Glechomanamides A–C, Germacrane Sesquiterpenoids with an Unusual Δ⁸-7,12-Lactam Moiety from Salvia scapiformis and Their Antiangiogenic Activity

Abstract

Three new germacrane sesquiterpenoid-type alkaloids with an unusual Δ8-7,12-lactam moiety, glechomanamides A–C (1–3), and two pairs of 7,12-hemiketal sesquiterpenoid epimers (4a/b, 5a/b) were isolated from Salvia scapiformis. Their structures were elucidated by spectroscopic methods including HRESIMS, IR, UV, and 1D and 2D NMR and also confirmed by single-crystal X-ray diffraction analysis. The chemical transformation of compounds 1–5 in a solution environment was analyzed by 2D NMR spectroscopy. The aza acetallactams (1–3) were stable in organic solvent, while single crystals of the hemiacetal esters (4a/b, 5a/b) underwent a tautomeric equilibrium after being dissolved. Single crystals of 4a, 4b, and 5a were obtained for the first time as their naturally occurring forms. Glechomanamide B (2) exhibited antiangiogenic activity by suppression of vascular endothelial growth factor (VEGF)-induced tube formation through modulation of VEGF receptor 2 (VEGFR2)-mediated signaling pathways in human umbilical vascular endothelial cells (HUVECs). In addition, compound 2 also showed the significant suppression of mRNA expression associated with glycolysis and angiogenesis biomarkers in high glucose (30 mM)-induced HUVECs. These findings suggest that compound 2 might be a potential lead compound candidate for the management of diabetic retinopathy.

Epoxinnamide: An Epoxy Cinnamoyl-Containing Nonribosomal Peptide from an Intertidal Mudflat-Derived Streptomyces sp.

“…These images were measured with the Angiogenesis Analyzer of the ImageJ program. The total segment lengths of the structures were used to calculate the tube-formation activity and to evaluate the degree of tube formation [ 68 ].…”

Natural Nitrogenous Sesquiterpenoids and Their Bioactivity: A Review

“…One γ-elemene-type sesquiterpenes, 8β(H)-elema-1,3,7(11)-trien-8,12-lactam (330) (Figure 8) was obtained from the rhizomes of Curcuma phaeocaulis [63]. Three new germacrane sesquiterpenoid-typealkaloids with an unusual ∆ 8 -7,12-lactam moiety, glechomanamides A-C (331-333) (Figure 8) were isolated from Salvia scapiformis [78]. In a tube formation assay, 332 showed the most potent antiangiogenic activity in primary screening, and its IC 50 value was determined to be 40.4 µM [78].…”

“…Three new germacrane sesquiterpenoid-typealkaloids with an unusual ∆ 8 -7,12-lactam moiety, glechomanamides A-C (331-333) (Figure 8) were isolated from Salvia scapiformis [78]. In a tube formation assay, 332 showed the most potent antiangiogenic activity in primary screening, and its IC 50 value was determined to be 40.4 µM [78]. In addition to VEGFR2, 332 decreased BMP4 expression, which regulates tube formation, and glycolysisrelated proteins, including GLUT1 and HK2, which suggests that the novel compound 332 is worthy of additional investigation for angiogenesis-associated pathological conditions [78].…”

“…In a tube formation assay, 332 showed the most potent antiangiogenic activity in primary screening, and its IC 50 value was determined to be 40.4 µM [78]. In addition to VEGFR2, 332 decreased BMP4 expression, which regulates tube formation, and glycolysisrelated proteins, including GLUT1 and HK2, which suggests that the novel compound 332 is worthy of additional investigation for angiogenesis-associated pathological conditions [78]. Onopornoids A-D (334-337) (Figure 8), three elemanes and one germacrane, were extracted from the whole aerial parts of Onopordum alexandrinum, which possess unique structures combining a sesquiterpenoid framework with an amino acid, L-proline [79].…”

Enantiomeric Resolution and Absolute Configuration of a Chiral δ-Lactam, Useful Intermediate for the Synthesis of Bioactive Compounds

“…In recent years, substituted lactams have emerged as an important pharmacophore for several drug classes, with a large spectrum of biological outcomes and various therapeutic applications [6][7][8]. From a structural standpoint, they can be four-, five-, six-and seven-membered rings, called β-lactams, γ-lactam, δ-lactam and ε-lactam, respectively.…”