Recent advances in the study of (–)clausenamide: chemistry, biological activities and mechanism of action

Abstract

Clausenamide (clau) is one of seven novel compounds isolated from Clausena lansium (Lour) skeels. Clau is unusual in that it contains 4 chiral centers yielding 8 pairs of enantiomers. After identification of the configuration of these enantiomers, the synthesis of 16 enantiomers, including optically active clau and (+) and (–)clau was carried out. During this study, many stereochemical and synthetic difficulties were solved and the Baldwin principle was updated. Production scale is now sufficient to meet the needs of clinical practice. In a pharmacological study numerous models and indicators showed that (–)clau is the active enantiomer, while (+)clau is inactive and elicits greater toxicity than (–)clau. The principal pharmacological effects of (–)clau are to increase cognition, demonstrated in ten models of memory impairment, as well as to inhibit β-amyloid (Aβ) toxicity, blocking neurofibrillary tangle formation by inhibiting the phosphorylation of tau protein. This anti-dementia effect is characterized by increased synaptic plasticity both in efficacy and in structure and provides new support for the theory that synaptic loss is the main cause of dementia. (–)Clau is considered to be a promising drug candidate for treatment of Alzheimer׳s disease and other neurodegenerative disorders.

CZ-7, a new derivative of Claulansine F, ameliorates 2VO-induced vascular dementia in rats through a Nrf2-mediated antioxidant responses

“…Clausenamide (Clau) is a newly found alkaloid that is isolated from the leaves of Clausena lansium (Lour) Skeels, and an evaluation of its activity showed that the principal pharmacological effects of (-)-Clau were to increase the cognition of mice/rats and inhibit, to different degrees, the pathological changes of AD through its multi-target effects [9,10]. Claulansine F (Clau F) is a new carbazole alkaloid isolated from the stem of C. lansium (Lour) Skeels [11].…”

Physiological signature of a novel potentiator of AMPA receptor signalling

“…Naturally occurring clausenamide is in racemic form, and like BRS-015, it acts as a LTP enhancer (Chu and Zhang, 2014; Chu et al, 2016; Xu et al, 2005). Both compounds are roughly equiactive with EC50 values in the range of 10–20 μM.…”

“…BRS–015 is structurally related to the excitotoxin – kainic acid, a potent AMPA/kainate receptor agonist, and to the natural product clausenamide extracted from the shrub Clausena lansium used in Chinese folk medicine. Clausenamide has been shown to enhance LTP (Feng et al, 2009) and is thought to possess anti–dementia properties (Chu and Zhang, 2014; Chu et al, 2016).…”

Balasubramide derivative 3C attenuates atherosclerosis in apolipoprotein E-deficient mice: role of AMPK-STAT1-STING signaling pathway

“…(+)-Balasubramide is an eight-membered lactam compound extracted from the leaves of the Sri Lankan plant Clausena indica . Previous studies have shown that clausenamide, a biosynthetic precursor of balasubramide, has anti-apoptosis [ 16 ] and anti-neuroinflammation effects, acting as an oxygen free radical scavenger and AMPK activator [ 17 , 18 ]. We have previously demonstrated a central role of AMPK-STAT1 axis in vascular inflammation regulation [ 19 ].…”