https://pubs.rsc.org/en/content/articlepdf/2019/NP/C8NP00092A

Marine natural products.

The marine environment has been explored in the search for new bioactive compounds over the last 50 years, becoming a highly important and rich source of potent molecules and drug leads reported to possess a wide scope of activities. Alkaloids constitute one of the largest classes of natural products and are synthesized by terrestrial and marine organisms on all evolutionary levels. Alkaloids are usually present in an organism as a mixture consisting of several major and a few minor compounds of the same biosynthetic origin and differing only in functional groups. This group of compounds has apparently evolved as a defense mechanism against predators and as a result alkaloids are often highly potent and toxic molecules.1 Marine invertebrates have proven to be an outstanding source of active molecules, one of the most promising being indole alkaloids. Although many of these marine alkaloids closely resemble the endogenous amines (serotonin, dopamine or histamine), their potential affinity to various neurological targets and consequential impact on animal behavior is virtually unexplored.

Indole alkaloids, their activity, synthesis and potential use in medicine have been already reviewed in several articles.2 In this review we provide information on current and potential pharmaceuticals including small molecule natural indole alkaloids, their biological properties, structure-activity relationship studies, and especially their potential for the treatment of neurological disorders.

1.1. The indole moiety in drugs
The indole moiety is present in a number of drugs currently on the market. Most of these belong to triptans which are used mainly in the treatment of migraine headaches (Fig. 1). All members of this group are agonists of migraine associated 5HT1B and 5HT1D serotonin receptors. Sumatriptan (Imitrex) was developed by Glaxo for the treatment of migraines and introduced into the market as the first member of the triptan family.3 Relative to the second generation triptans, sumatriptan has lower oral bioavailability and a shorter half-life. Frovatriptan (FROVA®) was developed by Vernalis for the treatment of menstruation associated headaches. Frovatriptan's affinity for migraine specific serotonin receptors 5HT1B is believed to be the highest among all triptans.4 In addition, frovatriptan binds to 5HT1D and 5HT7 receptor subtypes.5 Zolmitriptan marketed by AstraZeneca is used to treat acute migraine attacks and cluster headaches. GlaxoSmithKline's naratriptan (Amerge) is also used in the treatment of migraines and some of its side effects include dizziness, tiredness, tingling of the hands and feet and dry mouth. All available triptans are well tolerated and effective.6 The highest incidence of central nervous system (CNS) related side effects (dizziness, drowsiness) was reported for zolmitriptan (5 mg), rizatriptan (10 mg) and eletriptan (40 mg, 80 mg).7 The differences in side-effect profiles for triptans are not likely caused by their different affinity towards serotonin receptors or other neurological receptors in the CNS. There is a positive correlation between the lipophilicity coefficient and CNS side effects; these undesired effects are also dose-dependent.



Figure 1

Currently available drugs from the triptan group.




1.2. Serotonin receptors – possible targets for neurologically active marine indole alkaloids
Given that depression affects approximately 18 million Americans annually,8 it is crucial to develop new effective treatments for this disorder. Intensive studies are being conducted in the area of new targets for antidepressant drugs,9,10 but most antidepressant drugs still target the neurotransmitter systems, mainly serotonin, dopamine and noradrenaline.

Serotonin is one of the neurotransmitters present in the central and peripheral nervous system which plays an important role in normal brain function and regulates sleep, mood, appetite, sexual function, memory, anxiety and many others.11 Serotonin exerts its effects through seven families of receptors (5-HT1 – 5-HT7) further divided into several subclasses. Except for 5-HT3 receptor which is a ligand-gated ion channel, the serotonin receptors belong to the G-protein coupled receptor family. Due to a lack of selective ligands, there is still little known about several 5-HT receptor subclasses.12 Marine monoindole alkaloids, sharing structure similarities with serotonin, are certain to become useful tools to facilitate the understanding of serotonin receptor function and generate new drug leads for the treatment of depression, anxiety, migraines and other 5HT receptor related disorders.

/pdf/marine-indole-alkaloids-potential-new-drug-leads-for-the-g3w1waljf7.pdf

Marine indole alkaloids: potential new drug leads for the control of depression and anxiety

This Resource Is a peer-reviewed article by Gobi et al. published in the 2005-12-13 issue of the Proceedings of the National Academy of Sciences. The authors show, quoting from the Abstract: '[how] URB597, a selective inhibitor of the enzyme fatty-acid amide hydrolase, which catalyzes the intracellular hydrolysis of the endocannabinoid anandamide, exerts potent antidepressant-like effects in the mouse tail-suspension test and the rat forced-swim test... These actions are prevented by the CB1 antagonist rimonabant, are accompanied by increased brain anandamide levels... The findings support a role for anandamide in mood regulation and point to fatty-acid amide hydrolase as a previously uncharacterized target for antidepressant drugs.'

Antidepressant-Like Activity and Modulation of Brain Monoaminergic Transmission by Blockade of Anandamide Hydrolysis

The marine environment represents a relatively untapped source of functional ingredients that can be applied to various aspects of food processing, storage, and fortification. Moreover, numerous marine-based compounds have been identified as having diverse biological activities, with some reported to interfere with the pathogenesis of diseases. Bioactive peptides isolated from fish protein hydrolysates as well as algal fucans, galactans and alginates have been shown to possess anticoagulant, anticancer and hypocholesterolemic activities. Additionally, fish oils and marine bacteria are excellent sources of omega-3 fatty acids, while crustaceans and seaweeds contain powerful antioxidants such as carotenoids and phenolic compounds. On the basis of their bioactive properties, this review focuses on the potential use of marine-derived compounds as functional food ingredients for health maintenance and the prevention of chronic diseases.

https://www.mdpi.com/1660-3397/9/6/1056/pdf

Marine Bioactives as Functional Food Ingredients: Potential to Reduce the Incidence of Chronic Diseases

Cannabidiol: State of the art and new challenges for therapeutic applications

The antidepressant action of cannabis as well as the interaction between antidepressants and the endocannabinoid system has been reported. This study was conducted to assess the antidepressant-like activity of Δ9-THC and other cannabinoids. Cannabinoids were initially evaluated in the mouse tetrad assay to determine doses that do not induce hypothermia or catalepsy. The automated mouse forced swim (FST) and tail suspension (TST) tests were used to determine antidepressant action. At doses lacking hypothermic and cataleptic effects (1.25, 2.5, and 5 mg/kg, i.p.), both Δ9-THC and Δ8-THC showed a U-shaped dose response with only Δ9-THC showing significant antidepressant-like effects at 2.5 mg/kg (p < 0.05) in the FST. The cannabinoids cannabigerol (CBG) and cannabinol (CBN) did not produce antidepressant-like actions up to 80 mg/kg in the mouse FST, while cannabichromene (CBC) and cannabidiol (CBD) exhibited significant effect at 20 and 200 mg/kg, respectively (p < 0.01). The antidepressant-like action of Δ9-THC and CBC was further confirmed in the TST. Δ9 -THC exhibited the same U-shaped dose response with significant antidepressant-like action at 2.5 mg/kg (p < 0.05) while CBC resulted in a significant dose dependent decrease in immobility at 40 and 80 mg/kg doses (p < 0.01). Results of this study show that Δ9-THC and other cannabinoids exert antidepressant-like actions, and thus may contribute to the overall mood-elevating properties of cannabis.

Antidepressant-like effect of Δ9-tetrahydrocannabinol and other cannabinoids isolated from Cannabis sativa L.

Aaptamine (1; Figure 1) is commonly isolated in large yields from various species of the marine sponge genus Aaptos (Order Hadromerida: Family Suberitidae)a, along with a handful of related compounds such as isoaaptamine (2) which contain the benzonapthyridine core structure (1–7). The isolation of aaptamine from the taxonomically unrelated species Luffariella (Order Dictyoceratida: Family Thorectidae) (3), Hymeniacidon (Order Halichondrida: Family Halichondriidae) (6), and Xestospongia (7) (Order Haplosclerida: Family Petrosiidae)b, indicates the likelihood of production of aaptamine from a microbial source. In fact, several novel metabolites containing the aaptamine core have come from one particular sponge (7), underlining likely contributions of the microbial community associated with the producer of aaptamine. A number of total synthetic studies have been published along with a limited collection of semi-synthetic derivatives since its original discovery (8–16). Considering its low molecular weight, aaptamine is relatively difficult to synthesize from available starting materials. Attempts to complete the unique fused tricycle have been made through quinoline and isoquinoline precursors, the best overall yield being 13 percent over 14 steps. Although the synthetic yield is low, it is likely to be the more cost efficient choice for the production of aaptamine, unless a microbial producer is found.



Figure 1

Structures of major aaptamine related marine natural products.



The proposed biogenesis of aaptamine suggests a possible Pictet-Spengler type condensation commonly attributed to many other natural alkaloids (16). Likewise, three common pharmacophores can be recognized in the aaptamine scaffold: isoquinoline, the largest class of alkaloids isolated from medicinal plants; dopamine, a compound affecting the central nervous system and behavior; and finally, quinoline, known primarily for its anti-malarial properties.

Aaptamine's potential for drug development is further evidenced by the actual results of a highly diverse group of molecular targets already evaluated. In addition to antiviral (5,17) and anticancer (4,6,18) activities, the aaptamines have a strong in vitro radical scavenging capacity (19) and have been shown to block α-adrenoceptor action (1) as well as inhibit α-1,3-glucanase (20) and monoamine oxidase (21). Still, compounds which are active against a variety of targets are certain to encounter problems with indiscriminant toxicities. It is important to recognize toxicity as a hurdle for the development of aaptamine as a useful drug but not let it prohibit the evaluation of its derivatives for therapeutic potential. The ‘privileged structures’ approach (22) is dependent on exploiting a scaffold's common mechanism of drug-target interaction for multiple targets. In a similar fashion, a key for the development of the aaptamine scaffold is the identification of its common mechanism of drug-target interaction.

Although it is difficult to determine if broad-spectrum DNA-interaction is a compound's definitive mechanism of cytotoxicity, it is clear that DNA interaction has a measurable influence on the mechanism. Small molecules that bind to DNA do not necessarily interact in the same way, in fact, there are several modes by which a ligand can bind and affect the structure and function of this substrate (23). Of these modes, intercalation is most prevalent with planar polycyclic aromatic systems like the aaptamines which insert between adjacent base-pairs of intact DNA, depending primarily on p-bond interactions and sometimes stacking several molecules together in the same area between base pairs.

The quinoline portion found in aaptamine's tri-cyclic core has already been the focus of SAR studies with derivatives of acridine (24), a structure that resembles aaptamine and is a well studied anti-cancer pharmacophore that intercalates DNA. The observed DNA binding activity of aaptamine may serve to explain some aspects of the compound's mechanism of activity against whole cell and viral pathogens.

Considering the high availability of the natural material and the remarkably broad activity displayed, this heterocyclic small molecule has excellent potential as a scaffold from which numerous derivatives can be made in an attempt to improve selectivity and pharmacokinetics.

Based on the synthetic work already published by Shen et al. (18), Hibino et al. (12), Pettit et al. (25,26) and Gul et al. (27) a preliminary SAR has been developed for the aaptamine scaffold in regard to cytotoxicity, antiviral and antimicrobial activity. Table 1 summarizes what has been learned of this relationship from the synthetic and natural derivatives of aaptamine.



Table 1

Summary of reported relative structure activity relationships for aaptamine based on general improvements of either potency or selectivity



Utilizing the information from this SAR, a semi-synthetic series of N-alkyl aaptamine derivatives was produced to complement previously published N-alkylation efforts that improved activity, and to investigate the effects of increasing the lipophilic character of the pharmacophore. In addition, it was proposed that selective demethylation of the C-9 hydroxyl would significantly increase the potency of the first generation N-alkyl derivatives. Our speculation was based on the evidence wherein 2 consistently demonstrated higher potency than 1 in a variety of biological assays; likewise the selective demethylation of the aaptamine derivatives would produce isoaaptamine analogs with higher potency. Two smaller groups of analogs were specifically produced to investigate the effect of dimerization on biological activity and the pro-drug behavior of sulfonyl esters relative to those previously studied.

/pdf/antiviral-and-anticancer-optimization-studies-of-the-dna-33dbrvu8pq.pdf

Antiviral and Anticancer Optimization Studies of the DNA-binding Marine Natural Product Aaptamine

The marine environment is a valuable resource for drug discovery due to its diversity of life and associated secondary metabolites. However, there is very little published data on the potential application of marine natural products to treat neuropsychiatric disorders. Many natural products derived from chemically defended organisms in the marine environment have pharmacophores related to serotonin or clinically utilized antidepressant drugs. Therefore, in the present study, compounds selected for their structural similarity to serotonin or established antidepressants were evaluated for antidepressant-like activity using the forced swim and tail suspension tests in mice. The antidepressant positive controls, citalopram (selective serotonin reuptake inhibitor) and despiramine (tricyclic antidepressant) both dose-dependently reduced immobility time in the forced swim and tail suspension tests. Two marine natural product compounds tested, aaptamine and 5,6-dibromo-N,N-dimethyltryptamine, also produced significant antidepressant-like activity in the forced swim test. In the tail suspension test, the antidepressant-like effects of 5,6-dibromo-N,N-dimethyltryptamine were confirmed, whereas aaptamine failed to produce significant results. None of the tested compounds induced hyperlocomotion, indicating that nonspecific stimulant effects could not account for the observed antidepressant-like actions of the compounds. These studies highlight the potential to rationally select marine derived compounds for treating depression and other neuropsychiatric disorders.

K. D. Ivey

Papers

Antidepressant-like effect of Δ9-tetrahydrocannabinol and other cannabinoids isolated from Cannabis sativa L.

Antiviral and Anticancer Optimization Studies of the DNA-binding Marine Natural Product Aaptamine

Identification of antidepressant drug leads through the evaluation of marine natural products with neuropsychiatric pharmacophores.