Steroidal Alkaloids From the Apocynaceae Family: Their Isolation and Biological Activity

Abstract

Steroidal alkaloids are derived from the steroid skeleton with one or two nitrogen atoms. They are widely distributed in tropical and subtropical regions and possess a range of biological activities. The structures of steroidal alkaloids are comparable to those of anabolic steroids, steroidal hormones, and corticosteroids, making them a valuable source for drug discovery. Taxonomically, steroidal alkaloids are limited in distribution to certain plant families, predominantly the Apocynaceae, Buxaceae, Solanaceae, and Liliaceae. This review highlights the steroidal alkaloids from the Apocynaceae family and their biological activities. The articles published from 1919 to 2021 were included in this review. A total of 163 steroidal alkaloids and 12 biological activities were reported from plant species belonging to the Apocynaceae family in this period. Of the 410 genera in the Apocynaceae, only 10 contain steroidal alkaloids. Although some alkaloids from the Apocynaceae family were also reported in the Buxaceae family, especially tetracyclic triterpenes with a pregnane side chain, most steroidal alkaloids can only be found in several genera of the Apocynaceae family.

Keywords

antiplasmodial conessine

Introduction

A steroidal alkaloid has a basic steroid skeleton and contains at least one nitrogen atom where the nitrogen atom may be attached to either the side chain or the polycyclic system.¹ In addition, this nitrogen atom may be part of an additional ring such as a lactam ring, lactone ring, pyrrolidine ring, or pyrroline ring. Steroidal alkaloids are found in several plant families, notably Apocynaceae, Solanaceae, Buxaceae, and Liliaceae. Many steroidal alkaloids have become targets of pharmacological investigations due to their structural similarities with anabolic steroids, steroidal hormones, and corticosteroids.² In this review, the steroidal alkaloids from the Apocynaceae family are summarized. This family comprises woody climbers, tropical trees, shrubs, and herbs.³ Plants of the Apocynaceae are predominantly distributed in tropical and subtropical regions although are also well established in temperate zones.⁴ Steroidal alkaloids of the Apocynaceae are classified into four main structural groups: conanine, pregnane, paravallarine, and amino-glycosteroids (Figure 1).⁵ By high performance liquid chromatography (HPLC), some of the alkaloids can be detected at around 200 to 245 nm, but most can only be detected at around 200 nm.^6–8 The use of acetonitrile and water as mobile phases allows the detection at that wavelength. Of 410 genera in the Apocynaceae family,⁹ only 10 namely Beaumontia, Chonemorpha, Dictyophleba, Funtumia, Holarrhena, Kibatalia, Malouetia, Tabernaemontana, Vahadenia, and Wrightia, have been reported to contain steroidal alkaloids. Some steroidal alkaloids in the Apocynaceae family can also be found in the Buxaceae family. Steroidal alkaloids from these genera showed acetylcholinesterase (AChE),^10,11 antibacterial,^11–15 anticercarial,¹⁶ antidiarrheal,¹⁷ antifeedant,¹⁸ antimycobacterial,¹⁹ antiplasmodial,^20–22 antitrypanosomal,²³ cytotoxic,^{20,21,23–26} hypotensive,²⁷ leishmanicidal activities,²⁸ and antibiotic efficacies.²⁹

Figure 1.

Four structural groups of Apocynaceae.

Biosynthesis of steroidal alkaloids

The steroidal alkaloids isolated from the genus Holarrhena are biosynthesized from cholesterol.³⁰ According to Kumar et al., all pregnane-type steroidal alkaloids are derived from cholesterol (1) through pregnenolone (2).³¹ Cholesterol (1) is converted to pregnenolone (2) by hydroxylation at C-22 and C-20, followed by oxidative cleavage of the side chain at C-20/22 by a cytochrome P450 enzyme (P450scc, CYP11A1) (Figure 2).^32,33 This process creates two sites for the potential introduction of a nitrogen atom, C-3 and C-20.

Figure 2.

Biosynthesis of pregnenolone.

A steroidal alkaloid such as 3β-holaphyllamine (3) is produced from 2 by replacement of the hydroxyl group at C-3 with an amino group, while the formation of conessine (4) requires 2 amination reactions, one at C-3, and the other at C-20. The subsequent formation of ring E is the result of the attack of the C-20 amine on the C-18 methyl following oxidation of the group (Figure 3).^34,35

Figure 3.

Biosynthesis of some steroidal alkaloids.

Distribution of Steroidal Alkaloids

Beaumontia Species

There is only 1 report on steroidal alkaloids from the Beaumontia genus. A pregnane steroidal alkaloid, namely beaumontamine (5), was isolated from the stems of Beaumontia grandiflora Wall.³⁶ The presence of 3 methyl protons in the upfield region, an olefinic methine group, 2 hydroxyl groups, methine and tertiary, and an –NH₂ group linked to C-20 established the structure of the alkaloid. In terms of chemotaxonomy, alkaloid 5 has, thus far, only been found in Beaumontia sp.

Chonemorpha Species

There are 5 reports on steroidal alkaloids from the genus Chonemorpha. The roots of Chonemorpha fragrans (Moon) Alston yielded 3 pregnane-type steroidal alkaloids, namely N-formylchonemorphine (6), chonemorphine (7), and dictyophlebine (8).^37–39 Funtumafrine C (9) was isolated from an unstated part of the plant.⁴⁰ Alkaloid 6 was also found in the roots and stems of Sarcococca saligna (D.Don) Muell. and whole plants of Sarcococca hookeriana Baill. in the Buxaceae family.^41,42 Alkaloids 7 to 9 were also characterized in several Apocynaceae species (Table 1),^43–47 and alkaloid 9 is also present in the leaves of Sarcococca coriacea (Hook. f.) Sweet (Buxaceae).⁴⁸

Table 1.

Steroidal Alkaloids From the Apocynaceae Family.

Plant	Alkaloid	References
Beaumontia grandiflora	^abeaumontamine (5)	³⁶
Chonemorpha fragrans	^aN-formylchonemorphine (6), ^achonemorphine (7), ^adictyophlebine (8), ^afuntumafrine C (9), funtuphyllamine C (23)	^37–40
Dictyophleba lucida	^achonemorphine (7), ^adictyophlebine (8), ^adictyodiamine (10), ^airehamine (11)	^45,50
Funtumia africana (synonym: F. latifolia)	^achonemorphine (7), ^adictyophlebine (8), ^afuntumafrine C (9), ^airehamine (11), ^b12α-hydroxy-norcona-N(18),1,4-trienin-3-one (12), ^b11α,12α-dihydroxy-norcona-N(18),1,4-trienin-3-one (13), ^bholonamine (14), ^blatifoline (15), ^bnorlatifoline (16), ^blatifolinine (17), ^bfuntuline (18), ^bfuntessine (19), ^airehdiamine E (20), ^afuntuphyllamine A (21), ^afuntuphyllamine B (22), ^afuntuphyllamine C (23), ^afuntumafrine B (24), ^afuntumine (25), ^afuntumidine (26), ^afuntudiamine A (27), ^afuntudiamine B (28)	^{43,46,47,50,52–58}
Funtumia elastica	^bconessine (4), ^airehamine (11), ^airehdiamine E (20), ^bisoconessimine (29), ^bholarrhesine (30), ^bholarrhetine (31), ^airehine (32), ^airehdiamine A (33), ^airehdiamine B (34), ^birehline (35), ^a20-epi-irehdiamine-I (36), ^aregholarrhenine F (37), ^airehdiamine I (38), ^bconamine (39)	^{20,51,60–63}
Holarrhena congolensis	^bconessine (4), ^afuntumine (25), ^akisantamine (40), ^aholaphylline (41), ^bholarrhenine (42)	^50,62,85,86
Holarrhena curtisii	^a3β-holaphyllamine (3), ^birehline (35), ^aholaphylline (41), ^bN-formylconkurchine (43), ^bconessidine (44), ^aholafebrine (45), ^dN-acetylholacurtine (46), ^dN-acetyl-N-demethylholacurtine (47), ^dholacurtine (48), ^dN-demethylholacurtine (49), ^d17-epi-holacurtine (50), ^d17-epi-N-demethylholacurtine (51), ^dholacurtinol (52), ^a3α-amino-14β-hydroxypregnan-20-one (53), ^a15α-hydroxyholamine (54), ^aholamine (55)	^28,79,87
Holarrhena floribunda (synonym: H. africana)	^a3β-holaphyllamine (3), ^bconessine (4), ^bholonamine (14), ^afuntumine (25), ^bisoconessimine (29), ^bholarrhesine (30), ^bholarrhetine (31), ^bconamine (39), ^aholaphylline (41), ^bholarrhenine (42), ^aholamine (55), ^amethylholaphylline (56), ^aholaphyllinol (57), ^aholaphyllidine (58), ^a3β-dihydroholaphyllamine (59), ^abokitamine (60), ^aholaphyllamine acetamide (61), ^bholafrin (62), ^bholaline (63), ^bholadienine (64), ^bcona-4,6-dien-3-one (65), ^bcona-3,5-dien-7-one (66), ^bconessimine (67), ^bholarrheline (68), ^bholaromine (69), ^bconarrhimine (70), ^aholadysamine (71), kurchicine	^{14,16,19,23,24,66,69,73,88,92–95}
Holarrhena mitis	^bconessine (4), ^bisoconessimine (29), ^birehline (35), ^bholarrhenine (42), ^aholafebrine (45), ^bholadienine (64), ^dN-demethylmitiphylline (72), ^dmitiphylline (73), ^aN³-methylholarrhimine (74), ^aholarrhimine (75)	^70,100–102
Holarrhena pubescens (synonym: H. antidysenterica and H. febrifuga)	^a3β-holaphyllamine (3), ^bconessine (4), ^bholonamine (14), ^afuntumine (25), ^bisoconessimine (29), ^airehdiamine B (34), ^birehline (35), ^aregholarrhenine F (37), ^airehdiamine I (38), ^bconamine (39), ^aholaphylline (41), ^bconessidine (44), ^aholafebrine (45), ^aholamine (55), ^amethylholaphylline (56), ^bholadienine (64), ^bcona-3,5-dien-7-one (66), ^bconessimine (67), ^bconarrhimine (70), ^aholadysamine (71), ^aN³-methylholarrhimine (74), ^aholarrhimine (75), ^aholarricine (76), ^bantidysentericine (77), ^bconimine (78), ^bconkuressine (79), ^bisoconkuressine (80), ^bN-formylconessimine (81), ^bregholarrhenine A (82), ^bregholarrhenine B (83), ^bregholarrhenine C (84), ^bregholarrhenine D (85), ^bregholarrhenine E (86), ^bkurcholessine (87), ^aholadysenterine (88), ^aholacetine (89), ^bmokluangin A (90), ^bmokluangin D (91), ^bmalouetafrine (92), ^aholaphyllaminol (93), ^akurchiline (94), ^akurchiphylline (95), ^akurchiphyllamine (96), ^akurchaline (97), ^aholadysine (98), ^dholantosine A (99), ^dholantosine B (100), ^dholantosine C (101), ^dholantosine D (102), ^dholarosine A (103), ^dholarosine B (104), ^dholantosine E (105), ^dholantosine F (106), ^aN,N-dimethylfuntumine (107), ^aN-methylfuntumine (108), ^aN,N-dimethylholamine (109), ^aN-methylholamine (110), ^aN²⁰-methylholarrhimine (111), ^aholarrhidine (112), ^akurchimine (113), ^bdihydroisoconessimine (114), ^bholacine (115), holacimine, ^aholarrifine (116), ^bkurchinidine (117), ^bkurchinine (118), ^bpubescine (119), ^bnorholadiene (120), ^bpubescimine (121), ^bholamide (122), ^bpubescinine (123), ^bpubamide (124), ^bnorkurchamide (125), ^bpubatriol (126), ^bmokluangin B (127), ^bmokluangin C (128), ^b7α-hydroxyconessine (129), holarrhine	^{10–13,15,17,18,21,22,27,31,68,74,75,77,78,81,84,97,99,103–119}
K. arborea	^aholafebrine (45)	⁸⁹
Kibatalia gitingensis	^ckibataline (130), ^c20-epi-N-methylparavallarine (131), ^cgitingensine (132), ^clanitine (133), ^clanitinine (134), ^cparavallarine (135), ^cN-methylparavallarine (136), ^c20-epi-paravallarine (137), ^c2α-hydroxy-N-methyl-20-epiparavallarine (138)	^121–125
K. laurifolia (synonym: P. microphylla)	^cgitingensine (132), ^cparavallarine (135), ^cN-methylgitingensine (139), ^cN-acetylgitingensine (140), ^c3-epi-gitingensine (141), ^c7α-hydroxyparavallarine (142), ^ckibalaurifoline (143), ^cparavallaridine (144), ^cN-methylparavallaridine (145), ^c11α-hydroxyparavallarine (146), ^c7β-hydroxyparavallarine (147)	^25,127–131
K. macrophylla (synonym: P. macrophylla)	^c20-epi-N-methylparavallarine (131)	¹²⁶
K. maingayi (synonym: P. maingayi)	^bmaingayine (148)	¹³²
Malouetia arborea	^birehline (35), ^bmalarborine (149), ^bmalarboreine (150)	⁸³
M. bequaertiana	^achonemorphine (7), ^afuntumafrine C (9), ^afuntuphyllamine B (22), ^amalouphylline (151), ^amalouetine (152), ^bmalouphyllamine (153), ^amalouphyllinine (154)	^{44,47,80,133–135}
M. heudelotii	^blatifoline (15), ^blatifolinine (17), ^bmalouetafrine (92), ^bN-acetylconamine (155), ^bmalouetamide (156)	⁴⁴
M. tamaquarina	^bconessine (4), ^aregholarrhenine F (37), ^airehdiamine I (38), ^adihydrokurchessine (157)	⁸³
Tabernaemontana pachysiphon (synonym: C. pachysiphon)	^a20α-amino-3,5-pregnadiene (158), ^d20α-amino-3β-hydroxy-5-pregnene-β-D-glucoside (159)	¹³⁶
Vahadenia laurentii	^airehdiamine F (160)	¹³⁷
Wrightia arborea (synonym: W. tomentosa)	^bconessine (4), ^bisoconessimine (29), ^birehline (35), ^bconessidine (44), kurchicine, ^aholarrhimine (75), holarrhine	^72,96,116
W. pubescens (synonym: W. javanica)	^bwrightiamine A (161), ^awrightiamine B (162)	²⁶

Note. ^aPregnane.

Conanine.

Paravallarine.

Amino-glycosteroids.

Dictyophleba Species

There are 4 reports on steroidal alkaloids from the Dictyophleba genus. Investigation of the roots of Dictyophleba lucida yielded dictyodiamine (10) of the pregnane group,⁴⁵ which was also found in Pachysandra terminalis of the Buxaceae family.⁴⁹ Irehamine (11) was found in an unstated part of D lucida,⁵⁰ and was also reported from the leaves of Funtumia sp. (Table 1).⁵¹

Funtumia Species

Two species of Funtumia were reported to contain steroidal alkaloids. From the stem bark of Funtumia africana (Benth.) Stapf (synonym: F. latifolia), conanine-type steroidal alkaloids were characterized, namely 12α-hydroxy-norcona-N(18),1,4-trienin-3-one (12), 11α,12α-dihydroxy-norcona-N(18),1,4-trienin-3-one (13), and holonamine (14).⁵² Latifoline (15), norlatifoline (16), latifolinine (17), funtuline (18), and funtessine (19) were isolated from the bark of F africana.^53–56 Irehdiamine E (20) was isolated from the leaves of the plant.⁵⁷ Funtuphyllamine A (21), funtuphyllamine B (22), funtuphyllamine C (23), funtumafrine B (24), funtumine (25), funtumidine (26), funtudiamine A (27), and funtudiamine B (28) were found from F africana.^43,58

Alkaloid 20 was also reported in Funtumia elastica (Preuss) Stapf (Apocynaceae).⁵⁹ Isoconessimine (29), holarrhesine (30), holarrhetine (31), and alkaloid 4 were purified from the ethanolic stem bark extract of F elastica.²⁰ Irehine (32), irehdiamine A (33), irehdiamine B (34), and irehline (35) were isolated from the leaves of the plant.^51,60,61 20-Epi-irehdiamine-I (36), regholarrhenine F (37), irehdiamine I (38), conamine (39), and alkaloid 4 were also obtained from the seeds of F elastica.^62,63 Alkaloid 32 was reported in Buxaceae, namely B. sempervirens L.^64,65 The conanine type of steroidal alkaloids (eg, 14, 15, 17, 29-31, 34, and 39) are also present in the genera Holarrhena and Malouetia (Table 1).^{10,12,13,16,17,23,27,31,44,66–73} The pregnane steroidal alkaloids (eg, 22, 23, 25, 27, 28, 32, 35, 37, and 38) were also found in the genera Pachysandra, Sarcacocoa, and Buxus of the Buxaceae and the genera Chonemorpha, Holarrhena, Funtumia, Malouetia, and Wrightia (Table 1).^{21,23,24,31,49,58,59,62,64,65,70,72,74–84} In contrast, the alkaloids 12, 13, 16, 18, 19 to 21, 24, 26, 33, and 36 were only found in the genus Funtumia.

Holarrhena Species

All plants in the genus Holarrhena produce steroidal alkaloids. The leaves of Holarrhena congolensis Stapf contained the new alkaloid kisantamine (40) and the established holaphylline (41).⁶² Holarrhenine (42) and 4 were found in the bark of H congolensis.^85,86 Alkaloids 41 and 42 were also present in other Holarrhena species (Table 1).^21,23,70,79

Phytochemical investigation of the leaf extract of Holarrhena curtisii King & Gamble yielded N-formylconkurchine (43), conessidine (44), holafebrine (45), N-acetylholacurtine (46), N-acetyl-N-demethylholacurtine (47), holacurtine (48), N-demethylholacurtine (49), 17-epi-holacurtine (50), 17-epi-N-demethylholacurtine (51), holacurtinol (52), 3α-amino-14β-hydroxypregnan-20-one (53), 15α-hydroxyholamine (54), holamine (55), and 3.^28,79,87 Alkaloids 44, 45, and 55 were also found in Wrightia, Kibatalia, and other Holarrhena species (Table 1).^{23,24,70,72,74,77,79,88,89} Alkaloids 43, 46 to 54 are limited in their distribution to Holarrhena sp.

Methylholaphylline (56), holaphyllinol (57), holaphyllidine (58), 3β-dihydroholaphyllamine (59), bokitamine (60), holaphyllamine acetamide (61), and 3 were isolated from the leaves of Holarrhena floribunda (G.Don) T. Durand & Schinz (synonym: H. africana).^23,90,91 In addition, holafrin (62), holaline (63), holadienine (64), and alkaloid 4 were purified from the bark of H floribunda.^66,73,92 Investigation of the stem bark of H floribunda disclosed the presence of cona-4,6-dien-3-one (65), cona-3,5-dien-7-one (66), conessimine (67), holarrheline (68), together with 4, 14, and 64.^14,16,23 Holaromine (69), and compounds 63, 64, and 68 were also found in the husks of H floribunda,⁹³ while the seeds yielded conarrhimine (70), and 4.^69,94 Meanwhile, holadysamine (71) was purified from the aerial parts of H floribunda.¹⁹ There was a report on the isolation of kurchicine and 3 from H floribunda; however, the journal in which this was published is no longer available.^88,95 The structure of kurchicine remains unknown, although it was reported in W. arborea (Apocynaceae).^72,96 Alkaloid 56 was also reported in the bark and roots of Holarrhena pubescens (Apocynaceae).^11,21 Alkaloid 64 was found in both Apocynaceae and Buxaceae families, including H pubescens,⁹⁷ Holarrhena mitis,⁷⁰ and Didymeles madagascariensis.⁹⁸ Isolates 66, 67, 70, and 71 were identified in the seeds and leaves of H pubescens (Apocynaceae).^{10,12,17,71,99} The metabolites 57 to 63, 65, 68, and 69 were not found in other plant species.

Investigation of the leaves of H mitis R.Br. revealed N-demethylmitiphylline (72) and mitiphylline (73),^100,101 and N³-methylholarrhimine (74), holarrhimine (75), and 4 were obtained from the bark.^70,102 The alkaloid 74 was also reported in the bark of H pubescens (Apocynaceae)⁸⁴ while 75 was found in the bark of H pubescens (Apocynaceae)^78,81 and in an unstated part of W. arborea (Apocynaceae).⁷²

Phytochemical studies on the seed extract of H pubescens (Buch. Ham) (synonym: H. antidysenterica and H. febrifuga), yielded holarricine (76), antidysentericine (77), conimine (78), conkuressine (79), isoconkuressine (80), N-formylconessimine (81), and 4.^{10,12,15,17,103,104} Further investigation of the stem bark of H pubescens yielded regholarrhenine A (82), regholarrhenine B (83), regholarrhenine C (84), regholarrhenine D (85), regholarrhenine E (86), kurcholessine (87), holadysenterine (88), and 4.^31,75,105 The roots of H pubescens yielded holacetine (89), mokluangin A (90), mokluangin D (91), malouetafrine (92), holaphyllaminol (93), 3, 4, and 78.^21,106 Kurchiline (94), kurchiphylline (95), kurchiphyllamine (96), kurchaline (97), holadysine (98), holantosine A (99), holantosine B (100), holantosine C (101), holantosine D (102), holarosine A (103), holarosine B (104), holantosine E (105), holantosine F (106), N,N-dimethylfuntumine (107), N-methylfuntumine (108), N,N-dimethylholamine (109), and N-methylholamine (110) were isolated from the leaves of H pubescens.^{77,99,107–110} N²⁰-methylholarrhimine (111), holarrhidine (112), kurchimine (113), dihydroisoconessimine (114), holacine (115), holacimine, holarrifine (116), kurchinidine (117), kurchinine (118), pubescine (119), norholadiene (120), pubescimine (121), holamide (122), pubescinine (123), pubamide (124), norkurchamide (125), pubatriol (126), mokluangin B (127), mokluangin C (128), 7α-hydroxyconessine (129), and 3, 4, 77, and 90 were found in the bark of H pubescens.^{11,13,18,22,27,68,78,81,84,97,111–119} Holarrhine was previously isolated from H pubescens.¹¹⁶ The structures of holacimine and holarrhine remain unknown. Alkaloid 4 might be a marker for Holarrhena species as it was reported several times, including in H congolensis, H floribunda, H mitis, and H pubescens. Interestingly, isolate 88 was also produced by a fungus named Drechslera australiensis.¹²⁰ Compound 92 was also found in M. heudelotii (Apocynaceae).⁴⁴ N-Methylfuntumine (108) was also reported from 1 species of the Buxaceae, namely S coriacea,⁴⁸ while holarrhine was obtained from W. arborea (Apocynaceae).¹¹⁶ The alkaloids 76 to 87, 89 to 91, 93 to 107, and 109 to 129 have limited distribution to Holarrhena spp. (Table 1).

Kibatalia Species

Steroidal alkaloids were reported from five species of the Kibatalia genus. Kibatalia gitingensis (Elmen) Woodson yielded kibataline (130), 20-epi-N-methylparavallarine (131), and gitingensine (132).^121–123 Lanitine (133) and lanitinine (134) were isolated from the stem bark of K gitingensis,¹²⁴ while paravallarine (135), N-methylparavallarine (136), 20-epi-paravallarine (137), and 2α-hydroxy-N-methyl-20-epiparavallarine (138) were found in the bark of K gitingensis.¹²⁵ Alkaloid 131 was also reported in the leaves of Paravallaris macrophylla (synonym: K. macrophylla (Pierre) Woodson),¹²⁶ and 132 and 135 were reported in the leaves of K. laurifolia (synonym: P. microphylla).^25,127

N-methylgitingensine (139), N-acetylgitingensine (140), 3-epi-gitingensine (141), 7α-hydroxyparavallarine (142), and kibalaurifoline (143) were found in the leaves of K. laurifolia (Ridl.) Woodson.²⁵ In another study, paravallaridine (144), N-methylparavallaridine (145), 11α-hydroxyparavallarine (146), and 7β-hydroxyparavallarine (147) were isolated from K. laurifolia.^128–131 Only one steroidal alkaloid was isolated from the bark of P. maingayi (synonym: K. maingayi (Hook.f.) Woodson), namely maingayine (148).¹³² The alkaloids 130 to 147 are all of the paravallarine-type and are exclusively found in Kibatalia sp. Only one conanine-type steroidal alkaloid has been reported from Kibatalia sp., namely maingayine (148).

Malouetia Species

Steroidal alkaloids were reported from four species of the genus Malouetia. Malouetia arborea Miers. yielded malarborine (149) and malarboreine (150),⁸³ while the leaves of M. bequaertiana E. Woodson yielded malouphylline (151), malouetine (152), and malouphyllamine (153).^44,133,134 Malouphyllinine (154) was found in the wood of M. bequaertiana,¹³⁵ and N-acetylconamine (155) and malouetamide (156) were isolated from the leaves of M. heudelotii A. DC.⁴⁴ Meanwhile, dihydrokurchessine (157) and 4 were purified from an unstated part of M. tamaquarina (Aubl.) A. DC.⁸³ The steroidal alkaloids 149 to 157 have only been found in Malouetia spp.

Tabernaemontana Species

It is surprising that of 118 Tabernaemontana species, only one has been reported to contain steroidal alkaloids. Two pregnane-type steroidal alkaloids were isolated from the roots of Conopharyngia pachysiphon (synonym: T. pachysiphon Stapf), and deduced as 20α-amino-3,5-pregnadiene (158) and 20α-amino-3β-hydroxy-5-pregnene-β-D-glucoside (159).¹³⁶

Vahadenia Species

A study on the roots of V. laurentii (De Wild) Stapf resulted in the characterization of irehdiamine F (160),¹³⁷ which has not been reported from any other source.

Wrightia Species

Only two species of Wrightia contain steroidal alkaloids. Investigation of Wrightia tomentosa (synonym: W. arborea (Dennst.) Mabb.) resulted in the isolation of 4.⁷² Wrightiamine A (161) and wrightiamine B (162) were characterized from the leaves of W. javanica (synonym: W. pubescens),²⁶ and are limited to Wrightia spp.

In conclusion, 163 steroidal alkaloids have been successfully isolated from the 10 genera of the Apocynaceae family so far. Table 1 summarizes all the steroidal alkaloids obtained from the Apocynaceae family.

Chemotaxonomic Significance of Steroidal Akaloids in the Apocynaceae Family

Steroidal alkaloids are limited in distribution to particular plant families, for example, the cholestane type of steroidal alkaloids can be found in the families Solanaceae, Liliaceae, Berberidaceae, Asteraceae, Buxaceae, Alliaceae, and Verbenaceae. Pregnane, cyclopregnane, and conanine types of steroidal alkaloids are found in the Buxaceae and Apocynaceae. The paravallarine type of steroidal alkaloids is exclusively found in the genus Kibatalia of Apocynaceae.^25,121–127 The genera within the subfamily Apocynoideae mainly contain the pregnane and conanine types of steroidal alkaloids, except for the steroidal alkaloids in the tribe Apocyneae. Beaumontia sp. and Chonemorpha sp. in this tribe contain mainly pregnane-type steroidal alkaloids. Steroidal alkaloids from the tribes Malouetieae and Wrightieae are mainly pregnane and conanine types, except for the Kibatalia sp. Only K. arborea was reported to contain a pregnane alkaloid, namely holafebrine (45), which was also reported from H curtisii, H mitis, and H pubescens.

Conessine (4), a conanine type of steroidal alkaloid can be found in many plants of the subfamily Apocynoideae, specifically in the tribes Malouetieae and Wrightieae. It was reported in the genera Funtumia, Holarrhena, Malouetia, and Wrightia, but not from the tribe Apocyneae. Some steroidal alkaloids from the genus Holarrhena from the Malouetieae tribe are glycosylated at C-3 of the steroid skeleton.

Several steroidal alkaloids in the Apocynaceae family were also reported in the Buxaceae family, a small plant family with only five genera. Steroidal alkaloids found in both plant families are mainly pregnane tetracyclic triterpenes¹³⁸ with C-4 methyls, a 9β, 10β-cycloartenol system, and a degraded C-20 side chain.¹³⁹ Holadienine (64) has only been reported from the genus Holarrhena of the Apocynaceae. The Buxaceae family has afforded only one conanine type of steroidal alkaloid type, namely holadienine (64), in the genus Didymeles, suggesting some chemotaxonomic relationship between these two genera of two different plant families. Steroidal alkaloids of paravallarine moiety are exclusively found in the genus Kibatalia of the Apocynaceae family. Many steroidal alkaloids can only be found in the Apocynaceae family.

Biological Activities

AChE Activity

Conessine (4), conessimine (67), conarrhimine (70), and conimine (78) isolated from the seeds of H pubescens showed AChE inhibiting activity with IC₅₀ values ranging from 4 to 28 µM, which is less active in comparison with the positive control, huperzine A (IC₅₀ = 0.06 µM).¹⁰ Antidysentericine (77), mokluangin A (90), mokluangin B (127), and mokluangin C (128) showed AChE inhibiting activity with IC₅₀ values ranging from 1.4 to 23 µM, with mokluangin C (128) exhibiting the lowest IC₅₀ value.¹¹ However, those alkaloids also showed lower activity than galantamine (IC₅₀ = 0.56 µM).

Holarrhena-type steroidal alkaloids were found to bind to the allosteric site of the AChE enzyme.¹⁰ The presence of an N-methyl moiety and an unsubstituted N-H on the pyrrolidine ring are essential for AChE inhibitory activity, while cleavage of 1 or 2 N-methyl groups at C-3 reduces this inhibitory activity. In contrast, Cheenpracha et al. suggested that the cleavage at N,N-dimethyl group at C-3 significantly increases AChE activity of Hollarhena-type steroidal alkaloids.¹¹

Antibacterial Activity

Conimine (78) and N-formylconessimine (81) isolated from the seeds of H pubescens showed a synergistic effect when combined with penicillin and vancomycin against methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-sensitive S aureus (MSSA) with FIC values ranging from 0.12 to 0.23.¹² Mokluangin B (127) and mokluangin C (128) isolated from the barks of H pubescens inhibited Escherichia coli growth with a minimum inhibitory concentration (MIC) value of 16 µg/mL. Mokluangin B (127) also inhibited the growth of Bacillus subtilis with a MIC value of 16 µg/mL. These alkaloids showed weaker activity when compared to vancomycin and gentamycin with MIC values ranging from 0.13 to 0.25 µg/mL.¹¹

Conessine (4) isolated from the stem bark of H floribunda inhibited B. stearothermophilus, B subtilis, B. megaterium, and B. cereus with 25 mm, 23 mm, 23 mm, and 18 mm inhibition zones, respectively, at a dose of 30 µg. However, the activity was significantly lower when compared with chloramphenicol.¹⁴ Conessine (4) also showed antibacterial activity against Micrococcus luteus ATCC 9341 with a MIC value of about 16 µg/disc, which is weaker than that of streptomycin with a MIC value of 0.39 µg/disc.¹³ The alkaloids reported to possess weak antibacterial activity are of the conanine type, and typically are N-demethylated at C-3.

Anticercarial Activity

Conessine (4), holonamine (14), and holadienine (64) isolated from the stem bark of H floribunda showed anticercarial activity against Schistosoma haematobium cercariae with IC₅₀ values ranging from 33 to 471 µg/mL compared to praziquantel, with an IC₅₀ value of 696 µg/mL.¹⁶ Conessine (4) showed the highest anticercarial activity.

Antidiarrheal Activity

Conessine (4), isoconessimine (29), cona-3,5-dien-7-one (66), conarrhimine (70), and conimine (78) isolated from the seeds of H pubescens showed antidiarrheal activity with tension inhibition rates ranging from 5 to 33% and amplitude inhibition rates ranging from 11% to 60%, at a concentration of 0.5 mg/mL. However, the activities of those alkaloids were lower than that of atropine sulfate with 37% and 72%, respectively.¹⁷

Antifeedant Activity

Conessine (4) isolated from the bark of H. pubescens showed antifeedant activity of Spodoptera litura, the tobacco cutworm, and Pieris brassicae, the large white butterfly, at concentrations of 0.005% to 0.2%, respectively.¹⁸

Antimycobacterial Activity

Holadysamine (71) isolated from H. floribunda inhibited Mycobacterium ulcerans with a MIC value of 50 µg/mL, which is significantly lower activity than that of rifampicin, with a MIC value of 2 µg/mL.¹⁹

Antiplasmodial Activity

Conessine (4) isolated from the bark of H pubescens showed antiplasmodial activity in the schizont maturation and parasite lactate dehydrogenase (pLDH) assays with the IC₅₀ values of 1.9 and 1.3 µg/mL, respectively. The activity was much lower than that of chloroquine (IC₅₀ = 0.07 and 0.051 µg/mL, respectively) in the schizont maturation and pLDH assays. In addition, administration of 10 mg/kg of conessine (4) significantly reduced parasitemia by 89% in P. berghei-infected mice compared to vehicle control, which only reduced parasitemia by about 6% on day 7.²² Conessine (4), irehline (35), holaphylline (41), methylholaphylline (56), conimine (78), mokluangin A (90), and holaphyllaminol (93) isolated from the roots of H pubescens inhibited P. falciparum K1 strain with IC₅₀ values ranging from 1.2 to 12 µM; irehline (35) showed the most significant antiplasmodial activity. However, these activities were lower than that of dihydroartemisinin (IC₅₀ = 3.7 nM).²¹ Conessine (4), isoconessimine (29), holarrhesine (30), and holarrhetine (31) isolated from the stem bark of F elastica inhibited the chloroquine-resistant strain of P. falciparum (FcB1) with the IC₅₀ values ranging from 0.97 to 3.4 µM in which holarrhesine (30) exhibited the best activity. Holarrhesine (30) showed slightly lower activity when compared with chloroquine (IC₅₀ = 0.13 µM).²⁰ Many conanine-type steroidal alkaloids exert significant antiplasmodial activity, especially if the nitrogen at C-3 is demethylated. Several pregnane-type steroidal alkaloids showed antiplasmodial activity.

Antitrypanosomal Activity

Seventeen alkaloids isolated from the leaves and stem bark of H floribunda, namely 3β-holaphyllamine (3), conessine (4), holonamine (14), funtumine (25), isoconessimine (29), holarrhesine (30), holarrhetine (31), holaphylline (41), holarrhenine (42), holamine (55), 3β-dihydroholaphyllamine (59), holaphyllamine acetamide (61), holadienine (64), cona-4,6-dien-3-one (65), cona-3,5-dien-7-one (66), conessimine (67), and holarrheline (68) were assessed for their inhibition of Trypanosoma brucei rhodesiense. The IC₅₀ values of the compounds ranged from 0.075 to 21 µM. Conessine (4) (IC₅₀ = 0.42 µM), isoconessimine (29) (IC₅₀ = 0.17 µM), holarrhesine (30) (IC₅₀ = 0.12 µM), and conessimine (67) (IC₅₀ = 0.17 µM) showed good antitrypanosomal activity with selectivity indices of more than 100.²³ However, the alkaloids exhibited lower activity than melarsoprol (IC₅₀ = 0.002 µM). The conanine type of steroidal alkaloids exhibited better antitrypanosomal activity compared to the pregnane type, although the pregnane steroidal alkaloids with mono-N-methylation at C-3 showed improved activity.²³ The amino group of the pyrroline or pyrrolidine ring does not exert antitrypanosomal activity on its own, but together with a basic amine at C-3, the alkaloid showed improved activity.

Cytotoxic Activity

Irehline (35), holaphylline (41), mokluangin A (90), and holaphyllaminol (93) isolated from the roots of H pubescens showed weak cytotoxicity against NCI-H187 cell line (lung cancer) with IC₅₀ values in the range of 18 to 31 µM when compared with doxorubicin and ellipticine (IC₅₀ = 0.2 and 7.2 µM, respectively).²¹ Gitingensine (132), paravallarine (135), N-methyl-gitingensine (139), 3-epi-gitingensine (141), and kibalaurifoline (143) isolated from the leaves of K. laurifolia showed weak cytotoxic activity against KB cells with IC₅₀ values ranging from 13 to 42 µM, with paravallarine (135) showed the highest activity. Compounds showed lower activity in comparison with taxotere (IC₅₀ = 0.15 nM).²⁵ Funtumine (25), and holamine (55) isolated from the leaves of H floribunda showed very weak cytotoxicity against HT-29 (colon cancer), MCF-7 (breast cancer), and HeLa (cervical cancer) with IC₅₀ values of 22 to 53 µM; cisplatin exhibited IC₅₀ values of 2.9 to 11 µM.²⁴ 17-Epi-holacurtine (50) isolated from the leaves of H curtisii showed the highest cytotoxic activity against the HL-60 cell line (leukemia) (IC₅₀ = 0.01 µg/mL), while other alkaloids, namely holacurtine (48), N-demethylholacurtine (49), 17-epi-N-demethylholacurtine (51), holacurtinol (52), 15α-hydroxyholamine (54), and holamine (55) showed higher IC₅₀ values ranging from 0.2 to 2.6 µg/mL.²⁸ Conessine (4), isoconessimine (29), holarrhesine (30), and holarrhetine (31) isolated from the stem bark of F elastica showed weak cytotoxicity against rat L-6 cells, with IC₅₀ values ranging from 5.1 to 37 µM. The standard drug was not determined.²⁰ In another study, 3β-holaphyllamine (3), conessine (4), holonamine (14), funtumine (25), isoconessimine (29), holarrhesine (30), holarrhetine (31), holaphylline (41), holarrhenine (42), holamine (55), 3β-dihydroholaphyllamine (59), holaphyllamine acetamide (61), cona-4,6-dien-3-one (65), cona-3,5-dien-7-one (66), conessimine (67), and holarrheline (68) isolated from the leaves and stem bark of H floribunda showed cytotoxic activity against L-6 cells with IC₅₀ values in the range of 2.5 to 181 µM. However, they exhibited significantly lower activity than podophyllotoxin (IC₅₀ = 0.004 µM).²³ Both wrightiamine A (161) and wrightiamine B (162) isolated from the leaves of W. pubescens showed cytotoxic activity against vincristine-resistant murine leukemia P388 cells. The IC₅₀ values of wrightiamine A (161) in the presence and absence of vincristine were 2.0 and 3.1 µg/mL, respectively, while the IC₅₀ values of wrightiamine B (162) were 22 and 25 µg/mL, respectively.²⁶ The paravallarine type of steroidal alkaloids with the absence of a hydroxyl group at C-7 showed the strongest cytotoxic activity.²⁵

Hypotensive Activity

Holamide (122) and pubescinine (123) isolated from the bark of H pubescens were evaluated for hypotensive activity in vivo. Treatment with 3 mg/kg of pubescinine (123) and holamide (122) in rats significantly reduced diastolic mean blood pressure by 35% and 29%, respectively.²⁷ No positive control was used in this study.

Leishmanicidal Activity

Holacurtine (48), N-demethylholacurtine (49), 17-epi-holacurtine (50), 17-epi-N-demethylholacurtine (51), holacurtinol (52), 3α-amino-14β-hydroxypregnan-20-one (53), 15α-hydroxyholamine (54), and holamine (55) isolated from the leaves of H curtisii showed leishmanicidal activity against Leishmania donovani with IC₅₀ values ranging from 0.39 to 25 µg/mL.²⁸ There was no standard drug used in this study. Holamine (55), a pregnane steroidal alkaloid with N,N-demethylation at C-3, showed the strongest activity.

Restoration of Antibiotic Efficacy

The combination of conessine (4) isoalted from H pubescens with levofloxacin enhanced bacterial inhibition against Pseudomonas aeruginosa strains in vitro. In addition, the combination therapy restored levofloxacin efficacy in Galleria mellonella larvae infected with multi-drug-resistant strains of P aeruginosa. The combination of conessine with levofloxacin produced a lower MIC value of 1 mg/mL compared to the antibiotic alone with a MIC value of 2 mg/mL, with the strain overexpressing the MexAB-OprM efflux system.²⁹

Bioactive Steroidal Alkaloids

Table 2 summarizes the biological activities of steroidal alkaloids from the Apocynaceae family. Steroidal alkaloids with low basicity due to N-demethylation at C-3 showed better bioactivity compared to other alkaloids.²¹ This trend was observed in several bioassays.^11,23 The effect of methylation on the nitrogen of the pyrroline and pyrrolidine moieties varies, depending on the individual bioactivity being examined. Most bioactivities were reported as alkaloids derived from Holarrhena spp., and a few from Funtumia and Wrightia spp. As the most studied, Holarrhena steroidal alkaloids exhibited a wide spectrum of biological activities.

Table 2.

Biological Activities of Steroidal Alkaloids From Apocynaceae Family.

Alkaloid	Biological activity	References
Conessine (4)	Acetylcholinesterase, antibacterial, anticercarial, antidiarrheal, antifeedant, antiplasmodial, antitrypanosomal, restoring antibiotic efficacy	^{10,13–18,20–23,29}
Conessimine (67)	Acetylcholinesterase, antitrypanosomal	^10,23
Conarrhimine (70)	Acetylcholinesterase, antidiarrheal	^10,17
Conimine (78)	Acetylcholinesterase, antibacterial, antidiarrheal, antiplasmodial	^10,12,17,21
Antidysentericine (77)	Acetylcholinesterase	¹¹
Mokluangin A (90)	Acetylcholinesterase, antiplasmodial	^11,21
Mokluangin B (127)	Acetylcholinesterase, antibacterial	¹¹
Mokluangin C (128)	Acetylcholinesterase, antibacterial	¹¹
N-Formylconessimine (81)	Antibacterial	¹²
Holonamine (14)	Anticercarial	¹⁶
Holadienine (64)	Anticercarial, antitrypanosomal	^16,23
Holadysamine (71)	Antimycobacterial	¹⁹
Isoconessimine (29)	Antidiarrheal, antiplasmodial, antitrypanosomal	^17,20,23
Cona-3,5-dien-7-one (66)	Antidiarrheal, antitrypanosomal, cytotoxic (L-6 cells)	^17,23
Irehline (35)	Antiplasmodial	²¹
Holaphylline (41)	Antiplasmodial, antitrypanosomal, cytotoxic (L-6 cells)	^21,23
Holaphyllaminol (93)	Antiplasmodial	²¹
Methylholaphylline (56)	Antiplasmodial	²¹
Holarrhesine (30)	Antiplasmodial, antitrypanosomal	^20,23
Holarrhetine (31)	Antiplasmodial, antitrypanosomal	^20,23
3β-Holaphyllamine (3)	Antitrypanosomal, cytotoxic (L-6 cells)	²³
Holonamine (14)	Antitrypanosomal, cytotoxic (L-6 cells)	²³
Funtumine (25)	Antitrypanosomal, cytotoxic (HT-29, MCF-7, HeLa and L-6 cells)	^23,24
Holarrhenine (42)	Antitrypanosomal, cytotoxic (L-6 cells)	²³
Holamine (55)	Antitrypanosomal, cytotoxic (HT-29, MCF-7, HeLa, HL-60 and L-6 cells), leishmanicidal	^23,24,28
3β-Dihydroholaphyllamine (59)	Antitrypanosomal, cytotoxic (L-6 cells)	²³
Holaphyllamine acetamide (61)	Antitrypanosomal, cytotoxic (L-6 cells)	²³
Cona-4,6-dien-3-one (65)	Antitrypanosomal, cytotoxic (L-6 cells)	²³
Holarrheline (68)	Antitrypanosomal, cytotoxic (L-6 cells)	²³
Gitingensine (132)	Cytotoxic (KB cells)	²⁵
Paravallarine (135)	Cytotoxic (KB cells)	²⁵
N-methylgitingensine (139)	Cytotoxic (KB cells)	²⁵
3-Epi-gitingensine (141)	Cytotoxic (KB cells)	²⁵
Kibalaurifoline (143)	Cytotoxic (KB cells)	²⁵
17-Epi-holacurtine (50)	Cytotoxic (HL-60 cells), leishmanicidal	²⁸
Holacurtine (48)	Cytotoxic (HL-60 cells), leishmanicidal	²⁸
N-Demethylholacurtine (49)	Cytotoxic (HL-60 cells), leishmanicidal	²⁸
17-Epi-N-demethylholacurtine (51)	Cytotoxic (HL-60 cells), leishmanicidal	²⁸
Holacurtinol (52)	Cytotoxic (HL-60 cells), leishmanicidal	²⁸
3α-Amino-14β-hydroxypregnan-20-one (53)	Leishmanicidal	²⁸
15α-Hydroxyholamine (54)	Cytotoxic (HL-60 cells), leishmanicidal	²⁸
Wrightiamine A (161)	Cytotoxic (P388 cells)	²⁶
Wrightiamine B (162)	Cytotoxic (P388 cells)	²⁶
Holamide (122)	Hypotensive	²⁷
Pubescinine (123)	Hypotensive	²⁷

Conclusion

The isolation of steroidal alkaloids was first reported in 1919. These compounds are found in a limited number of plant families, including the Apocynaceae. A total of 163 steroidal alkaloids have been reported from the Apocynaceae family from 1919 to 2021. Of the 410 genera in the Apocynaceae, only 10 contain steroidal alkaloids. Holarrhena is the most well studied compared to the other genera, while conessine (4) is the most widely distributed steroidal alkaloid. Steroidal alkaloids have exhibited several biological activities, particularly, cytotoxic and antiparasitic activities. Conanine steroidal alkaloids are widely reported, and those with monomethylation at C-3 exert stronger activities than those which are N,N-demethylated, and dimethylation. Their structural similarities with anabolic steroids, steroidal hormones, and corticosteroids make them a potential source of drug candidates.

Footnotes

Acknowledgements

The authors would like to thank Universiti Teknologi MARA for financial support via MyRA Road to HiCOE Research Grant (600-RMC/GPM COE 5/3 (052/2021)) and for the facilities provided. The authors would also like to thank Professor Emeritus Geoffrey A. Cordell for proofreading this manuscript.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research and/or authorship of this article: The research was supported by Universiti Teknologi MARA via MyRA Road to HiCOE Research Grant (600-RMC/GPM COE 5/3 (052/2021)).

ORCID iDs

Hidayatul Atiqah Abd Karim

Nor Hadiani Ismail

Che Puteh Osman

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