Bisindole Alkaloids from Alstonia Species

Bisindole Alkaloids from Alstonia Species: Comparison

Please note this is a comparison between Version 4 by Conner Chen and Version 3 by Conner Chen.

Bisindoles are structurally complex dimers and are intriguing targets for partial and total synthesis. They exhibit stronger biological activity than their corresponding monomeric units. Bisindole alkaloids are naturally occurring alkaloids containing two indole nuclei and are the products of late-stage biosynthetic processes in higher plants by combining two monomeric units. Depending on the monomeric units involved, bisindoles can be a homo- or heterodimer. As a result, bisindole alkaloids comprise much higher structural complexity than both of the monomeric units that comprise them.

Alstonia

, a major genus in the Apocynaceae family of plants, has more than 150 species and is found all over the world. Robert Brown named it in 1811 in honor of Charles Alston (1685–1760), an eminent botanist at the University of Edinburgh. The

Alstonia

genus’ trees and shrubs are prevalent in the tropical and subtropical parts of Africa, Asia, and Australia. They contribute significant pharmacological activity, including anticancer, antileishmanial, antimalarial, antitussive, antiviral, antiarthritic, and antibacterial activities.

Apocynaceae
Alstonia species
Sarpagine-macroline-ajmaline type indole alkaloids
Pleiocarpamine
Bisindole synthesis
Isolation of bisindoles
Bioactivity of bisindoles

1. Bisindole Alkaloids in drug discovery

Nature has been a substantial and sustainable pool of biologically active compounds. Since ancient times natural product extracts (in crude form) have been used in traditional and folk medicines in many countries. In modern times pure (isolated) natural products and their derivatives play an important role in drug discovery, as indicated by their prevalence in approved drugs for clinical use. Out of the 1881 newly FDA-approved drugs over the last four decades (1 January 1981 to 30 September 2019), a significant portion comprising 506 (26.9%) were either natural products or derived from or inspired by natural products ^[1]. It is expected that the advent of modern and innovative technologies such as computational software, cheminformatics, artificial intelligence, automation, and quantum computing will further boost natural product-based drug discovery. A synergy among these technological milestones would accelerate hit to lead to clinic pathways of drug discovery, and natural products are expected to remain an important source ^[2]. Moreover, pharmacophores and their unique stereochemical interactions with natural products may stimulate more demanding targets such as protein–protein interactions in the near future and open up a new avenue in modern drug discovery ^[3]. The majority of biologically active natural products are produced in plants, known traditionally as medicinal plants. Alkaloids, the most important class of natural products with structural diversity and significant pharmacological effects, are mainly found in higher plants such as the Apocynaceae, Ranunculaceae, Papaveraceae, and Leguminosae families ^[4]. These natural products, along with flavonoids, fatty acids, etc., are the major classes of secondary metabolites that are believed to be parts of the plants’ defense mechanism. To date, many monoterpenoid indole and bisindole alkaloids have been found in the Alstonia genus ^[5]. Modern clinical application of many of these alkaloids are similar to their traditional or folklore applications; for example, cocaine and morphine were used as anesthetics while caffeine and nicotine were used as stimulants ^[6]. Recently, Fielding et al. illustrated that several anti-coronavirus alkaloids showed potential therapeutic value against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in their in silico studies ^[7].

The indole motif is present in many naturally occurring and biologically active compounds. Some of them have been used in the clinic. In addition, there are numerous examples of synthetic compounds with useful medicinal properties that bear the indole moiety. Consequently, the indole scaffold is one of the few “privileged structures” in modern medicinal chemistry and drug discovery

^[8][9]

. The prevalence of bioactivity of indole-containing molecules may be attributed to their similarity to the essential amino acid tryptophan, as well as important biomolecules such as tryptamine and serotonin. Many plant extracts, which likely include alkaloids, have been used from time immemorial in folk medicines for fever, general weakness, dysentery, pain, liver diseases, gastrointestinal diseases, and cancer

^[10]

. Currently, there are many indole alkaloid-based marketed drugs such as sumatriptan for the treatment of migraine; vincristine and vinblastine for the treatment of various cancers, including leukemia and lung cancer; as well as reserpine for the treatment of hypertension and to decrease severe agitation in patients with mental disorders

^[11]

More structural diversity can be achieved via bisindole-based drug discovery by changing both monomeric units to furnish unnatural and

pseudo

-natural alkaloids. As such, bisindole alkaloids offer a large pool of natural, semi-natural, and chimeric drug candidates that have greater drug-like characteristics. As a result, due to their important biological applications and complex structural features, bisindole alkaloids have engendered the profound interest of synthetic organic and medicinal chemists, computational chemists, and chemical biologists.

2. Isolation and Plant' Morphology of Bisindoles from Alstonia Species

Among various species of the

Alstonia

genus,

A. macrophylla

and

A. angustifolia

are the two major sources of bisindole alkaloids discussed herein (

vide infra

Table 1

). (+)-Alstomacroline

, a bisindole alkaloid consisting of a macroline and an ajmaline unit (monomeric units not shown here: please visit

https://doi.org/10.3390/molecules26113459

for details), was isolated from the bark

of A. macrophylla

^[12]

and the leaves, stem-bark, and root-bark extracts of

A. scholaris, A. glaucescens, and A. macrophylla^[13][14]

. (+)-Alstomacrophylline

(macroline–macroline-type) was isolated from the bark

of A. macrophylla

^[12]

and the leaves, stem-bark, and root-bark extracts of

A. scholaris, A. glaucescens, and A. macrophylla

^[14]

. (-) Alstonisidine

, which contains a quebrachidine and a macroline unit, was isolated from the bark of

A. muelleriana

^[15][16]

. The structure of (-)-alstonisidine

was confirmed by X-ray crystallographic data

^[17]

. Yeap et al. recently isolated seven novel bisindoles from the methanol extract of the stem-bark of Malayan

A. penangiana

^[18]

. This includes (-)-angustilongine E

, (-)-angustilongine F

, (+)-angustilongine G

, (+)-angustilongine H

, (+)-angustilongine J

, (+)-angustilongine K

, and (-)-angustilongine L

(macroline–pleiocarpamine type). (+)-Angustilongine K

was converted into (+)-

-acetylangustilongine K

by stirring it with 10 equivalents of pyridine and 15 equivalents of acetic anhydride for 6 h at room temperature in

95%

yield

^[18]

. Among those, angustilongine G

and angustilongine H

are C-19 methyl substituted

^[19]

bisindoles. The structures of the angustilongines were confirmed by various spectroscopic data, including

H NMR,

¹³

C NMR, 2D NMR, IR, and HRMS by Yeap et al.

^[18]

. Angustilongine E

, angustilongine F

, angustilongine G

, angustilongine H

, angustilongine J

, and angustilongine K

are macroline–sarpagine coupled bisindoles. Angustilongine G

and angustilongine H

differ in stereochemistry only at the C-20 position.

Table 1.

Structures of bisindole alkaloids from

Alstonia

species including semi-synthetic derivatives.

Macroline-macroline type





Macroline-sarpagine type




Macroline-ajmaline type

Macroline-pleiocarpamine type

Two macroline units are contained in (-)-lumusidine A

, (-)-lumusidine B

, (-)-lumusidine C

, and (-)-lumusidine D

bisindoles. They were isolated from the stem-bark of

A. macrophylla

and the structures were confirmed via NMR spectroscopy, mass spectrometry, UV spectroscopy, and X-ray crystallography

^[12]

. After isolation, the group of Kam et al. converted oily (-)-lumusidine A

, (-)-lumusidine B

, and (-)-lumusidine D

into the corresponding crystalline dimethyl diiodide salts (structures not shown) by treatment with an excess of iodomethane for 24 h. The crystalline salts were employed to obtain X-ray crystallographic data to elucidate the exact stereochemical confirmation

^[12]

. (-)-Lumusidine D

is also known as thungfaine

^[20]

. (+)-Lumutinine A

, (-)-lumutinine B

, (+)-lumutinine C

, and (+)-lumutinine D

are linearly fused bisindoles isolated from the stem-bark of

A. macrophylla

as a light yellowish oil

^[21]

. (+)-Lumutinine A

and (-)-lumutinine B

are macroline–macroline-type bisindoles, while (+)-lumutinine C

, (+)-lumutinine D

, and (+)-lumutinine E

are macroline–sarpagine-type bisindoles. The structures of the lumutinines were elucidated using spectroscopic means including 1D and 2D NMR, IR, as well as mass spectrometric analysis

^[21]

. The structure of (+)-lumutinine D

was confirmed by X-ray crystallographic data

^[22]

. (+)-Lumutinine E

, a macroline–sarpagine-type bisindole, was isolated from the stem-bark of

A. angustifolia

^[23]

(+)-Macralstonidine

(macroline–sarpagine-type) was isolated from the bark of

A. macrophylla

^[24][25]

, as well as from

A. somersentenis

^[24]

and

A. spectabilis

^[26]

. (+)-Macralstonine

was isolated from the leaves, stem-bark, and root-bark extracts of

A. scholaris, A. glaucescens, and A. macrophylla

extracts

^[14]

A. macrophylla

^{[24][25][27][28][29]}

A. muelleriana

^[30]

A. angustifolia

^[31]

, as well as from

A. glabriflora

^[26]

. The structure of (+)-macralstonine

was confirmed by various NMR spectroscopy, mass spectrometry, and X-ray crystallography

^[28]

. The (+)-macralstonine

-related bisindole, (+)-

-acetylmacralstonine

25,

was isolated from the leaves, stem-bark, and root-bark extracts of

A. scholaris, A. glaucescens, and A. macrophylla

^[14]

. Also, (+)-

O-

methylmacralstonine

was isolated from the leaves, stem-bark, and root-bark of

A. scholaris, A. glaucescens, and A. macrophylla

extracts

^[14]

. (-)-Anhydromacralstonine

was isolated from the stem-bark of

A. angustiloba

^[23]

and contains (-)-alstophylline and (+)-macroline as monomeric units. Another (-)-alstophylline

and (+)-macroline monomeric bisindole, (+)-

Des-N’a

-methylanhydromacralstonine

30,

was isolated from the bark of

A. muelleriana

^[14][30]

, the stem-bark of

A. angustifolia

^[28]

, and

A. glabriflora

^[26]

. (+)-Macrocarpamine

, a hetero-dimeric bisindole containing a (+)-pleiocarpamine and (-)-anhydromacrosalhinemethine monomeric unit was isolated from the leaves, stem-bark, and root-bark of

A. scholaris, A. glaucescens, and A. macrophylla

^[14]

, as well as the stem-bark of

A. angustifolia

^[23]

. 10-Methoxymacrocarpamine

and 10-methoxymacrocarpamine

N4′

-oxide

are structurally related bisindoles. These bisindoles were isolated from

A. angustifolia

leaves

^[31]

Lim et al.

^[28]

reported the isolation of new macroline–macroline-type bisindoles, (-)-perhentidine A

, (-)-perhentidine B

, and (-)-perhentidine C

from the ethanolic extract of the stem-bark of Malayan

A. macrophylla

and

A. angustifolia.

The structurally related bisindole, (-)-perhentinine

(macroline–macroline-type), was isolated from the stem-bark and leaves of

A. macrophylla

and the leaves of

A. angustifolia

^[12]

. The exact structure of (-)-perhentinine

was confirmed by X-ray crystallography, converting it into the dimethyl diiodide salt by treating it with an excess of iodomethane. The X-ray crystallographic data of (-)-perhentinine

also helped in the structural characterizations of perhentidines A–C (

36–38

)

^[28]

. Tan et al. isolated three macroline–sarpagine-type bisindoles: (+)-perhentisine A

, (-)-perhentisine B

, and (+)-perhentisine C

from the stem-bark of

A. angustifolia

as a light yellow-colored oil together with other bisindoles

^[23]

. The structures of these bisindoles were also elucidated using various NMR and MS techniques

^[23]

. (+)-Villastonine

, a macroline–pleiocarpamine-type bisindole, was isolated from the stem-bark, root-bark, and leaves of various

Alstonia

species, including

A. spectabilis

^[24]

and

A. muelleriana

^[32]

by LeQuesne et al.,

A. macrophylla

^[25][27][33]

, and

A. angustifolia

^[31][34]

. Schmid et al. elucidated the structure of (+)-villalstonine

by spectroscopic means, accompanied by degradation, and Nordman et al. confirmed the structure by X-ray crystallography

^[33][35]

Table 2.

Isolation of bisindoles from various part' of

Alstonia

species.

Bisindoles	Alstonia Species	Morphology and References
(+)-Alstomacroline 1	A. scholaris, A. glaucescens, and A. macrophylla extracts	Leaves, stem-bark, and root-bark ^[13]^[14]
(+)-Alstomacroline 1	A. macrophylla	Bark ^[12]
(+)-Alstomacrophylline 2	A. macrophylla	Bark ^[13]
	A. scholaris, A. glaucescens, and A. macrophylla extracts	Leaves, stem-bark, and root-bark ^[14]
Stem-bark
^[
²³
^]

Species

Studies from various groups have shown that bisindoles have anticancer activity in different cell lines, including vincristine-resistant KB/VJ300 cells. Bisindoles are also reported to have other biological activities, including antiprotozoal activity against

Plasmodium falciparum

and antileishmanial activity against promastigotes of

Entamoeba histolytica

. The reported biological activity of bisindoles from various

Alstonia

species including the semi-synthetic derivatives reviewed herein are listed in

Table 3

. (+)-Alstomacroline

and (+)-alstomacrophylline

bisindoles were active against the K1 (multi-drug resistant) strain of

P. falciparum

with an IC

₅₀

1.12 ± 0.35 μM and IC

₅₀

1.10 ± 0.30 μM, respectively

^[37]

. Newly isolated macroline-sarpagine-type bisindoles, (−)-angustilongines E

, (-)-angustilongine F

, (+)-angustilongine G

, (+)-angustilongine H

, (+)-angustilongine J

, and (+)-angustilongine K

showed

in-vitro

growth inhibitory activity against human cancer cell lines, inclusive of KB, vincristine-resistant strains of KB, HCCT 116, PC-3, MDA-MB-231, LNCaP, MCF7, HT-29, and A549 cells with IC

₅₀

values ranging from 0.02 to 9.0 μM in the study from the group of Kam

^[18]

. Kam et al.

^[12]

also reported the anticancer activity of (−)-lumusidine A

, (−)-lumusidine B

, (−)-lumusidine C

, and (−)-lumusidine D

. These bisindoles were cytotoxic against KB/VJ300 cells ranging from IC

₅₀

0.16 to 5.03 μg/mL (μM) values with 0.12 μM vincristine added

^[12]

. Lumutinine A

, lumutinine B

, lumutinine C

, lumutinine D

, and lumutinine E

exhibited moderate anticancer activity against KB/VJ300 cells ranging in IC

₅₀

value from 0.10 to 4.61 μg/mL (μM) again with 0.12 μM vincristine added in the studies from the same group (Kam)

^[12]

Table 3.

Bioactivity of bisindoles (including semisynthetic derivatives) from

Alstonia

species.

Bisindoles	Bioactivity	References

(+)-Alstomacroline 1	Antimalarial, with IC₅₀ values of 1.12 ± 0.35 and 10.0 ± 0.4 μM against the K1 strain and T9-96 strain of P. falciparum, respectively.	^[14]
(+)-Alstomacrophylline 2	Antimalarial, with an IC₅₀ value of 1.10 ± 0.30 μM against the K1 strain of P. falciparum.	^[14]
Angustilongines E, F, G, H, J, and K (6–11)	Anticancer, cytotoxic against various human cancer cell lines including KB, vincristine-resistant KB, HCCT 116, PC-3, MDA-MB-231, LNCaP, MCF7, HT-29, and A549 cells with IC₅₀ values ranging from 0.02 to 9.0 μM.	^[18]
(−)-Lumusidine A, B, and C (14–16)	Anticancer, moderately cytotoxic in KB/VJ300 cells with IC₅₀ values of 0.16, 0.70, and 1.19 μg/mL (μM), respectively. The assay with 0.12 μM added vincristine did not influence KB/VJ300 cell growth.	^[12]
(−) Alstonisidine 3	A. muelleriana	Bark ^[15]^[16]
(−)-Lumusidine D 17	Anticancer, cytotoxic in KB/VJ300 cells with an IC₅₀ value of 5.03 μg/mL (μM). The assay with 0.12 μM added vincristine did not influence KB/VJ300 cell growth.
(−)-Angustilongine E 6	A. penangiana	Stem-bark ^[18]
^[	¹²	^]
Lumutinine A, B, C, D, and E (18–22)	Anticancer, moderately cytotoxic in KB/VJ300 cells with IC₅₀ 0.21, 0.10, 4.61, 3.93, and 2.74 μg/mL (μM) values, respectively. The assay with 0.12 μM added vincristine did not influence KB/VJ300 cell growth.	^[12]
(−)-Angustilongine F 7	A. penangiana
(+)-Macralstonine 24	Anticancer, strongly cytotoxic in KB/VJ300 cells with an IC₅₀ 1.71 μg/mL (μM) value. The assay with 0.12 μM added vincristine did not influence KB/VJ300 cell growth.
(+)-Macralstonine 24	Stem-bark	^[	^18]
^[	¹²	^]
(+)-Angustilongine G 8	A. penangiana	Stem-bark ^[18]
Antimalarial, active against the K1 strain of P. falciparum with an IC₅₀ 8.92 ± 2.95 μM value.	^[14]
(+)-Angustilongine H 9	A. penangiana	Stem-bark ^[18]
(−)-Anhydromacralstonine 27	Anticancer, moderately cytotoxic in KB/VJ300 cells with an IC₅₀ value of 0.44 μg/mL (μM). The assay with 0.12 μM added vincristine did not influence KB/VJ300 cell growth.	^[12]
(+)-Angustilongine J 10	A. penangiana
(+)-O-Acetyl macralstonine 25	Antimalarial, with IC₅₀ values 0.53 ± 0.09 and 12.4 ± 1.6 (μM) against the K1 strain and T9-96 strain of P. falciparum, respectively.
Stem-bark	^[	^18]
^[	¹⁴	^]
(+)-Angustilongine K 11	A. penangiana
(+)-O-Methyl macralstonine 26	Antimalarial, active against the K1 strain of P. falciparum with an IC₅₀ 0.85 ± 0.20 μM value.
Stem-bark	^[	^18]
^[	¹⁴	^]
(−)-Angustilongine L 12	A. penangiana
O-Acetyl-E-seco-macralstonine 53
Stem-bark	^[	^18]
Anticancer, strongly cytotoxic in KB/VJ300 cells with an IC	₅₀ value of 0.27 μg/mL (μM). The assay with 0.12 μM added vincristine did not influence KB/VJ300 cell growth.	^[12]
(−)-Anhydromacralstonine 27	A. angustifolia	Stem-bark ^[23]
(+)-Des-N’a-Methylanhydromacralstonine 30	A. muelleriana	Bark ^[14]
	A. angustifolia	Stem-bark ^[28]
	Anticancer, cytotoxic in KB/VJ300 cells with	IC₅₀ values of 0.52 and 0.30 μg/mL (μM), respectively. The assay with 0.12 μM added vincristine did not influence KB/VJ300 cell growth.	^[12]
A. muelleriana	Leaves, stem-bark and root-bark ^[14]^[30]
(−)-Lumusidine A 14
(+)-Macralstonidine 23	Anticancer, moderately cytotoxic in KB/VJ300 cells with an IC₅₀ value of 0.13 μg/mL (μM). The assay with 0.12 μM added vincristine did not influence KB/VJ300 cell growth.	^[12]
A. macrophylla	Stem-bark	^[12]
(+)-Macrocarpamine 21	Anticancer, strongly cytotoxic in KB/VJ300 cells with an IC₅₀ value of 0.53 μg/mL (μM). The assay with 0.12 μM added vincristine did not influence KB/VJ300 cell growth.	^[12]
(+)-Macrocarpamine 21	(−)-Lumusidine B 15	A. macrophylla
Strong antimalarial activity against the K1 strain of P. falciparum with an IC₅₀ value of 0.36 ± 0.06 μM. Active against the T9-96 strain of P. falciparum with an IC₅₀ >39 μM value.	^[14]
Stem-bark	^[	^12]
(−)-Lumusidine C 16	A. macrophylla
	Strong antiprotozoal activity in vitro against E. histolytica and P. falciparum with ED₅₀ 8.12 (95% C.I.) μM and ED₅₀ 9.36 (95% C.I.) μM values, respectively.
Stem-bark	^[	^12]
^[	³⁸	^]
(+)-Villalstonine 43	Anticancer, cytotoxic in KB/VJ300 cells with an IC₅₀ value of 0.42 μg/mL (μM). The assay with 0.12 μM added vincristine did not influence KB/VJ300 cell growth.	^[12]
	(−)-Perhentisine B 41	A. angustifolia	Stem-bark ^[23]
	(+)-Perhentisine C 42	A. angustifolia	Stem-bark ^[23]
		A. muelleriana	Leaves and stem-bark ^[32]
(+)-Villalstonidine A
(−)-Perhentidine A 36 and (-)-perhentidine B 37	Anticancer, strongly cytotoxic in KB/VJ300 cells with IC₅₀ values of 2.29 and 0.84 μg/mL (μM), respectively. The assay with 0.12 μM added vincristine did not influence KB/VJ300 cell growth.	^[12]
(−)-O-Acetylperhentidine A 54 and (-)-O-Acetylperhentidine B 55	Anticancer, strongly cytotoxic in KB/VJ300 cells with IC₅₀ 0.36 and 0.28 μg/mL (μM) values, respectively. The assay with 0.12 μM added vincristine did not influence KB/VJ300 cell growth.
(−)-Lumusidine D 17	A. macrophylla	Stem-bark ^[12]
(+)-Lumutinine A 18	A. macrophylla	Stem-bark ^[21]
Anticancer, cytotoxic against the HT-29 cell line with an ED₅₀ 8.0 μM value (paclitaxel was used as the positive control).	^[34]
(−)-Lumutinine B 19
Antimalarial, with IC
A. macrophylla
₅₀ values of 0.27 ± 0.06 and 0.94 ± 0.07 μM against the K1 strain and T9-96 strain of P. falciparum
Stem-bark	^[	^21]
, respectively.	^[14]
(+)-Lumutinine C 20	A. macrophylla	Stem-bark ^[21]
Antiamoebic activity against E. histolytica with an ED₅₀ of 2.04 μM.	^[38]	(+)-Lumutinine D 19
Villalstonine
Villalstonine	A. macrophylla
N(4)-oxide 44	Antileishmanial activity against promastigotes of L. mexicana with an IC₅₀ value of 80.3 μM (amphotericin B was used as the positive control).
N(4)-oxide 44	Stem-bark	^[	^21]
^[	³⁴	^]
(+)-Lumutinine E 21
Antimalarial, active against the K1 strain of P. falciparum with an IC
A. angustifolia
₅₀ 10.7 ± 1.9 (μM) value.
Stem-bark	^[	^23]
47	A. angustifolia	Stem-bark ^[23]
^[	¹²	^]
^[	^14]
(+)-Macralstonidine 23	A. macrophylla
	(+)-Villalstonidine B 48 and (+)-villalstonidine F 52	Anticancer, strongly cytotoxic in KB/VJ300 cells with IC₅₀ values of 0.35 and 5.64 μg/mL (μM), respectively. The assay with 0.12 μM added vincristine did not influence KB/VJ300 cell growth.
	Bark	^[	^24]^[
^[	¹²	^]
²⁵	^]
A. somersentenis
(+)-Villalstodinine D 50
Bark	^[24]
Antileishmanial, active against promastigotes of	L. mexicana with an IC₅₀ value of 120.4 μM (amphotericin B was used as the positive control).	^[34]
A. spectabilis	Bark ^[26]
(+)-Macralstonine 24	A. scholaris, A. glaucescens, and A. macrophylla extracts	Leaves, stem-bark and root-bark ^[13]
(+)-O-Acetylmacralstonine 25	A. macrophylla	^[24]^[25]^[27]^[28]^[29]
	A. angustifolia	^[31]
	A. muelleriana	^[30]
	A. glabriflora Mgf.	^[26]
	A. scholaris, A. glaucescens, and A. macrophylla extracts	^[14]
(+)-O-Methylmacralstonine 26	A. scholaris, A. glaucescens, and A. macrophylla extracts
(+)-Villalstonidine E 51	Anticancer, cytotoxic against HT-29 cell lines with an ED₅₀ 6.5 μM value (paclitaxel was used as the positive control).	^[34]
(+)-Villalstonidine E 51	Antileishmanial against promastigotes of L. mexicana with an IC₅₀ 78 μM value (amphotericin B was used as the positive control).
^[	¹⁴	^]
^[	^34]	(+)-Macrocarpamine 31	A. scholaris, A. glaucescens, and A. macrophylla extracts	Leaves, stem-bark, and root-bark ^[14]
	A. angustifolia	Stem-bark ^[23]
10-Methoxy macrocarpamine 34	A. angustifolia	Leaves ^[36]
10-Methoxy macrocarpamine 4′-N-oxide 35	A. angustifolia
(+)-Villalstonidine B 48	A. angustifolia	Stem-bark ^[23]
(+)-Villalstonidine B 48	A. macrophylla	Stem-bark ^[22]
(+)-Villalstonidine C 49	A. angustifolia	Stem-bark ^[23]
(+)-Villalstonidine D
(−)-Perhentinine 39 and O
50	A. angustifolia	Stem-bark ^[23]
(+)-Villalstonidine E 51	A. angustifolia	Stem-bark ^[23]
(+)-Villalstonidine F 52	A. macrophylla	Stem-bark ^[22]
-Acetylperhentinine 56
Leaves	^[	^36]
(−)-Perhentidine A 36	A. macrophylla and A. angustifolia	Stem-bark ^[23]^[28]
(−)-Perhentidine B 37	A. macrophylla and A. angustifolia	Stem-bark ^[28]
(−)-Perhentidine C 38	A. macrophylla and A. angustifolia	Stem-bark ^[23]^[28]
(−)-Perhentinine 39	A. macrophylla	Stem-bark ^[12]
	A. angustifolia	Leaves ^[12]
	A. macrophylla	Leaves ^[12]
(+)-Perhentisine A 40	A. angustifolia
(+)-Villalstonine 43	A. angustifolia	Leaves and stem-bark ^[23]^[31]^[34]^[36]
	A. macrophylla	^[36]
	A. villosa	^[36]
	A. verticillosa	^[36]
	A. somersentensis	^[36]
Villalstonine N(4)-oxide 44	A. angustifolia	Stem-bark ^[23]
Villalstonine N(4)-oxide 44	A. scholaris, A. glaucescens, and A. macrophylla extracts	Leaves, stem-bark, and root-bark ^[14]^[25]^[27]^[33]
(+)-10-Methoxy villalstonine 45	A. angustifolia	Leaves ^[36]
10-Methoxy villalstonine 4′-N-oxide 46	A. angustifolia	Leaves ^[36]

Villalstonine

(4)-oxide

was isolated from the stem-bark of

A. angustifolia

^[23]

References

Newman, D.J.; Cragg, G.M. Natural products as sources of new drugs over the nearly four decades from 01/1981 to 09/2019. J. Nat. Prod. 2020, 83, 770–803.
Thomford, N.E.; Senthebane, D.A.; Rowe, A.; Munro, D.; Seele, P.; Maroyi, A.; Dzobo, K. Natural products for drug discovery in the 21st century: Innovations for novel drug discovery. Int. J. Mol. Sci. 2018, 19, 1578.
Harvey, A.L.; Edrada-Ebel, R.; Quinn, R.J. The re-emergence of natural products for drug discovery in the genomics era. Nat. Rev. Drug Discov. 2015, 14, 111–129.
Lu, J.J.; Bao, J.L.; Chen, X.P.; Huang, M.; Wang, Y.T. Alkaloids isolated from natural herbs as the anticancer agents. Evid. Based Complement. Altern. Med. 2012, 2012, 485042.
Paul, A.T.; George, G.; Yadav, N.; Jeswani, A.; Auti, P.S. Pharmaceutical Application of Bio-actives from Alstonia Genus: Current Findings and Future Directions. In Bioactive Natural Products for Pharmaceutical Applications; Pal, D., Nayak, A.K., Eds.; Springer International Publishing: New York, NY, USA, 2021; pp. 463–533.
Calvert, M.B.; Sperry, J. Bioinspired total synthesis and structural revision of yuremamine, an alkaloid from the entheogenic plant Mimosa tenuiflora. Chem. Commun. 2015, 51, 6202–6205.
Fielding, B.C.; da Silva Maia Bezerra Filho, C.; Ismail, N.S.M.; de Sousa, D.P. Alkaloids: Therapeutic potential against human coronaviruses. Molecules 2020, 25, 5496.
Namjoshi, O.A.; Cook, J.M. Chapter Two—Sarpagine and Related Alkaloids. In The Alkaloids: Chemistry and Biology; Knӧlker, H.-J., Ed.; Academic Press: San Diego, CA, USA, 2016; Volume 76, pp. 63–169.
Evans, B.E.; Rittle, K.E.; Bock, M.G.; DiPardo, R.M.; Freidinger, R.M.; Whitter, W.L.; Lundell, G.F.; Veber, D.F.; Anderson, P.S.; Chang, R.S.L.; et al. Methods for drug discovery: Development of potent, selective, orally effective cholecystokinin antagonists. J. Med. Chem. 1988, 31, 2235–2246.
Zeng, J.; Zhang, D.-B.; Zhou, P.-P.; Zhang, Q.-L.; Zhao, L.; Chen, J.-J.; Gao, K. Rauvomines A and B, two monoterpenoid indole alkaloids from Rauvolfia vomitoria. Org. Lett. 2017, 19, 3998–4001.
Zhang, M.-Z.; Chen, Q.; Yang, G.-F. A review on recent developments of indole-containing antiviral agents. Eur. Med. Chem. 2015, 89, 421–441.
Lim, S.H. Alkaloids from Alstonia Macrophylla. Ph.D. Thesis, University of Malaya, Kuala Lampur, Malaysia, 2013.
Keawpradub, N.; Houghton, P.J. Indole alkaloids from Alstonia macrophylla. Phytochemistry 1997, 46, 757–762.
Keawpradub, N.; Kirby, G.C.; Steele, J.C.; Houghton, P.J. Antiplasmodial activity of extracts and alkaloids of three Alstonia species from Thailand. Planta Med. 1999, 65, 690–694.
Elderfield, R.C.; Gilman, R.E. Alkaloids of Alstonia muelleriana. Phytochemistry 1972, 11, 339–343.
Burke, D.E.; Cook, G.A.; Cook, J.M.; Haller, K.G.; Lazar, H.A.; Le Quesne, P.W. Further alkaloids of Alstonia muelleriana. Phytochemistry 1973, 12, 1467–1474.
Hoard, L.G. The Crystal Structures of Altstonisidine, C42H48N4O4, and Anhydrous Cholesterol, C27H46O. Ph.D. Thesis, University of Michigan, Ann Arbor, MI, USA, 1977.
Yeap, J.S.; Saad, H.M.; Tan, C.H.; Sim, K.S.; Lim, S.H.; Low, Y.Y.; Kam, T.S. Macroline-sarpagine bisindole alkaloids with antiproliferative activity from Alstonia penangiana. J. Nat. Prod. 2019, 82, 3121–3132.
Hamaker, L.K.; Cook, J.M. The Synthesis of Macroline Related Sarpagine Alkaloids. In Alkaloids: Chemical and Biological Perspectives; Pelletier, S.W., Ed.; Elsevier Publications: Amsterdam, The Netherlands, 1995; Volume 9.
Kitajima, M.; Takayama, H. Chapter Four-Monoterpenoid Bisindole Alkaloids. In The Alkaloids: Chemistry and Biology; Knölker, H.-J., Ed.; Academic Press: San Diego, CA, USA, 2016; Volume 76, pp. 259–310.
Lim, S.-H.; Tan, S.-J.; Low, Y.-Y.; Kam, T.-S. Lumutinines A–D, linearly fused macroline–macroline and macroline–sarpagine bisindoles from alstonia macrophylla. J. Nat. Prod. 2011, 74, 2556–2562.
Lim, S.-H.; Low, Y.-Y.; Subramaniam, G.; Abdullah, Z.; Thomas, N.F.; Kam, T.-S. Lumusidines A− D and villalstonidine F, macroline–macroline and macroline–pleiocarpamine bisindole alkaloids from Alstonia macrophylla. Phytochemistry 2013, 87, 148–156.
Tan, S.-J.; Lim, K.-H.; Subramaniam, G.; Kam, T.-S. Macroline–sarpagine and macroline–pleiocarpamine bisindole alkaloids from Alstonia angustifolia. Phytochemistry 2013, 85, 194–202.
Sharp, T.M. 265. The alkaloids of Alstonia barks. Part II. A. macrophylla, wall., A. somersetensis, FM Bailey, A. verticillosa, F. Muell., A. villosa, blum. J. Chem. Soc. 1934, 1227–1232.
Kishi, T.; Hesse, M.; Vetter, W.; Gemenden, C.; Taylor, W.; Schmid, H. Macralstonin. Helv. Chim. Acta 1966, 49, 946–964.
Hart, N.; Johns, S.; Lamberton, J. Tertiary alkaloids of Alstonia spectabilis and Alstonia glabriflora (Apocynaceae). Aust. J. Chem. 1972, 25, 2739–2741.
Keawprdub, N.; Houghton, P.; Eno-Amooquaye, E.; Burke, P. Activity of extracts and alkaloids of Thai Alstonia species against human lung cancer cell lines. Planta Med. 1997, 63, 97–101.
Lim, S.-H.; Low, Y.-Y.; Tan, S.-J.; Lim, K.-H.; Thomas, N.F.; Kam, T.-S. Perhentidines A–C: Macroline–macroline bisindoles from Alstonia and the absolute configuration of perhentinine and macralstonine. J. Nat. Prod. 2012, 75, 942–950.
Changwichit, K.; Khorana, N.; Suwanborirux, K.; Waranuch, N.; Limpeanchob, N.; Wisuitiprot, W.; Suphrom, N.; Ingkaninan, K. Bisindole alkaloids and secoiridoids from Alstonia macrophylla Wall. ex G. Don. Fitoterapia 2011, 82, 798–804.
Cook, J.; Le Quesne, P. Macralstonine from Alstonia muelleriana. Phytochemistry 1971, 10, 437–439.
Ghedira, K.; Zeches-Hanrot, M.; Richard, B.; Massiot, G.; Le Men-Olivier, L.; Sevenet, T.; Goh, S. Alkaloids of Alstonia angustifolia. Phytochemistry 1988, 27, 3955–3962.
Cook, J.M.; Le Quesne, P.; Elderfield, R. Alstonerine, a new indole alkaloid from Alstonia muelleriana. J. Chem. Soc. Chem. Commun. 1969, 1306–1307.
Hesse, M.; Hürzeler, H.; Gemenden, C.; Joshi, B.; Taylor, W.; Schmid, H. Die Struktur des Alstonia-Alkaloides Villalstonin Vorläufige Mitteilung. Helv. Chim. Acta 1965, 48, 689–704.
Pan, L.; Terrazas, C.; Muñoz Acuña, U.; Ninh, T.N.; Chai, H.; Carcache de Blanco, E.J.; Soejarto, D.D.; Satoskar, A.R.; Kinghorn, A.D. Bioactive indole alkaloids isolated from Alstonia angustifolia. Phytochem. Lett. 2014, 10, 54–59.
Nordman, C.; Kumra, S. The structure of villalstonine1. J. Am. Chem. Soc. 1965, 87, 2059–2060.
Buckingham, J.; Baggaley, K.H.; Roberts, A.D.; Szabo, L.F. Dictionary of Alkaloids with CD-ROM; CRC Press: Boca Raton, FL, USA, 2010.
Keawpradub, N.; Eno-Amooquaye, E.; Burke, P.; Houghton, P. Cytotoxic activity of indole alkaloids from Alstonia macrophylla. Planta Med. 1999, 65, 311–315.
Wright, C.; Allen, D.; Cai, Y.; Phillipson, J.; Said, I.; Kirby, G.; Warhurst, D. In vitro antiamoebic and antiplasmodial activities of alkaloids isolated from Alstonia angustifolia roots. Phytother. Res. 1992, 6, 121–124.
Gan, T.; Cook, J.M. General approach for the synthesis of macroline/sarpagine related indole alkaloids via the asymmetric Pictet-Spengler reaction: The enantiospecific synthesis of (−)-anhydromacrosalhine-methine. Tetrahedron Lett. 1996, 37, 5033–5036.
Bi, Y.; Zhang, L.-H.; Hamaker, L.K.; Cook, J.M. Enantiospecific synthesis of (-)-alstonerine and (+)-macroline as well as a partial synthesis of (+)-villalstonine. J. Am. Chem. Soc. 1994, 116, 9027–9041.

1. Bisindole Alkaloids in drug discovery

2. Isolation and Plant' Morphology of Bisindoles from Alstonia Species

Species

Bisindoles

Bioactivity

3. Bioactivity of Bisindoles from Alstonia

5. Conclusions

References