- Inhibition of amyloid-β aggregation by coumarin analogs can be manipulated by functionalization of the aromatic center
-
Aggregation of the amyloid-β protein (Aβ) plays a pathogenic role in the progression of Alzheimer's disease, and small molecules that attenuate Aβ aggregation have been identified toward a therapeutic strategy that targets the disease's underlying cause. Compounds containing aromatic structures have been repeatedly reported as effective inhibitors of Aβ aggregation, but the functional groups that influence inhibition by these aromatic centers have been less frequently explored. The current study identifies analogs of naturally occurring coumarin as novel inhibitors of Aβ aggregation. Derivatization of the coumarin structure is shown to affect inhibitory capabilities and to influence the point at which an inhibitor intervenes within the nucleation dependent Aβ aggregation pathway. In particular, functional groups found within amyloid binding dyes, such as benzothiazole and triazole, can improve inhibition efficacy. Furthermore, inhibitor intervention at early or late stages within the amyloid aggregation pathway is shown to correlate with the ability of these functional groups to recognize and bind amyloid species that appear either early or late within the aggregation pathway. These results demonstrate that functionalization of small aromatic molecules with recognition elements can be used in the rational design of Aβ aggregation inhibitors to not only enhance inhibition but to also manipulate the inhibition mechanism.
- Soto-Ortega, Deborah D.,Murphy, Brandon P.,Gonzalez-Velasquez, Francisco J.,Wilson, Kelly A.,Xie, Fang,Wang, Qian,Moss, Melissa A.
-
experimental part
p. 2596 - 2602
(2011/06/17)
-
- Synthesis and anti-angiogenesis activity of coumarin derivatives
-
A series of 7-diethylaminocoumarin compounds were synthesized and the cytotoxicities were tested against human umbilical vein endothelial cell (HUVEC) and some cancer cells. We found that the introduction of cyano groups at the 4-position will promote the bioactivity. In particular, compounds 9 and 10 strongly inhibited the proliferation of various cancer cell lines, and 12 and 15 showed a high selectivity for HUVEC. Therefore, these coumarin molecules can be utilized as lead compounds to develop potential nontoxic angiogenesis inhibitors and small molecular ligands to target HUVEC.
- Lee, Seokjoon,Sivakumar, Krishnamoorthy,Shin, Woon-Seob,Xie, Fang,Wang, Qian
-
p. 4596 - 4599
(2007/10/03)
-
