Monoterpenoid Indole Alkaloids from Inadequately Dried Leaves of Alstonia scholaris

Six new indole alkaloids,named alstoniascholarines L–Q(1–6),together with nineteen known analogues were isolated from the inadequately dried leaves of Alstonia scholaris.Their structures were elucidated on the basis of extensive analysis of spectroscopic data and by comparison of their physical and spectroscopic data with the literature values.In addition,the new alkaloids were tested for their cytotoxic and neurite outgrowth-promoting activities.

Indole Alkaloids Inhibiting Neural Stem Cell from Uncaria rhynchophylla

Uncaria rhynchophylla is commonly recognized as a traditional treatment for dizziness,cerebrovascular diseases,and nervous disorders in China.Previously,the neuro-protective activities of the alkaloids from U.rhynchophylla were intensively reported.In current work,three new indole alkaloids(1–3),identified as geissoschizic acid(1),geissoschizic acid N4-oxide(2),and 3b-sitsirikine N4-oxide(3),as well as 26 known analogues were isolated from U.rhynchophylla.However,in the neural stem cells(NSCs)proliferation assay for all isolated compounds,geissoschizic acid(1),geissoschizic acid N4-oxide(2),isocorynoxeine(6),isorhynchophylline(7),(4S)-akuammigine N-oxide(8),and(4S)-rhynchophylline N-oxide(10)showed unexpected inhibitory activities at 10 μM.Unlike previous neuro-protective reports,as a warning or caution,our finding showcased a clue for possible NSCs toxicity and the neural lesions risk of U.rhynchophylla,while the structure–activity relationships of the isolated compounds were discussed also.

Three New Indole Alkaloids from Tabernaemontana divaricata

Three new monoterpene indole alkaloids,3a-hydroxymethyl-ibogamine(1),3a-acetatemethoxyl-ibogamine(2),16a-hy-droxyl-ibogamine(3)together with six known alkaloids were isolated from the branches and leaves of Tabernaemontana divaricata(Apocynaceae).The structures of these alkaloids were determined by spectroscopic analyses.All isolated compounds showed no significant cytotoxicity against SGC-7901 gastric cancer,HeLa,and A-549 lung cancer cell lines(IC50>20μM).

Acute and Sub-chronic Toxicity of Indole Alkaloids Extract from Leaves of Alstonia scholaris (L.) R. Br. in Beagle Dogs

Alstonia scholaris(L.)R.Br.,an evergreen tropical plant rich in indole alkaloids with significant physiological activity,is traditionally used to treat respiratory diseases in China.This study was conducted to establish the toxicity profile of the alkaloid extract(TA)of A.scholaris leaves in non-rodents.After oral administration of a single dose(4 g/kg.bw),a num-ber of transient symptoms,such as unsteady gait,drooling,emesis,and reddening of peri-oral mucosa,were observed,but no treatment-related mortality.A sub-chronic toxicity study with a range of doses of TA(20,60 and 120 mg/kg.bw)was conducted for a 13-week treatment period,followed by 4-week recovery observation.Except for emesis and drooling in majority of animals in 120 mg/kg.bw treatment group,no clinical changes were observed in TA-treated animals.Data from electrocardiography,bone marrow,urine,fecal,hematology and clinical chemistry analyses were comparable between TA-treated and control animals.No significant differences in the relative organ weights and histopathological characteristics were evident between the TA-treated and control groups.Accordingly,the non-observed-adverse-effect-level(NOAEL)of TA was established as 120 mg/kg.bw.Our results add further knowledge to the safety database for indole alkaloid extracts from A.scholaris with potential utility as novel drug candidates.

Acute and Chronic Toxicity of Indole Alkaloids from Leaves of Alstonia scholaris (L.) R. Br. in Mice and Rats

Alstonia scholaris(L.)R.Br.(Apocynaceae)is an evergreen tree that has been used to treat lung diseases.In this study,the toxicity profile of indole alkaloids from leaves of A.scholaris was investigated.In acute toxicity tests,mice were adminis-tered total alkaloids(TA)and five indole alkaloids.In a chronic toxicity test,rats were continuously administered TA(50,100,and 300 mg/kg bw)for 13 weeks,followed by a 4-week recovery.A single administration of TA affected the behavior of mice,and at 12.8 g/kg bw,prone position,shortness of breath,wheezing,and convulsion were observed.The half-lethal dose(LD50)in mice was 5.48 g/kg bw,almost 2740 times the clinical dose in humans.Among the five indole alkaloids,the maximum tolerance dose in mice ranged from 0.75 to 4 g/kg bw.The TA-treated rats did not die and showed no adverse effects or dose-dependent changes in weight or food and water consumption,despite fluctuations in hematological and bio-chemical parameters compared with historical data.Furthermore,both gross and histopathological observations revealed no abnormalities in any organ.With daily oral administration to rats,the non-observed-adverse-effect-level of TA was 100 mg/kg bw.The results indicate that TA is safe for clinical use.

STUDIES ON THE INDOLE ALKALOIDS OF GELSEMIUM ELEGANS

The modified Hofmann degradation of koumine(1) has proved abortive. The struture and stereochemistry of the main product(3) were deduced by spectral methods and confirmed by X-ray diffration analysis. From the roots of Gelsemium elegans, dihydrokounine was first isolated as a natural product.

Genotoxicity and Safety Pharmacology Studies of Indole Alkaloids Extract from Leaves of Alstonia scholaris (L.) R. Br.

Indole alkaloids extract(IAAS)was prepared from leaves of Alstonia scholaris(L.)R.Br.,an evergreen tropical plant widely distributed throughout the world.This plant has been used historically by the Dai ethnic people of China to treat respiratory diseases.This study evaluated the genotoxicity and safety pharmacology of IAAS to support clinical use.The bacterial reverse mutation(Ames)test,in vitro mammalian chromosomal aberration test,and in vivo mammalian erythrocyte micronucleus(MN)test were performed to evaluate genotoxicity.Mice were administered IAAS(240,480,or 960 mg/kg bw)once orally to observe adverse central nervous system effects.Furthermore,beagle dogs were administered IAAS(10,30,60 mg/kg bw)once via the duodenum to evaluate its effects on the cardiovascular and respiratory systems.IAAS with or without S9-induced metabolic activation showed no genotoxicity in the Ames test up to 500μg/plate,in the mammalian chromosomal aberration test up to 710μg/mL,or in the MN test up to 800 mg/kg bw.No abnormal neurobehavioral effects were observed in mice following treatment with up to 960 mg/kg bw of IAAS.Moreover,blood pressure,heart rate,electrocardiogram parameters,and depth and rate of breathing in anesthetized beagle dogs did not differ among the IAAS doses or from the vehicle group.These data indicated that IAAS did not induce mutagenicity,clastogenicity,or genotoxicity,and no pharmaco-toxicological effects were observed in the respiratory,cardiovascular,or central nervous systems.Our results increased understanding of safety considerations associated with IAAS,and may indicate that IAAS is a possible drug candidate.

Two new indole alkaloids from Nauclea officinalis

Two new indole alkaloids, 4-oxo-4,12-dihydroindolo[2,3-a]quinolizine-3-carbaldehyde (1) and 1,6,7-trihydro-indolo- [2,3-a]furan[3,4-g]quinolizine-3,4(13H)-dione (2), were isolated from Nauclea officinalis. Their structures were determined on the basis of 1D and 2D NMR spectral data.

Diprenylated Indole Alkaloids from Fruits of Hexalobus monopetalus

New hexalobine type alkaloid,5-(200,300-epoxy-300-methylbutyl)-3-(30-hydroxy-30-methyl-10-acetyloxy-but-20-yl)indole(1)alongside the known hexalobines 3-(20,30-dihydroxy-30-methylbutyl)-5-(300-methylcrotonoyl)indole(2),3,5-hexalobine C(3)and 3,5-hexalobine D(4)were isolated from fruits of Hexalobus monopetalus.Compounds 3 and 4 exhibited antifungal activity against Candida albicans.

TWO NEW INDOLE ALKALOIDS FROM MELODINUS MORSEI

Two new indole alkaloids named 152-hydroxy-14,15-dihydro-vindo- linine and 152-hydroxy-14,15-dihydro-16-epi-vindolinine were isolated from Melodinus morsei.Their structures were established by spectroscopic means and comparison with related compounds.

Indole Alkaloids from the Roots of Ervatamia hainanensis

Two new indole alkaloids, named ibogamine-18-carboxylic acid, 3, 4-didehydro-7, 8-dioxo-methyl ester 1, ibogamine-18-carboxylic acid, 16, 17-didehydro-9, 17-dihydro-9-hydroxy （2-oxopropyl）-methyl ester 2, were isolated from Ervatamia hainanensis. Their structures were elucidated on the basis of spectroscopic methods.

Four new indole alkaloids from Plantago asiatica

Four new indole alkaloids,plasiaticines A-D(1-4),together with two known ones,were isolated from the seeds of Plantago asiatica.The structures of the new compounds were elucidated on the basis of comprehensive analysis of spectroscopic data.All compounds were tested for their cytotoxic activity,and all compounds except 4 were tested for their acetylcholinesterase(AChE)inhibitory activities.

Monoterpenoid indole alkaloids from Alstonia rostrata

Four new monoterpenoid indole alkaloids,alstrostines C-F together with thirteen known alkaloids were isolated from the leaves and twigs of Alstonia rostrata.All structures of new compounds were elucidated based on NMR,FTIR,UV,and MS spectroscopic data.Alstrostines C-E might originate from keto-enol tautomerism of preakummicine during biogenetic pathway of akummicine.

Three new indole alkaloids from Rauvolfia yunnanensis

One rare tetracyclic macroline-type indole alkaloid,named rauvoyunine A(1),and two new picraline-type alkaloids rauvoyunines B and C(2 and 3)were isolated from the aerial parts of Rauvolfia yunnanensis.Their structures were elucidated on the basis of extensive spectroscopic analysis.Compounds 2 and 3 were evaluated for their in vitro cytotoxicity against five human tumor cell lines.

Rauvotetraphyllines A-E, new indole alkaloids from Rauvolfia tetraphylla

Five new indole alkaloids rauvotetraphyllines A-E(1-5),together with eight known analogues,were isolated from the aerial parts of Rauvolfia tetraphylla.The structures were established by means of spectroscopic methods.

Hybrid Monoterpenoid Indole Alkaloids Obtained as Artifacts from Rauvolfia tetraphylla

Five new hybrid monoterpenoid indole alkaloids bearing an unusual 2,2-dimethyl-4-oxopiperidin-6-yl moiety,namely rauvotetraphyllines F–H(1,3,4),17-epi-rauvotetraphylline F(2)and 21-epi-rauvotetraphylline H(5),were isolated from the aerial parts of Rauvolfia tetraphylla.Their structures were established by extensive spectroscopic analysis.The new alkaloids were evaluated for their cytotoxicity in vitro against five human cancer cell lines.

New Iboga‑Type Indole Alkaloids from Tabernaemontana divaricata

Two hitherto unknown iboga-type indole alkaloids,namely(3R)-7,19-di-epi-3-methoxytabernoxidine(1)and(3R,19R)-19-hydroxy-3-(2-oxopropyl)voacangine(2),together with eight known alkaloids(3-10),were isolated from the twigs and leaves of Tabernaemontana divaricata.Their structures were established on the basis of spectroscopic data interpretation,single crystal X-ray diffraction analysis and circular dichroism spectrum.

Antimicrobial indole alkaloids from Tabernaemontana corymbosa

Four unreported monoterpene indole alkaloids,tabernaecorymines B−E(1−4),together with twenty-one known indole alkaloids(5−25)were obtained from the stem bark of Tabernaemontana corymbosa.Their structures and absolute configurations were elucidated by extensive spectroscopy,quantum chemical calculations,DP4+probability analyses and Mo2(OAc)4-induced electronic circular dichroism experiment.The antibacterial and antifungal activities of these compounds were evaluated and some of them showed significant activity against Staphylococcus aureus,Bacillus subtilis,Streptococcus dysgalactiae and Candida albicans.

Terpenoid Indole Alkaloids Biosynthesis and Metabolic Engineering in Catharanthus roseus

Catharanthus roseus L. （Madagascar periwinkle） biosynthesizes a diverse array of secondary metabolites including anticancer dimeric alkaloids （vinblastine and vincristine） and antihypertensive alkaloids （ajmalicine and serpentine）. The multi-step terpenoid indole alkaloids （TIAs） biosynthetic pathway in C. roseus is complex and is under strict molecular regulation. Many enzymes and genes involved in the TIAs biosynthesis have been studied in recent decades. Moreover, some regulatory proteins were found recently to control the production of TIAs in C. roseus. Based on mastering the rough scheme of the pathway and cloning the related genes, metabolic engineering of TIAs biosynthesis has been studied in C. roseus aiming at increasing the desired secondary metabolites in the past few years. The present article summarizes recent advances in isolation and characterization of TIAs biosynthesis genes and transcriptional regulators involved in the second metabolic control in C. roseus. Metabolic engineering applications in TIAs pathway via overexpression of these genes and regulators in C. roseus are also discussed.

Direct Synthesis of Structurally Divergent Indole Alkaloids from Simple Chemicals

A direct and structurally divergent synthesis of indole alkaloids from very simple 2-vinylanilines, alkynes and TBN via a novel substrate flag- mentation/cycloaddition strategy has been developed, which provides an efficient noble-metal-free approach to access a library of highly valuable indole derivatives of tryptamines and tryptamine-related oximes, lactams, and lactones, as well as β-carbolines, spiroindolines, and hexa-hydropyrrolo[2,3-b]- indoles.