Conolodinines A–D, Aspidosperma–Aspidosperma Bisindole Alkaloids with Antiproliferative Activity from Tabernaemontana corymbosa

Abstract

Examination of the EtOH extract of the leaves of the Malayan Tabernaemontana corymbosa resulted in the isolation of four new (1−4) and two known bisindole alkaloids (5, 6) of the Aspidosperma−Aspidosperma type. The structures of these alkaloids were determined based on analysis of the spectroscopic data (NMR and HRESIMS). Xray diffraction analyses of the related bisindole alkaloids conophylline (5) and conophyllinine (6) established the absolute configurations. Treatment of the bisindole alkaloid conophylline (5) with benzeneselenic anhydride gave, in addition to the known bisindole polyervinine (7) previously isolated from another Malayan Tabernaemontana, another bisindole product, 8, an isolable tautomer of 7. X-ray diffraction analyses yielded the absolute configurations of both bisindoles and in addition showed that polyervinine (7) exists primarily as the neutral dione structure. The bisindoles (1−8) and the related conophylline-type bisindoles (9−13) showed pronounced in vitro growth inhibitory activity against an array of human cancer cell lines, including KB, vincristine-resistant KB, PC-3, LNCaP, MCF7, MDA-MB-231, A549, HT-29, and HCT 116 cells, with IC 50 values for the active compounds in the 0.01−5 μM range.T he genus Tabernaemontana (Apocynaceae) comprises a large number of species (more than 100) that are distributed over the tropical and subtropical regions of the world, including Africa, Asia, parts of the Americas, the Pacific Islands, and Australia. 1 About 13 species are known to occur in Malaysia (Peninsular Malaysia and Malaysian Borneo), with T. corymbosa being the most varied, as well as the most widely distributed. 1,2 Plants of this genus have been shown to be rich sources of biologically active alkaloids, especially indole alkaloids. 3−9 In continuation of the investigation of the Malayan Tabernaemontana, 10,11 we report herein the isolation, structure, and biological activity of new Aspidosperma− Aspidosperma bisindole alkaloids from T. corymbosa (sample occurring near Taiping, Perak). ■ RESULTS AND DISCUSSIONCompound 1 (conolodinine A) was isolated as a light yellowish oil, with [α] 25 D −180 (c 0.25, CHCl 3 ). The UV spectrum showed absorption maxima at 209, 220, 249, and 324 nm, while the IR spectrum showed bands due to OH/NH at 3376 cm −1 and carbonyl functions at 1716, 1674, and 1609 cm −1 . The HRESIMS data ([M + H] + m/z 793.3448) established the molecular formula as C 44 H 48 N 4 O 10 . The 1 H NMR data (Table 1

From the Spectroscopic Reassessment of Authentic Alkaloid Samples to the Molecular Networking-Guided Discovery of Criophylline-Related Analogues from Callichilia inaequalis

“…The sulfur-containing nature of compound 4 is a genuine structural oddity, as only few monoterpene indole alkaloids (MIAs) incorporate this heteroelement. It seems that only six such structures have been reported so far: pagisulfine, hemitheion, theionbrunonines A–C, ,− and mitrasulgynine . To the best of our knowledge, 14′- O -sulfocriophylline ( 4 ) represents the first sulfated MIA ever reported.…”

Indole-Containing Natural Products 2019–2022: Isolations, Reappraisals, Syntheses, and Biological Activities

“…Compounds 11 and 12 are eudistomin-type alkaloids isolated from the tunicate families Eudistoma and Pseudodistoma, whereas compounds 13 and 14 are novel nucleosides isolated from Didemnidae, also a tunicate [ 21 ]. Lastly, compounds 15 and 16 are bisindole alkaloids, while compounds 17 and 18 are MIAs, with all four being isolated from the leaves of Tabernaemontana corymbosa ( Figure 3 ) [ 22 ].…”

“…None of the compounds exhibited inhibitory activity against three pathogenic fungi ( F. oxysporum Schlecht, A. solani Sorauer, and R. solani ) [ 20 ]. Compounds 15–18 displayed potent (sub-micromolar) cytotoxicities against many cell lines, especially against KB/S cells [ 22 ]. Compounds 19 to 23 were tested for cytotoxicity against L5178Y cells using the MTT assay.…”

Semi-syntheses and interrogation of indole-substituted Aspidosperma terpenoid alkaloids

“…28 Although there is limited biological characterization for this monomer, the dimeric version, conophylline, has demonstrated much better anticancer activity than other Aspidosperma bisindole alkaloids. 18,21,29…”