Covering: up to July 2022Stemmadenine alkaloids are a restrictive sub-group of monoterpene indole alkaloids, represented by two congeners: stemmadenine and vallesamine. Their skeleton is defined by the cleavage of the C-3-C-7 bond of the Strychnos group\'s pentacyclic scaffold in monoterpene indole alkaloids. The parent alkaloid stemmadenine acts as a key intermediate in the biosynthesis of several major monoterpene indole alkaloid families, including regular Strychnos alkaloids, Aspidosperma alkaloids, and Iboga alkaloids. In this review, a complete coverage of the stemmadenine alkaloids, from the early reports till the present day at 2022, are presented, and their diverse biological activities are briefly described. Moreover, the biosynthetic proposal for stemmadenine and the proposed biogenetic conversion of stemmadenine-type alkaloids into vallesamine-type congeners are discussed in detail. Moreover, the successful synthetic strategies to access the strained stemmadenine scaffolds are fully reviewed.

OBJECTIVE: Oral cancer is the 6th most prevalent type of cancer and is responsible for high human morbidity and mortality. The present study was designed to investigate the anticancer effects of Voacangine against human oral cancer and to decipher the underlying molecular mechanisms responsible for its anticancer properties.
METHODS: CCC-1 oral cancer cell line and normal hTRET-OME cell line were used in this study. Cell viability was determined by MTT assay. Acridine orange (AO)/ ethidium bromide (EB) and annexin V/propidium iodide (PI) assay were used for assessment of apoptosis. Cell cycle analysis and reactive oxygen species (ROS) determination was done by flow cytometry. The protein expression was determined by western blot analysis.
RESULTS: The results showed that Voacangine caused a remarkable decline in proliferation of SCC-1 human oral cancer cells with negligible toxic effects on the normal human hTRET-OME cells. The IC50 of Voacangine was 9 µM against SCC-1 cells relative to IC50 of 100 µM against normal hTRET-OME cells. The reduction of the proliferative rates was attributed to the induction of ROS triggered apoptosis which was associated with activation of Caspase-3, upregulation of Bax and suppression of Bcl-2. Voacangine induced G2/M cell cycle arrest in a dose-dependent manner. Additionally, the anticancer effects of Voacangine on oral cancer cells were exerted through the inhibition of PI3K/AKT signaling cascade.
CONCLUSIONS: Taken all together, we conclude that Voacangine is a potent anticancer molecule and may be utilized for the development of systemic therapy for oral cancer.

Little is known about the impact of sex-specific differences in calculating the pretest probability (PTP) of obstructive coronary artery disease. We sought to determine whether the calculation of PTP differ by sex in symptomatic patients referred to coronary computed tomographic angiography (CCTA).
The characteristics of 5777 men and women who underwent CCTA were compared. For each patient, PTP was calculated according to the updated Diamond-Forrester method (UDFM) and the Duke clinical score (DCS), respectively. Follow-up clinical data were also recorded. Area under the receiver operating characteristic curve, integrated discrimination improvement, net reclassification improvement, and the Hosmer-Lemeshow goodness-of-fit statistic were used to assess the models\' performance.
The area under the receiver operating characteristic curve of UDFM and DCS showed little difference in men (0.782 vs. 0.785, P=0.4708) and women (0.668 vs. 0.654, P=0.1255), and calibration of neither model was satisfactory. Compared with UDFM, DCS showed positive integrated discrimination improvement (10% in men, P<0.0001, and 8% in women, P<0.0001, respectively), net reclassification improvement (12.17% in men, P<0.0001, and 27.19% in women, P<0.0001, respectively), and obviously reduced unnecessary noninvasive testing for women with negative CCTA.
Although the performance of neither model was favorable, DCS offered a more accurate calculation of PTP than UDFM and application of DCS instead of UDFM would result in a significant decrease in inappropriate testing, especially in women.

Monoterpenoid indole alkaloids are a large (∼3000 members) and structurally diverse class of metabolites restricted to a limited number of plant families in the order Gentianales. Tabernanthe iboga or iboga (Apocynaceae) is native to western equatorial Africa and has been used in traditional medicine for centuries. Howard Lotsof is credited with bringing iboga to the attention of Western medicine through his accidental discovery that iboga can alleviate opioid withdrawal symptoms. Since this observation, iboga has been investigated for its use in the general management of addiction. We were interested in elucidating ibogaine biosynthesis to understand the unique reaction steps en route to ibogaine. Furthermore, because ibogaine is currently sourced from plant material, these studies may help improve the ibogaine supply chain through synthetic biology approaches. Here, we used next-generation sequencing to generate the first iboga transcriptome and leveraged homology-guided gene discovery to identify the penultimate hydroxylase and final O-methyltransferase steps in ibogaine biosynthesis, herein named ibogamine 10-hydroxylase (I10H) and noribogaine-10-O-methyltransferase (N10OMT). Heterologous expression in Saccharomyces cerevisiae (I10H) or Escherichia coli (N10OMT) and incubation with putative precursors, along with HPLC-MS analysis, confirmed the predicted activities of both enzymes. Moreover, high expression levels of their transcripts were detected in ibogaine-accumulating plant tissues. These discoveries coupled with our publicly available iboga transcriptome will contribute to additional gene discovery efforts and could lead to the stabilization of the global ibogaine supply chain and to the development of ibogaine as a treatment for addiction.

One known bis-indole alkaloid-voacamine was isolated from Voacanga africana Stapf and Surface Plasmon Resonance imaging (SPRi) exprement showed that this alkaloid could be combine with Protein Tyrosine Phosphatase1B (PTP1B). Then the PTP1B activity inhibition experiment display that the compound showed an outstanding promoting activity to PTP1B.

Noribogaine is the main psychoactive metabolite of the hallucinogenic drug ibogaine, and is a particularly interesting compound potentially useful to treat dependence and various psychiatric disorders. Here, we report the effects of noribogaine on anxiety and locomotion in zebrafish (Danio rerio), a new promising model organism in neurobehavioral and psychopharmacological research. Adult zebrafish were subjected to the 5min novel tank test (NTT) following an acute, 20-min drug immersion in 1, 5 and 10mg/L noribogaine. Overall, noribogaine produced robust anxiolytic-like behavior in zebrafish (increasing the time spent and transitions to the top half compartment and reducing freezing bouts) without overt effects on fish locomotion. Taken together, these results indicate that noribogaine modulates the components of the acute stress response related to emotionality and anxiety behaviors, implicating this drug as a potentially useful non-sedative anxiolytic agent.

A new monoterpenoid indole alkaloid compound (1) and six known monoterpenoid indole alkaloids compounds (2-7) were isolated from the barks of Voacanga africana Staph. The structures were established by spectral analysis as ibogamine-16-carboxylic acid,17,20-didehydro-5,6-dioxo-10-methoxy-methyl ester (1), voacamine (2), vobasine (3), voacangine (4), voacristine (5), 19-epi-voacristine (6) and 19-epi-heyneanine (7). Compound 1 was confirmed by X-ray crystallographic analysis. All of the isolated compounds were evaluated for cytotoxicity against five cell lines (HEPG-2, A375, MDA-MB-231, SH-SY5Y, CT26). Among them, compounds 2 and 6 displayed significant inhibitory activities, compounds 3, 4 and 5 showed moderate inhibitory activities, while compounds 1 and 7 showed no inhibitory activities against the five cell lines.

The iboga alkaloids are a class of naturally occurring and synthetic compounds, some of which modify drug self-administration and withdrawal in humans and preclinical models. Ibogaine, the prototypic iboga alkaloid that is utilized clinically to treat addictions, has been associated with QT prolongation, torsades de pointes and fatalities. hERG blockade as IKr was measured using the whole-cell patch clamp technique in HEK 293 cells. This yielded the following IC50 values: ibogaine manufactured by semisynthesis via voacangine (4.09 ± 0.69 µM) or by extraction from T. iboga (3.53 ± 0.16 µM); ibogaine\'s principal metabolite noribogaine (2.86 ± 0.68 µM); and voacangine (2.25 ± 0.34 µM). In contrast, the IC50 of 18-methoxycoronaridine, a product of rational synthesis and current focus of drug development was >50 µM. hERG blockade was voltage dependent for all of the compounds, consistent with low-affinity blockade. hERG channel binding affinities (K i) for the entire set of compounds, including 18-MC, ranged from 0.71 to 3.89 µM, suggesting that 18-MC binds to the hERG channel with affinity similar to the other compounds, but the interaction produces substantially less hERG blockade. In view of the extended half-life of noribogaine, these results may relate to observations of persistent QT prolongation and cardiac arrhythmia at delayed intervals of days following ibogaine ingestion. The apparent structure-activity relationships regarding positions of substitutions on the ibogamine skeleton suggest that the iboga alkaloids might provide an informative paradigm for investigation of the structural biology of the hERG channel.

Seven new iboga-type alkaloids, ervaoffines A-D (1-4), (7S)-3-oxoibogaine hydroxyindolenine (5), ibogaine-5,6-dione (6), and 19-epi-5-oxovoacristine (7), and 10 known alkaloids were isolated from Ervatamia officinalis. The absolute configurations of 1-7 were determined through X-ray diffraction and electronic circular dichroism (ECD) analyses. Ervaoffines A and B represent the first iboga-type pseudoindoxyl alkaloids in which the C-2 spiro carbon configuration is opposite to that of other members of this class, such as iboluteine (8). The relationship between the absolute configuration of the spiro carbons and the Cotton effect in the ECD spectrum is established for the first time for iboga-type pseudoindoxyl and oxindole alkaloids. Additionally, a plausible biogenetic pathway for these alkaloids is proposed.

OBJECTIVE: To study the alkaloids of Voacanga africana.
METHODS: The alkaloids were isolated by normal phase silica gel and Sephadex LH-20 column chromatography. Their structures were elucidated by analysis of spectroscopic data.
RESULTS: Eight alkaloids were isolated and their structures were elucidated as voacangine(1), voacangine hydroxyindolenine(2), 19R-epi-voacristine(3), epi-ibogaine(4), vobasine(5), 19-epi-heyneanine(6), vobtusine(7) and voacamine(8).
CONCLUSIONS: Compounds 2-4 and 6 are isolated from this plant for the first time.