vascular-disrupting properties. The results support the rationale of the pseudo-ring concept and suggest further investigation of A-ring modification in these benzophenones.