Total Synthesis And Preliminary Structure-activity Relationship Study Of An Eight-membered Lactam Compound Extracted From Clausena Indica(Datz).Oliv

Studies have shown that five-membered and ring-bridged lactam compounds extracted from Clausena Indica have extensive biological activities. However, the biological activity of the eight-membered lactam compound is rarely reported. With the purpose of studying the eight-membered lactam compound with a indole ring, this paper has designed and synthesized natural product(+)-balasubramide and its analog(+)-norbalasubramide. Trans-cinnamaldehyde was selected as a starting materia which was used to prepare(+)-balasubramide and(+)-norbalasubramide by amine-ester interchange reaction and intramolecular cyclization.(+)-Balasubramide was obtained with 44% overall yield and 99% enantioselectivity, and(+)-norbalasubramide was 57% overall yield and 99% enantioselectivity. Moreover, in order to study these compounds’ bioactivities and perform a preliminary analysis of the Structure-Activity Relationship, substituents with varying electronegativity were introduced into the 6-phenyl ring. Trans-cinnamaldehydes with different substitutions were employed to prepare(+)-norbalasubramide derivatives with 35-54% overall yield and 95-99% enantioselectivity.Owing to the five-membered lactam’s stereostructure having a great influence on activities, we need to study the Stereostructure-Activity Relationship of the eight-membered lactam compound. Because(±)-norbalasubramide was easy to prepare, it was sellected as the substrate. Utilizing the secondary hydroxy group in its lactam ring,(±)-norbalasubramide enantiomers were separated by chiral resolution reagent,(-)-Menthoxyacetic Acid.(+)-Norbalasubramide was obtained with 30.0% overall yield, and >94% enantioselectivity, and(-)-norbalasubramide was 30.7% overall yield, and >99% enantioselectivity.With we reviewing the type of pharmacological activities in the five-membered lactam compounds extracted from Clausena Indica,(+)-balasubramide, and(+)-norbalasubramide and its derivatives were evaluated for neuroprotective, antioxidative, and anti-neuroinflammatory effects using the MTT assay and ELISA. The compounds with different electronegative groups in the 6-phenyl ring produced little neuroprotection and antioxidation, but induced strong anti-neuroinflammatory effects in BV-2 microglial cells(with the exception of 3g). Compound 3c, with a trifluoromethyl group in its 6-phenyl ring, was a particularly effective anti-neuroinflammatory agent. These results demonstrated that the electronegativity of the 6-phenyl ring of(+)-balasubramide is an important determinant of its inhibitory effect on neuroinflammation. More electronegative substituents result in stronger anti-neuroinflammatory effects. Cytotoxicity assays indicated no significant effects of the tested compounds.To conclude, the studies show that(+)-balasubramide, and(+)-norbalasubramide and its derivatives have a good resistance to nerve inflammation effect with low cytotoxicity, and compound 3c merits additional study due to its strong anti-neuroinflammatory effect.