Recent progress in chemistry and bioactivity of monoterpenoid indole alkaloids from the genus gelsemium: a comprehensive review

Figures & data

Figure 1. Six representative members of gelsemium MIAs. Gelsemium MIAs can be classified into six categories: gelsedine-, koumine-, gelsemine-, humantenine-, sarpagine-, and yohimbane-type. Gelsemine-type, humantenine-type and gelsedine-type alkaloids bear peculiar spiro-indolinone nuclei, while koumine-, sarpagine- and yohimbane-type alkaloids have normal indole groups.

Table 1. Summary of novel MIAs from the genus of Gelsemium.

Structure types	Compounds (Number)	Parts of plants	Isolation sources	Structure identification	Reference
Gelsedine-type alkaloids	gelseleganins D (7), A (11), B (12), E (19), and C (21)	Leaves and branches	G. elegans	UV, HR-ESI-MS, ^13C and ^1H NMR	^16
	19-hydroxygelselegine (8)	Stems	G. elegans	HR-ESI-MS, ECD, ^13C and ^1H NMR, iJ/dJ-DP4 analysis	^17
	14-hydroxygelselegine (9)	Roots	G. elegans	HR-ESI-MS, ECD, ^13C and ^1H NMR, X-ray analysis	^15
	14β-hydroxygelselenidine (10), 11-methoxygelseziridine (14), and 14β-hydroxygelsedethenine (17)	Aerial parts	G. elegans	UV, IR, HR-ESI-MS, ECD, ^13C and ^1H NMR	^18
	gelsedethenine (13)	Roots	G. elegans	HR-ESI-MS, ECD, ^13C and ^1H NMR, X-ray analysis	^19
	gelsekoumidines A (15) and B (16)	Roots	G. elegans	HR-ESI-MS, ECD, ^13C and ^1H NMR, X-ray analysis	^20
	14-hydroxygelseziridine (18)	Roots and stems	G. elegans	HR-ESI-MS, ECD, ^13C and ^1H NMR	^21
	11-methoxy-14-hydroxygelsedilam (20), 11-methoxy-14,15-dihydroxygelsedine (37), and 11-methoxy-14,15-dihydroxy-19-oxogelsenicine (38)	Leaves and branches	G. elegans	HR-FAB-MS, ^13C and ^1H NMR	^22
	gelsepyrrodines A (22), B (23), and C (24)	Roots	G. elegans	HR-ESI-MS, ECD, ^13C and ^1H NMR	^23
	gelsecorydines A (25), B (26), C (27), D (28), and E (29)	Fruits	G. elegans	UV, IR, HR-ESI-MS, ECD, ^13C and ^1H NMR	^24
	gelserancines A (30), B (31), C (32), D (33), and E (34)	Roots	G. elegans	HR-ESI-MS, ECD, ^13C and ^1H NMR	^25
	geleganimines A (35) and B (36)	Aerial parts	G. elegans	HR-ESI-MS, ECD, ^13C and ^1H NMR	^26
	gelselegandines A (39), B (40), and C (41)	Roots	G. elegans	HR-ESI-MS, ECD, ^13C and ^1H NMR	^27
Humantenine-type alkaloids	19,20-epoxyhumantenine (42)	Roots	G. elegans	HR-ESI-MS, ECD, ^13C and ^1H NMR, X-ray analysis	^19
	gelselegandines D (43) and E (44)	Roots and stems	G. elegans	HR-ESI-MS, ECD, ^13C and ^1H NMR	^28
	geleganidines A (45) and C (46)	Roots	G. elegans	HR-ESI-MS, ECD, ^13C and ^1H NMR, X-ray analysis	^29
	11-hydroxyhumantenine N4-oxide (47), N-desmethoxyhumantenine N4-oxide (48), and gelstriamine A (50)	Stems	G. elegans	HR-ESI-MS, ECD, ^13C and ^1H NMR, iJ/dJ-DP4 analysis	^17
	N4-methyl-19,20-dihydrorankinidine (49)	Roots	G. elegans	HR-ESI-MS, ECD, ^13C and ^1H NMR, X-ray analysis	^15
	14β,20α-dihydroxydihydrorankinidine (51), 11-methoxy-19,20α-dihydroxydihydrorankinidin (52), and norhumantenine A (53)	Leaves and stems	G. elegans	HR-ESI-MS, ^13C and ^1H NMR	^30
Koumine-type alkaloids
	19-dehydrokouminol (54), koureamine (55), (4R)-dihydrokoumine N4-oxide (56), (4S)-dihydrokoumine N4-oxide (57), isodihydrokoumine-N1-oxide (65), and (4R)-isodihydrokoumine-N4-oxide (66)	Roots	G. elegans	HR-ESI-MS, ECD, ^13C and ^1H NMR, X-ray analysis	^31
	N4-demethyl-21-dehydrokoumine (58), 21α-hydroxylkoumine (59), 21β-hydroxylkoumine (60), and (19S)-hydroxydihydrokoumine N4-oxide (61)	Leaves and stems	G. elegans	UV, HR-ESI-MS, ECD, ^13C and ^1H NMR	^30
	21-oxokoumine (62) and furanokoumine (63)	Roots	G. elegans	UV, HR-ESI-MS, ECD, ^13C and ^1H NMR	^32
	18, 19-dihydro-21-oxokoumine (64)	Roots	G. elegans	HR-ESI-MS, ECD, ^13C and ^1H NMR, X-ray analysis	^15
Yohimbane-type alkaloids	sempervirinoxide (67) and seco-semperviroic acid (68)	Leaves and stems	G. elegans	UV, HR-ESI-MS, ECD, ^13C and ^1H NMR	^30
	gelsechizines A (69) and B (70)	Fruits	G. elegans	UV, IR, HR-ESI-MS, ECD, ^13C and ^1H NMR	^33
Sarpagine-type alkaloids	epi-koumidine N4-oxide (71)	Stems	G. elegans	HR-ESI-MS, ECD, ^13C and ^1H NMR, iJ/dJ-DP4 analysis	^17
Gelsemine-type alkaloids	(4R)-19-oxo-gelsevirine N4-oxide (72)	Roots	G. elegans	HR-ESI-MS, ECD, ^13C and ^1H NMR, X-ray analysis	^19
Other-type alkaloids	10,11-dimethoxy-N1-demethoxy-gelsemamide (73) and 11-demethoxy-gelsemazonamide (74)	Roots	G. elegans	HR-ESI-MS, ECD, ^13C and ^1H NMR, X-ray analysis	^19
	geleganamide (75)	Aerial parts	G. elegans	HR-ESI-MS, ECD, ^13C and ^1H NMR	^26
	geleganidine B (76)	Roots	G. elegans	HR-ESI-MS, ECD, ^13C and ^1H NMR, X-ray analysis	^29

ECD: electronic circular dichroism; ESI: electron spray ionisation; FAB: fast atom bombardment; HR-MS: high resolution mass spectrometry; IR: infra-red; NMR: nuclear magnetic resonance; UV: ultraviolet.

Figure 3. The chemical structures of novel gelsedine-type alkaloids.

Figure 4. The chemical structures of novel humantenine-type alkaloids.

Figure 5. The chemical structures of novel koumine-type alkaloids.

Figure 6. The chemical structures of novel gelsemium MIAs alkaloids. (A). yohimbane-type; (B). sarpagine-type; (C). gelsemine-type.

Figure 7. The chemical structures of novel other-type alkaloids.

Table 2. The pharmacological effects of gelsemium MIAs in vivo and in vitro experiments.

Bioactivity	Compounds	Route	In vivo doses (mg/kg)	In vitro doses (μM)	Possible mechanisms	In vivo model (s)	In vitro mode (s)	Reference
Analgesic activity	Koumine (2)	s.c.	0.4-10	–	Inducing TSPO allostery	Formalin-induced mice	–	^36
			1.0	–		Collagen-induced rats	–
			0.28	–		CCI-induced rats	–
			10.0	–	Inducing TSPO allostery; increasing neurosteroid levels	Formalin-induced mice	–	^37
			7.0	–		CCI-induced rats	–
			0.28-7.0	–	Enhancing 3α-HSOR mRNA expression and bioactivity	CCI-induced rats	–	^38
			0.28-7.0	–	Inhibiting glial activation; suppressing proinflammatory cytokines	Plantar incision-induced rats	–	^39
			0.28-7.0	25.0-200.0	–	CCI-induced rats	LPS-induced BV2 cells	^40
			0.28-7.0	25.0-100.0	Inhibiting astrocyte activation and pro-inflammatory cytokines; promoting autophagy; reducing apoptosis	CCI-induced rats	LPS-induced primary astrocytes	^41
			0.28-7.0	–	–	STZ-injected rats	–	^42
			0.28-7.0	–	Inhibiting microglial M1 polarisation and proinflammatory mediators via blocking the Notch-RBP-Jκ pathway	STZ-injected rats	–	^43
			0.28-7.0	–	Reducing the clearance of koumine	STZ-injected rats	–	^44
	gelsemine (3)	i.t.	0.03-10.0 (μg)	0.1-100.0	Activating spinal α3 glycine receptors	Formalin-induced rats	–	^45
						Bone cancer-induced rats	–
						L5/L6 SNL-induced rats	–
		-	–	0.1-100.0	Modulating glycine receptors	–	Glycine receptors-expressed HEK293 cells	^46
		i.t.	10.0 (μg)	0.001-0.1	Stimulating 3α-HSOR expression	L5/L6 SNL-induced rats	Primary neuronal cells	^47
		i.p.	1.0-4.0	–	–	PSNL-induced mice	–	^48
	N-desmethoxyhumantenine N4-oxide (48)	i.p.	1.0	–	–	Acetic acid-induced mice	- -	^17
	gelstriamine A (50)		0.04, 0.2	–
Antitumor activity	sempervirine (6)	i.p.	4.0, 8.0	1.0-8.0	Mediating autophagy and apoptosis; blocking Akt/mTOR pathway	Xenograft U251 cells bearing nude mice	U251 cells	^49
		i.p.	1.0	0.1-1.0	Inducing apoptosis; blocking the cell cycle in the G1 phase; upregulating p53 and downregulating cyclin D1, cyclin B1, and CDK2; inactivating the Wnt/β-catenin pathway	Xenograft HepG2 cells bearing nude mice	HepG2 cells	^50
		–	–	0.8-5.0	Degradating RNA polymerase I; disrupting ribosomal content; blocking MDM2 via inhibition of E2F1/pRB pathway	–	Testicular germ cell tumours cells	^51
	14β-hydroxygelsedethenine (17)	–	–	8.3-90.3 (IC50)	–	–	NCI-H1975, PC9, NCI-H460, NCI-H661, and H292 cell lines	^18
	gelseleganin C (21)	–	–	<10.0 (IC50)	–	–	A-549, SPC-A cells, 1D356, OC3, Tca8113, SACC83, and MEC1 cells	^16
	11-methoxy-14,15-dihydroxygelsedine (37)	–	–	10.9-12.1 (IC50)	–	–	Hep-2, LSC-1, TR-LCC-1 and FD-LSC-1 cells	^22
	geleganidine C (46)	–	–	16.1 (IC50)	–	–	PC-12 cells	^29
	geleganidine B (76)	–	–	38.4 (IC50)	–	–	MCF-7 cells
	norhumantenine A (53) and N4-demethyl-21-dehydrokoumine (58)	–	–	4.6-9.3 (IC50)	–	–	HL-60, SMMC-7721, A-549, MCF-7, SW480 and BEAS-2B cells	^30
	koumine (2)	p.o.	2.0	25.0-125.0	Inducing cell apoptosis and suppressing glycolysis via inhibiting Akt/mTOR/HK2 pathway and promoting HK2 disassociation to VDAC-1 via targeting PDK1	Xenograft HCT116 cells bearing nude mice	HCT116 and HT29 cells	^46
Anxiolytic activity	koumine (2)	i.g.	0.25-4.0	–	–	Mice	–	^53
		s.c.	0.167-1.5	–	–	Rats	–
		s.c.	0.167-1.5	–	Binding to TSPO protein; suppressing ACTH and CORT levels; increasing progesterone and allopregnanolone levels	Predatory sound stress-induced rats	–	^54
	gelsemine (3)	s.c.	0.0001, 1.0 (μM)	–	–	Rats	–	^55
		i.p.	0.4-10.0	–	Activating NLRP3 inflammasome; upregulating CREB and BDNF expressions	CUMS-induced mice	–	^56
Anti-inflammatory activity	koumine (2)	i.p.	0.8-7.2	50.0-200.0	Blocking ROS/NF-κB/NLRP3 pathway	MSU-induced mice	LPS/ATP/MSU-induced BMDM and THP cells	^57
	gelsekoumidine B (16)	–	–	33.2 (IC50)	–	–	LPS-induced RAW 264.7 cells	^20
	gelsecorydines A (25), C (27), D (28) and E (29)	–	–	4.2-16.2 (IC50)	–	–	LPS-induced RAW 264.7 cells	^24
	gelserancines B (31), C (32) and D (33)	–	–	50.0	–	CuSO4-induced zebrafish	–	^25
	geleganimine B (36)	–	–	10.2 (IC50)	–	–	LPS-induced BV2 cells	^26
	gelsechizines A (69) and B (70)	-	12.5, 25.0	12.5, 25	Inhibiting the recruitment of neutrophils and macrophages; reducing the secretion of TNF-α and IL-6	LPS-induced zebrafish	LPS-induced RAW 264.7 cells	^33
	(4R)-19-oxo-gelsevirine N4-oxide (72) and 10,11-dimethoxy-N1-demethoxy-gelsemamide (73)	–	–	6.2, 12.2 (IC50)	–	–	LPS-induced RAW 264.7 cells	^19
Anti-rheumatoid arthritis and immuno suppressive activities	gelsevirine (77)	i.p.	5.0	6.25, 50.0	Promoting the K48-ubiquitination of STING	STING-deficient mice and medial meniscus-operated mice	IL-1β-stimulated mouse primary chondrocytes	^58
	koumine (2)	p.o.	0.6-15.0	–	Inhibiting B lymphocytes-induced immune complexes and secondary inflammation	CFA-induced Rats; Collagen-induced rats	–	^59
		p.o.	0.6-15.0	25.0-100.0	Reducing astrocyte activation and pro-inflammatory cytokines	Collagen-induced rats	LPS-induced primary astrocytes	^60
		p.o.	0.4-10.0	10.0-70.0	–	TD Ag NP-CGG-immunized C57BL/6J mice	LPS-induced B cells	^61
		p.o.	4.0, 8.0	–	Regulating RORγt/Foxp3 expressions; correcting Th17/Treg immune imbalance	Collagen-induced mice	–	^62

CCI: chronic constriction injury; CFA: complete Freund’s adjuvant; CUMS: chronic unpredictable mild stress; HSOR: hydroxysteroid oxidoreductase; i.p.: intraperitoneal; i.t.: intrathecal; LPS: lipopolysaccharide; MSU: monosodium urate; PSNL: partial sciatic nerve ligation; s.c.: subcutaneous; SNL: spinal nerve ligation; STZ: streptozocin; TSPO: translocator protein 18 kDa.

Figure 8. Schematic summary of previous total syntheses of gelsedine-type alkaloids (2013–2022).

Figure 9. Schematic summary of previous total syntheses of koumine-type alkaloids (2013–2022).

Scheme 1 Carreira’s total synthesis of (±)-gelsemoxonine.

Scheme 2 Fukuyama’s total syntheses of five gelsedine-type alkaloids.

Scheme 3 Zhao’s total synthesis of gelsedilam.

Scheme 4 Ferreira’s total synthesis of (-)-gelsenicine.

Scheme 5 Ma’s total syntheses of four gelsedine-type alkaloids.

Scheme 7 Qiu’s total synthesis of (+)-gelsemine.

Scheme 8 Vanderwal’s synthetic route to the polycyclic core of gelsemine.

Scheme 9 Takayama’s asymmetric total synthesis of koumine.

Scheme 10 Kerr’s total synthesis of two koumine-type alkaloids.

Scheme 11 De Paolis’ asymmetric synthetic route to the bicyclic core of koumine.

Scheme 12 Tanja’s total synthesis of koumidine.

Scheme 13 Zhang’s total syntheses of three koumine-type alkaloids.

Scheme 15 Malhotra’s total synthesis of sempervirine.

Scheme 16 Bannister’s total synthesis of sempervirine triflate.

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