cis‐Clerodane Diterpenoids with Structural Diversity and Anti‐inflammatory Activity from Tinospora crispa

Abstract

Comprehensive Summary Twelve new cis‐clerodane diterpenoids, designated as crispinoids A—L (1—12), together with three known analogues (13—15), were isolated from Tinospora crispa. Their structures were fully assigned by comprehensive spectroscopic techniques, single‐crystal X‐ray diffraction experiments, and electronic circular dichroism (ECD) analyses. The isolated clerodanes displayed diverse heterocyclic frameworks including 6/6/6‐, 6/5/6/6‐, 6/6/5‐, 6/6‐, and 6/5/6‐fused ring systems. Some of the isolates showed ATP‐citrate lyase (ACLY) and nuclear factor kappa B (NF‐κB) pathway inhibition. The NF‐κB inhibitors further suppressed the lipopolysaccharide (LPS)‐induced inflammatory responses in RAW 264.7 cells.

Structural Revision of Tinotufolins from Tinospora crispa Leaves Guided by Empirical Rules and DFT Calculations

“…The relative configuration of 7 was confirmed to be identical to that of tinotufolin C ( 3 ) by the NOESY correlations and 1 H– 1 H coupling constants. The absolute configuration of compound 7 (3 S ,4 S ,5 R ,8 S ,9 R ,10 S ) was elucidated by comparing its negative optical rotation ([α] 25 D −14.2) with that of another isolated ent - neo -clerodane diterpene [crispinoid K, [α] 25 D −11.7], whose absolute configuration was established by single-crystal X-ray diffraction analysis . Consequently, the structure of compound 7 was established as methyl (−)-(3 S ,4 S ,5 R ,8 S ,9 R ,10 S )-3-acetoxy-15,16-epoxy-4-hydroxy- ent - neo -cleroda-13(16),14-dien-18-oate, which was named tinotufolin G.…”

“…Finally, the ECD spectrum of 5 displayed a positive Cotton effect at 220 nm that agreed with that of another ent-neo-clerodane [crispinoid H, ECD (CH 3 OH) λ max (Δε): 221 (+1.90)] isolated from T. crispa, whose absolute configuration was determined by X-ray analysis. 29 Therefore, the structure of tinotufolin E was revised to a CC-type [methyl (−)-(4R,5R,8S,9R,10S)-15,16-epoxy-4hydroxy-ent-neo-cleroda-2,13(16),14-trien-18-oate ( 5 3 and 4). The presence of an acetoxy group at C-3 was confirmed according to the HMBC correlation from H-3 to C-1′.…”

“…Therefore, the revised structure 5 was established and supported by the statistical parameters obtained from the experimental and calculated 13 C NMR chemical shifts (Figure H). Finally, the ECD spectrum of 5 displayed a positive Cotton effect at 220 nm that agreed with that of another ent - neo -clerodane [crispinoid H, ECD (CH 3 OH) λ max (Δε): 221 (+1.90)] isolated from T. crispa , whose absolute configuration was determined by X-ray analysis . Therefore, the structure of tinotufolin E was revised to a CC-type [methyl (−)-(4 R ,5 R ,8 S ,9 R ,10 S )-15,16-epoxy-4-hydroxy- ent - neo -cleroda-2,13­(16),14-trien-18-oate ( 5 )].…”