Classification, Toxicity and Bioactivity of Natural Diterpenoid Alkaloids

Diterpenoid alkaloids are natural compounds having complex structural features with many stereo-centres originating from the amination of natural tetracyclic diterpenes and produced primarily from plants in the Aconitum, Delphinium, Consolida genera. Corals, Xenia, Okinawan/Clavularia, Alcyonacea (soft corals) and marine sponges are rich sources of diterpenoids, despite the difficulty to access them and the lack of availability. Researchers have long been concerned with the potential beneficial or harmful effects of diterpenoid alkaloids due to their structural complexity, which accounts for their use as pharmaceuticals as well as their lousy reputation as toxic substances. Compounds belonging to this unique and fascinating family of natural products exhibit a broad spectrum of biological activities. Some of these compounds are on the list of clinical drugs, while others act as incredibly potent neurotoxins. Despite numerous attempts to prepare synthetic products, this review only introduces the natural diterpenoid alkaloids, describing ‘compounds’ structures and classifications and their toxicity and bioactivity. The purpose of the review is to highlight some existing relationships between the presence of substituents in the structure of such molecules and their recognised bioactivity.

DAs extracted from some plants belonging to the Ranunculaceae family, especially genera Delphinium, Aconitum and Consolida, are often distinctive and recognised as cytotoxic against cancer [9]. Aconitum spp. (monkshood) is one of the most extracted and isolated sources of DAs, where more than half of natural DAs were isolated from [10][11][12][13][14][15].
DAs have long been used all over the world. People extract Aconitum due to either medicinal and beneficial properties or toxic and harmful ones. In the ancient past, Aconitum seasoned the top of arrows used for hunting animals and in wars. Of note, a Chinese tribe Compounds 1-6 contain a 7,8-methylenedioxy group, while compoun ture a 10-OH. In particular, alkaloids 1-2 have a 16-OH group instead of unit, usual in C18-DAs [22][23][24][25][26].
On the other hand, compound 10 in Figure 1 has a double bond in distinguishes it from the rest of the group, and vaginatunine (11, in Figure  presence of a methoxy substitute in C8 [28].
Alkaloids 13 and 14 in Figure 1 have an N-acetylanthranoyloxy subst furthermore, they have fewer ester groups, suggesting that they are less tox
Minor toxicity characterises plant roots containing weisaconitine comp tures 15-18 in Figure 2) [30]. Structurally, the lactam carbonyl and acetoxy g cific to weisaconitine compounds 16 and 17, respectively. Furthermore, a ch tion in C4 and two hydroxyl groups in C1 and C3 are natural to sinomontani

Lappaconitine Group
The methine unit in C7 characterises the lappaconitine compounds; examples are natural to various Aconitum and Delphinium species [5,8].
On the other hand, compound 10 in Figure 1 has a double bond in C2-C3, which distinguishes it from the rest of the group, and vaginatunine (11, in Figure 1) shows th presence of a methoxy substitute in C8 [28].
Alkaloids 13 and 14 in Figure 1 have an N-acetylanthranoyloxy substituent in C17 furthermore, they have fewer ester groups, suggesting that they are less toxic [29].

Lappaconitine Group
The methine unit in C7 characterises the lappaconitine compounds; examples ar natural to various Aconitum and Delphinium species [5,8].

Rearranged Group
Sinomontadine (19 in Figure 3), isolated from Aconitum sinomontanum, shows a surpassing skeleton unlike other DAs compounds; it exhibits a seven-membered ring [31] instead of six, by the incorporation of a carbon atom into the six-ring system with the Molecules 2021, 26, 4103 4 of 28 expansion to a seven carbons ring. The result is a set of new compounds such as puberudine (20, Figure 3) and puberunine (21, Figure 3), isolated from Aconitum barbatum var. puberulum and recognised as an exceptional class of DAs [27].

Rearranged Group
Sinomontadine (19 in Figure 3), isolated from Aconitum sinomontanum, shows a sur passing skeleton unlike other DAs compounds; it exhibits a seven-membered ring [31 instead of six, by the incorporation of a carbon atom into the six-ring system with th expansion to a seven carbons ring. The result is a set of new compounds such as puber udine (20, Figure 3) and puberunine (21, Figure 3), isolated from Aconitum barbatum var puberulum and recognised as an exceptional class of DAs [27]. Puberudine (compound 20 in Figure 3) has a distinctive characteristic in the A ring which is an open ring (1,2-Seco), and also a specific double bond between C2 and C3, in addition to the carbonyl group on C1 instead of the methoxyl or hydroxyl group [27,31].

C19-Diterpenoid Alkaloids
C19-is the largest category of the DAs, belonging to pentacyclic compounds. Most of th C19-DAs are isolated from Aconitum, Delphinium, and the roots of Aconitum carmichaelii [9].
C19-DAs are compounds classified into seven types (lactone, aconitine, lycoctonine 7,17-Seco, franchetine, rearranged class, and glycosides) according to the oxygen-contain ing groups on C7 and the difference of skeleton as shown in Figure 4 [20,21]. The plurality of C19-DAs are lycoctonine and aconitine types, which are isolated from Delphinium. The presence of the oxygen-substituent group in the lycoctonine-type on C7 constitutes the difference between them. Puberudine (compound 20 in Figure 3) has a distinctive characteristic in the A ring, which is an open ring (1,2-Seco), and also a specific double bond between C2 and C3, in addition to the carbonyl group on C1 instead of the methoxyl or hydroxyl group [27,31].

C 19 -Diterpenoid Alkaloids
C 19 -is the largest category of the DAs, belonging to pentacyclic compounds. Most of the C 19 -DAs are isolated from Aconitum, Delphinium, and the roots of Aconitum carmichaelii [9]. C 19 -DAs are compounds classified into seven types (lactone, aconitine, lycoctonine, 7,17-Seco, franchetine, rearranged class, and glycosides) according to the oxygen-containing groups on C7 and the difference of skeleton as shown in Figure 4 [20,21].

Rearranged Group
Sinomontadine (19 in Figure 3), isolated from Aconitum sinomontanum, shows a sur passing skeleton unlike other DAs compounds; it exhibits a seven-membered ring [31 instead of six, by the incorporation of a carbon atom into the six-ring system with th expansion to a seven carbons ring. The result is a set of new compounds such as puber udine (20, Figure 3) and puberunine (21, Figure 3), isolated from Aconitum barbatum var puberulum and recognised as an exceptional class of DAs [27]. Puberudine (compound 20 in Figure 3) has a distinctive characteristic in the A ring which is an open ring (1,2-Seco), and also a specific double bond between C2 and C3, in addition to the carbonyl group on C1 instead of the methoxyl or hydroxyl group [27,31].

C19-Diterpenoid Alkaloids
C19-is the largest category of the DAs, belonging to pentacyclic compounds. Most of th C19-DAs are isolated from Aconitum, Delphinium, and the roots of Aconitum carmichaelii [9].
Furthermore, DAs 61-62, isolated from the roots of A. carmichaelii, are characterised by the presence of quaternary amine (cation) having a positive charge (+HN-3R), which tolerate a function similar to that of a nitrone (+NO=C) [52].
Furthermore, DAs 61-62, isolated from the roots of A. carmichaelii, are characterised by the presence of quaternary amine (cation) having a positive charge (+HN-3R), which tolerate a function similar to that of a nitrone (+NO=C) [52].
The known, naturally occurring alkaloids of the amine subtypes in the aconitine and lycoctonine types possess the following distinctive features: (i) In most cases, they have oxygenated functionalities at C1, C6, C8, C14, C16, and C18.
Interestingly, the positions of these oxygenated groups are specific for the resulting structural tendency from simple to complex: C13 or C10 to C3/C13 or C3/C10 to C3/C13/C15 or C3/C10/C13/C15 [32,50]. (ii) Many alkaloids contain only the common oxygenated groups, e.g., methoxyl and hydroxyl group(s). In most cases, the methoxyl groups locate at C1, C16, and C18. The hydroxyl groups mainly located at C8 and C14. The presence of hydroxyl groups at C3, C10, C13, and C15 may lead to their structural diversity [53,54,63]. (iii) Some alkaloids contain only the common ester groups, e.g., acetoxy group and benzoyloxy. There are a few examples with other ester groups. Among them, the acetoxy group presents a chemotaxonomic characteristic. The ester groups locate at C8, C14, or C8/C14 [3,32]. (iv) They contain an N-ethyl structural unit. Very few alkaloids possess an N-methyl group [33]. (v) The oxygenated substituents at the C1, C6, and C15 positions of the alkaloids possess an a-orientation in most cases [42].
The known, naturally occurring alkaloids of the amine subtypes in the aconitine and lycoctonine types possess the following distinctive features: (i) In most cases, they have oxygenated functionalities at C1, C6, C8, C14, C16, and C18.
Interestingly, the positions of these oxygenated groups are specific for the resulting structural tendency from simple to complex: C13 or C10 to C3/C13 or C3/C10 to C3/C13/C15 or C3/C10/C13/C15 [32,50]. (ii) Many alkaloids contain only the common oxygenated groups, e.g., methoxyl and hydroxyl group(s). In most cases, the methoxyl groups locate at C1, C16, and C18. The hydroxyl groups mainly located at C8 and C14. The presence of hydroxyl groups at C3, C10, C13, and C15 may lead to their structural diversity [53,54,63]. (iii) Some alkaloids contain only the common ester groups, e.g., acetoxy group and benzoyloxy. There are a few examples with other ester groups. Among them, the acetoxy group presents a chemotaxonomic characteristic. The ester groups locate at C8, C14, or C8/C14 [3,32]. (iv) They contain an N-ethyl structural unit. Very few alkaloids possess an N-methyl group [33]. (v) The oxygenated substituents at the C1, C6, and C15 positions of the alkaloids possess an a-orientation in most cases [42].
Grandiflodine B (compound 106 in Figure 11) from Delphinium grandiflorum is distinctive of a remarkable skeleton with the cleavage of N-C19 and C7-C17 bonds [76].
Grandiflodine B (compound 106 in Figure 11) from Delphinium grandiflorum is distinctive of a remarkable skeleton with the cleavage of N-C19 and C7-C17 bonds [76].
Grandiflodine B (compound 106 in Figure 11) from Delphinium grandiflorum is distinctive of a remarkable skeleton with the cleavage of N-C19 and C7-C17 bonds [76].

C20-Denudatine Class
Most of the denudatine DAs (compounds 81-89 in Figure 14) originate from Aconitum spp, except DAs 123-124 obtained from the whole herb of Delphinium anthriscifolium var. savatieri [81]. A hydroxyl group and an oxygenated group are respectively on C16 and

C20-Denudatine Class
Most of the denudatine DAs (compounds 81-89 in Figure 14) originate from Aconitum spp, except DAs 123-124 obtained from the whole herb of Delphinium anthriscifolium var. savatieri [81]. A hydroxyl group and an oxygenated group are respectively on C16 and
Molecules 2021, 26, x FOR PEER REVIEW

C20-Hetidine Class
The smallest group in the hetidine classification consists of three compoun 141 in Figure 16) [99,101,102]. It is distinguished by the presence of the N=CH gr endocyclic double bond, and a hydroxyl at C5 in all hetidine-DAs [97][98][99]101]. Ro sine F (structure 139 in Figure 16) exhibits a cardicine chloride in C17, whereas the shows the hordenine group in the same position, and DA 141 brings a (2-methox benzene ethanol moiety [99].
Molecules 2021, 26, x FOR PEER REVIEW

C20-Hetidine Class
The smallest group in the hetidine classification consists of three compo 141 in Figure 16) [99,101,102]. It is distinguished by the presence of the N=CH endocyclic double bond, and a hydroxyl at C5 in all hetidine-DAs [97][98][99]101]. sine F (structure 139 in Figure 16) exhibits a cardicine chloride in C17, whereas shows the hordenine group in the same position, and DA 141 brings a (2-met benzene ethanol moiety [99].

C20-Anopterine Class
DAs in this classification come from Anopterus /Anopterus macleayanus spec 156 in Figure 19). All anopterine DAs are similar; they have two hydroxyl group Me and an endocyclic double bond [108]. They differ only the substituent in C pounds 154 and 155 show a hydroxymethyl butenoate, whereas the DA-156 ex O-benzoyl group [108].

C 20 -Anopterine Class
DAs in this classification come from Anopterus/Anopterus macleayanus species (154-156 in Figure 19). All anopterine DAs are similar; they have two hydroxyl groups, an N-Me and an endocyclic double bond [108]. They differ only the substituent in C11; compounds 154 and 155 show a hydroxymethyl butenoate, whereas the DA-156 exhibits an O-benzoyl group [108].

C20-Anopterine Class
DAs in this classification come from Anopterus /Anopterus macleayanus species (154-156 in Figure 19). All anopterine DAs are similar; they have two hydroxyl groups, an N-Me and an endocyclic double bond [108]. They differ only the substituent in C11; compounds 154 and 155 show a hydroxymethyl butenoate, whereas the DA-156 exhibits an O-benzoyl group [108].  Compound 159 is isolated from D. grandiflorum. Compared to the hetisine class skeleton, the bond between the N atom and C17 was open due to forming a five-member ring, including C4, C5, C6, C18, and the N atom [109]. DA 160 is obtained from the roots of Delphinium trichophorum. Its skeleton contains a rearranged C-ring, a pentacyclic structure, and is not hexacyclic, as in a hetisane class [111,112].
Almost all of the C20-diterpenoid alkaloids contain oxygenated groups. However, in contrast to the C19-diterpenoid alkaloids, C20-DAs possess the following distinctive features : (i) Most of them do not contain a methoxy group in their structures as C19-DAs [108]; (ii) Some alkaloids contain an acetoxy group or benzoyloxy ester group, or both, and do not include other ester groups [56,93]; (iii) Most C20-DAs possess exocyclic methylene, and many of them have a secondary hydroxyl function in the allylic position [109,157]; (iv) Few atisine and hetidine-type alkaloids contain N,O-mixed acetal/ketal units [77,78,99,101].
Compound 159 is isolated from D. grandiflorum. Compared to the hetisine class skeleton, the bond between the N atom and C17 was open due to forming a five-member ring, including C4, C5, C6, C18, and the N atom [109]. DA 160 is obtained from the roots of Delphinium trichophorum. Its skeleton contains a rearranged C-ring, a pentacyclic structure, and is not hexacyclic, as in a hetisane class [111,112].
Almost all of the C 20 -diterpenoid alkaloids contain oxygenated groups. However, in contrast to the C 19 -diterpenoid alkaloids, C 20 -DAs possess the following distinctive features : (i) Most of them do not contain a methoxy group in their structures as C 19 -DAs [108]; (ii) Some alkaloids contain an acetoxy group or benzoyloxy ester group, or both, and do not include other ester groups [56,93]; (iii) Most C 20 -DAs possess exocyclic methylene, and many of them have a secondary hydroxyl function in the allylic position [109,157]; (iv) Few atisine and hetidine-type alkaloids contain N,O-mixed acetal/ketal units [77,78,99,101].

Marine Diterpenoid
Natural products of marine origin have become progressively substantial lead structures for drug discovery [159][160][161][162][163][164][165][166]. However, their structural variety often distinguishes them from products obtained from plants [159]. In this context, the scant availability of material from natural sources often poses a significant limitation to their utilisation.
Diterpenoids obtained from soft corals of the genus Xenia show a vast range of biological activities such as antiproliferative [160], antiangiogenic [161], or bactericidal [162] effects.

Marine Diterpenoid
Natural products of marine origin have become progressively substantial lead structures for drug discovery [159][160][161][162][163][164][165][166]. However, their structural variety often distinguishes them from products obtained from plants [159]. In this context, the scant availability of material from natural sources often poses a significant limitation to their utilisation.
Diterpenoids obtained from soft corals of the genus Xenia show a vast range of biological activities such as antiproliferative [160], antiangiogenic [161], or bactericidal [162] effects.
Pachyclavulide B (179 in Figure 22), isolated from the Okinawan soft coral, Pachyclavularia violacea, is a briarane-type diterpenoid containing eight chiral centres and a highly oxygenated tricyclic system [168]. It exhibits moderate growth-inhibitory activity against cancer cells (SNB-75) of the central nervous system [169].
Pachyclavulide B (179 in Figure 22), isolated from the Okinawan soft coral, Pachyclavularia violacea, is a briarane-type diterpenoid containing eight chiral centres and a highly oxygenated tricyclic system [168]. It exhibits moderate growth-inhibitory activity against cancer cells (SNB-75) of the central nervous system [169].
Toxic DAs mainly affect the central nervous system and the heart, with gastrointestinal side effects. Overdose can lead to death due to the development of ventricular arrhythmias and cardiac arrest [114,119,120]. With the ubiquitous tradition of using DAs as herbal medicines, often disguised as ornamental plants, poisoning cases are notoriously widespread [119,121].
In general, the Aconitum roots used in traditional medicines follows specialised processing methods, such as soaking, boiling, or hydrolysing; this causes a decrease in aconitine derivatives toxicity (benzylaconine or aconine) [147,150]. When comparing the proportion of aconitine in raw chuanwu to processed chuanwu (soaked or boiled), the balance of aconitine in the raw material is more remarkable. For this reason, the exposure to poisoning is higher when using raw chuanwu [119].
The cardiotoxicity and neurotoxicity of aconitines are in virtue of their actions on the voltage-sensitive sodium channels of the cell membranes of excitable tissues, including the myocardium, nerves, and muscles. Aconitine binds to open sensitive, high-voltage sodium channels, causing continuous sodium channel activation, becoming resistant to excitation. The electrophysiological mechanism of induction of arrhythmias due to delayed post-depolarisation and early post-depolarisation is triggered [114,119,[121][122][123].
Aconitine 'DAs' arrhythmic properties are part of its cholinergic (anticholinergic) effects mediated by the vagus nerve. Aconitine has a positive inotropic effect by prolonging sodium's influx during the action potential [114,122].
It has antihypertensive and bradycardia actions by virtue of the activation of the ventral nucleus in the hypothalamus. By acting on voltage-sensitive sodium channels in axons, aconitine inhibits neuromuscular transmission by reducing acetylcholine's induced quantitative release. On the other hand, aconitine DAs can cause severe contractions of the ileum by releasing acetylcholine from the posterior node cholinergic nerves [114,122].
Studies conducted on the effect of aconitine in mice concluded that it induces cell death by promoting excess Ca 2+ in the ventricular muscle cells, causing disruption of the Na + /Ca 2+ exchange system and reducing the regulation of the sarco-endoplasmic network of Ca 2+ -ATPase [124,125].
Unfortunately, there is no specific treatment for Aconitum poisoning. In contrast, supportive cardiovascular therapy is usual in poisoning cases [114,122].

Analgesic Activities
Opioids, salicylates, propionic acid derivatives, oxicam, and other non-steroidal anti-inflammatory drugs, usually used to control pain, have harmful side effects in gastrointestinal damage by inhibiting prostaglandin production in addition to the potential for addiction and adverse effects on the nervous system to opioid users [129].
Investigations on the effectiveness of analgesics obtained from C 18 -and C 19 -DAs showed that aconitine and lappaconitine affect sodium channels. Aconitine inhibits nerve conduction by continuous depolarisation, while lappaconitine may block Na+ channels and act as a local anaesthetic [129,138].
Lappaconitine (C18-DAs) shows pain-relief properties. However, lappaconitine sulfate, obtained by the modification of lappaconitine, exerts a more noticeable analgesic action than lappaconitine, which is poorly soluble in water [139,140].
Studies on the analgesic activity of C 19 -DAs demonstrated that compound 60 in Figure 5b, extracted from A. carmichaelii, exerts an analgesic effect on mice when used in acetic acid with a non-toxic dose of 0.5 mg/kg of body weight [141].
Compounds 100 in Figure 10 and 101 in Figure 11, administered in acetic acid using doses of 1.0, 0.3, and 0.1 mg/kg, showed a weak analgesic effect on mice using the higher amount of 1 mg/kg, with a pain suppression rate of 78.34%, whereas the rate was less than 20% for compounds 98 and 99 in Figure 10 [21]. The lack of the methoxy group in C6, as for compounds 94 and 95, seems to exert a fairly noticeable effect on the analgesic activity, whereas the presence of a methoxyl group in C1, as for the compounds 98 and 99, significantly decreases the activity [21].
The structure-activity relationship (SAR) analysis revealed the fundamental structures necessary for observing the analgesic activity of the C 19 -DAs. For example, substituents in C8 should be either the acetoxyl or ethoxyl group, a tertiary amine is essential in the cyclohexane ring, and substituents in C14 different from an aromatic ester would reduce the effectiveness. Furthermore, the hydroxylation at C15 is requisite to undergo bioactivation [5,135].
The characteristic skeletons, showing low toxicity in C 20 -DAs, encouraged researchers to conduct studies on their analgesic effects. In contrast to the substantial toxicity of C 18 -DAs and C 19 -DAs, C 20 -DAs may be effective candidate drugs for the management of pain treatments. In addition, the sulfonated compound (157 in Figure 20), extracted from the lateral roots of A. carmichaelii, also showed a significant analgesic activity [142].
Compound 144 in Figure 17 inhibits the activity of cyclooxygenase-2 (COX-2) with inhibitory concentration (IC 50 ) nearly equal to that of acetylsalicylic acid (29.75 µM and 29.30 µM, respectively); this is what makes it a possible alternative to aspirin [105].
The activity of compound 55 in Figure 5b and compound 87 in Figure 8 on inhibiting NO production in lipopolysaccharide cells (LPS) stimulated the macrophage cell line RAW 264.7, with a behaviour similar to dexamethasone. IC 50 values were 7.46 ± 0.89 µM and 8.09 ± 1.31 µM for compounds 87 and 55, respectively, and 8.32 ± 1.45 µM for dexamethasone [68,70]. Swatinine (compound 64 in Figure 6, obtained from Aconitum baikalense has an anti-inflammatory activity similar to indomethacin, with an inhibition rate of 38.71% and 42.02%, respectively [55]. Therefore, given their particular activity, various DAs can provide good resources for exploring promising anti-inflammatory drugs. Bulleyanines A and B (168 and 169 in Figure 21, respectively), two novel compounds, were isolated from Aconitum bulleyanum. Compound A showed a marked effect on antiinflammatory activity with an inhibition rate of 74.60% (40 µmol L −1 ), compound B showed as inactive, as compared to positive control dexamethasone (78.70%) at 100 µg mL −1 [158].

Antimicrobial Activities
Several researchers demonstrate the antimicrobial activity of some DAs. For example, sinchiangensine (compound 59 in Figure 5b) has potent antibacterial activity against Staphylococcus aureus with minimum inhibitory concentration (MIC) value 0.147 mmol mL −1 ; furthermore, lipodeoxyaconitine (analogue of sinchiangensine) is active against the same bacterium with MIC value 0.144 mmol mL −1 [144].
Compound 50A in Figure 5b, obtained from the roots of Aconitum duclouxi, also show antibacterial activity against B. subtilis with an MIC of 147.73 mmol L −1 ; moreover, compounds 50A and 50B show antifungal activity against Candida albicans with MIC of 51.84 and 128 mg mL −1 , respectively [146,147].
Extensive laboratory experiments are helpful promoters for the preparation of new antimicrobial formulations.

Antioxidant Activities
Diterpenoid alkaloids showed auspicious 1,1-diphenyl-2-picrylhydrazyl (DPPH)-like scavenging activity. Aconitine-type C 19 -DAs could be suitable antioxidants because of their ability for binding to metal ions [105]. Swatinine compounds (64 and 73 in Figure 6) offered an effective DPPH radical scavenging ratio of 65.3% and 63.4%, respectively, at 1 µM, whereas butylated hydroxytoluene (standard antioxidant) inhibited to 92.1% at the same concentration [55]. These results indicate that C 19 -DAs could also offer new antioxidant agents, selecting substances with lower toxicity in this group.

Cytotoxic Activity
Various 'DAs' anticancer activities have been widely studied from different parts of Aconitum, Consolida, and Delphinium in the last decade [148]. The most effective natural DAs with anticancer properties in Aconitum were C 19 -DAs and some derivatives of C 20 -DAs. SAR analysis showed that DA activity increased in correspondence with simple structural modification of these compounds, but their anticancer mechanisms need further studies.
SAR of antitumor DAs indicates that the number and position of the hydroxyl and ester groups in C 19 -DAs may play an essential role in cytotoxicity, especially substitutions in C1, C3, C6, and C8 [50,53,92,105,144,148,152,153].

Conclusions
Over the past decade, more than 300 DAs were discovered and extracted from plants, particularly Aconitum, Delphinium, and Consolida genera.
Structurally, DAs derived from four isoprenyl 'units' condensation subdivide into more than 45 classes based on their central structure arrangement and different substituent. These compounds display a broad area of pleasant chemical properties and biological activity, such as analgesic, anti-inflammatory, antimicrobial, cytotoxic activity, and toxic effects. Their toxic effect is manifested in the nervous and cardiovascular systems, acting as potent neurotoxins and cardiotoxins. The toxicity of C 18 -DAs and C 19 -DAs groups has justified their development into new therapeutic drugs, except glycosidic DAs, which have additional sugar moieties in their structures that facilitate their water solubility unlike the other DA groups. This observation gives future hope to discovering new chemical compounds with low toxicity and useful bio-activity in the aqueous extracts of alkaloids with SAR similar to C 19 -DAs. The complex nature of the diterpenoid-alkaloids' SAR suggests the need for an accurate knowledge of individual compound properties to discover further safe and valuable applications of novel bioactive compounds.
The 'researchers' competition, turned to deeper study of C 20 -DAs after a SAR analysis, displayed their chemical structure diversity and their little toxicity compared to C 19 -DAs. In addition, their classification into seven groups with different SARs facilitates the search for biologically active molecules and potential new drugs.
Many research efforts, oriented to studying the anti-inflammatory, analgesic, and anticancer activity of DAs, highlighted that numerous C 19 -DAs and C 20 -DAs have noticeable effectiveness. The C 20 -hetisine class showed the highest possibilities with the lowest toxicity among the other DAs. For this reason, the hetisine compounds may be good starters for developing novel anticancer drugs using alkaloids. Institutional Review Board Statement: Ethical review and approval were waived for this review, which does not report new experimental results obtained by authors but contains a summary of already published data.