Synthesis of A/B Ring Analogs of Territrem B and Evaluation of Their Biological Activities

Abstract

Two series of territrem B analogs, i.e., 5 ± 10, containing both the 2-en-1-one-A-ring and the aromatic-Ering pharmacophores were designed and synthesized from jujubogenin (4a). The anti-acetylcholinesterase (antiAChE), anti-caspase-3, and other biological activities of these territrem-B analogs and their intermediates were assessed. Compound 9b, 22a, and 24f were shown to be weak inhibitors of AChE. None of the synthesized compounds exhibited significant inhibitory activity on caspase-3. On the other hand, compounds 22e, 24a, 7b, and 8a showed mild cytotoxicity on cultured KB cells, with IC 50 values of 2.0, 3.5, 6.5, and 14 mm, respectively. In addition, compounds 23b and 5f were active against injury arising from oxygen-glucose deprivation.

Design, Synthesis, and Biological Evaluation of New Territrem B Analogues

“…gorge of AChE, in contrast to the planar territrem B (1) [12]. This is in agreement with the choking hypothesis by Chen and Ling [8], in which the planar territrem B is proposed to enter the gorge of AChE and to act with aromatic protein residues and fixed H 2 O molecules [8].…”

“…Eventually, the electron-rich moieties act as H-bond acceptors, thus stabilizing the complex with AChE. This may also rationalize the lower inhibitory activities of the compounds reported in a previous paper [12], in which fewer H-bond acceptors were present. The lower activity of 5o relative to 5p and or 5r might, therefore, be due to the presence of the electron-withdrawing ethoxycarbonyl group.…”

“…Zhao et al reported the preparation of territrem B analogues from triterpenoids, and found that the enone and aromatic moieties play important roles in the synthetic compounds [11] [12]. Recently, the total synthesis of the territrem B analogue (AE)-arisugacin A (3) was achieved via a complicated multistep synthesis, but neither the bioactivity of 3 nor an SAR study of its derivatives have been reported [13 ± 15].…”

Design, Synthesis, and Examination of Neuron Protective Properties of Alkenylated and Amidated Dehydro-Silybin Derivatives

“…The organic phase was separated and washed with brine (2 Â 10 mL), dried over Na 2 SO 4 , and evaporated under reduced pressure. The residue was then column chromatographed over repeated silica gel and Sephadex LH-20 to afford (()-1a-f. N,N-Diethyl-2-{2-[3-(4-diethylcarbamoylmethoxy-3-methoxy-phenyl)-2-hydroxylmethyl-2,3-dihydro-benzo [1,4]dioxin-6yl]-3,5-dihydroxy-4-oxo-4H-chromen-7-yloxy}-acetamide ((()-1a). This compound was prepared by the general method with silybin and 2-bromo-N,N-diethyl-acetamide (97 mg, 0.5 mmol) as starting materials and purified on silica gel chromatography using CHCl 3 /MeOH (40:1) as eluent.…”

“…A definitive hypothesis on the development of AD, which may unify the enormous number of neuropathological and neurochemical findings, has not been established. Although acetylcholine degradation was evidenced to be related to AD syndrome, wherein AChE inhibition continues to be an efficient therapeutic modality for AD treatment, 3,4 increasing studies suggest that excessive reactive oxygen species (ROS) produces oxidative stress and has been implicated in the pathogenesis of neurodegenerative diseases including AD and PD. [5][6][7] Clonal pheochromocytoma PC12 cells provide a convenient and well-studied model system for investigation of neuronal injury in vitro.…”