Current Topics in Medicinal Chemistry - Volume 14, Issue 2, 2014

Phenanthroindolizidine alkaloids are a well-known class of compounds due to their interesting biological activities, especially anticancer ones. Represented by more than 60 substances, they are mainly isolated from plants of the Moraceae and Asclepiadaceae families. In the last 30 years, a great effort has been made aiming the synthesis of these compounds and analogues to be applied in medicinal chemistry.

Introduction: alkaloids are a group of naturally occurring chemical compounds that contain mostly basic nitrogen atoms. In particular berberine is a quaternary ammonium salt from the protoberberine group of isoquinoline alkaloids with anti-lipogenic and hypoglycemic effects. On the other hand, mate plant has reported to have high antioxidant potential, including an inhibitory ability against plasma and LDL oxidation. Areas covered: Most of the studies reported in literature about alkaloids are pre-clinical trials, and we have already discussed them in a previous review we conducted. This time we want to focus our attention on clinical studies about berberine, and mate plant, so the aim of this review is to evaluate berberine and mate plant efficacy and safety in humans. Conclusion: Berberine is a potent oral hypoglycemic agent with a good effect on lipid metabolism. It is safe and the cost of treatment is very low. Also mate plant seems to have antioxidant and hypolipidemic actions, even if further studies are necessary.

An intensive research effort during the last 25 years has generated an impressive number of alkaloids isolated from marine ascidians, which remain unique among marine invertebrates in that they overwhelmingly produce this kind of metabolites. The present review is focused on some major groups of ascidians’ bioactive alkaloids, useful as lead structures in the search and development of new drugs or as biological probes for physiological investigation. They include the lamellarins, the ecteinascidins, bis-steroidal pyrazines and pyridoacridines. Their often extraordinary structures and significant biological activities are illustrated, reported syntheses are outlined, and structure/activity relationships are discussed where sufficient data are available to draw such conclusions. Recent discoveries concerning the current state of potential and /or development of some of them as new drugs as well as the current knowledge regarding their modes of action are also summarized.

Organocatalysis and cooperative catalysis are fast growing research areas. In these fields, cinchona alkaloids and their derivatives play a major role. The ready availability of both pseudo-enantiomeric pairs from natural sources makes them outstanding catalysts for reactions including oxidation, alkylation, cycloaddition, and carbene insertion. This short review focuses on recent achievements in the field of asymmetric carbon-nitrogen atom bond formation reactions using cinchona alkaloids and their derivatives.

Research into novel therapeutic strategies for schizophrenia with high efficacy and low side effects has been progressed in recent years. In the present study, anti-schizophrenia activities of 2-(dimethylamino)- and 2-(methylamino)- 7H-naphtho[1,2,3-de]quinolin-7-one derivatives (D1-D10) have been evaluated in ketamine-induced experimental schizophrenia model in mice. For this aim, experimental animals was submitted to ketamine intraperitoneal injection at 100 mg/kg/day. Then, D1-D10 were administrated intra-cerebroventricularly to mice and in next step, animals depressive-like behaviors have been examined by despair swimming test. The obtained results demonstrate that 7H-naphtho[1,2,3- de]quinolin-7-one derivatives, specifically D9, reduced depressive-like behaviors via the decrease of the immobility time and the increase of the swim and climb times. Overall, these results showed that these alkaloids have anti-schizophrenia efficacy and due to their low side effects, they can be used as a new strategy for the treatment of depressive symptoms of schizophrenia patients.

In this study we evaluate the in vivo antidepressant effect of a natural phenolic compound, trans-resveratrol, and a synthetic derivative from Menispermum dauricum DC (Menispermaceae) 5-methoxy-7H-dibenzo[de,h]quinolin-7- one known as 5-methoxyoxoisoaporphine (OXO 4). The antidepressant-like effect of trans-resveratrol and OXO 4 were evaluated through a Forced Swimming Test (FST), and they were compared with reference antidepressants: imipramine, desipramine, nomifensine, bupropion, nisoxetine, citalopram and moclobemide. Trans-resveratrol (10 mg/kg, intraperitoneally i.p. significantly decreased the immobility time in mouse model of despair test (69.03 ± 8.74 sec) p<0.05, as well as OXO 4 (1mg/kg, i.p. (60.92 ± 11.37 sec); p<0.05. We also evaluate the OXO 4 at 15, 30 and 45 min. affording the mayor reduction at 30 minutes after the administration. Thus, our results suggest that OXO 4 has a great antidepressant effect non-reported for this type of isoquinoline alkaloids. The pharmaceutical use of OXO 4 in the treatment of depressive disorders is a therapeutic alternative to be studied.

Alkaloid molecules can act, depending on a type of amine functionality present in alkalods, as either hydrogenacceptor or hydrogen-donor for hydrogen bonding that is critically important for the interaction (binding) between targets (enzymes, proteins and receptors) and drugs (ligands). Because of this unique property, alkaloid scaffolds are therefore present in several drugs and lead compounds. This review highlights alkaloid scaffolds in drugs, particularly those recently approved in 2012; it also covers the scaffolds in leads and drug candidates which are in clinical trials and preclinical pipeline. The review focuses on three therapeutic areas including treatments of cancer, tuberculosis, and tobacco cessation. Alkaloid scaffolds in drugs and leads are inspired by those of naturally occurring alkaloids, and these scaffolds include pyridine, piperidine, quinoline, quinolinone, quinazoline, isoquinoline, indole, indolinone, isoindole, isoxazole, imidazole, indazole, thiazole, pyrazole, oxazolidinone, oxadiazole, and benzazepine. In addition to medicinal chemistry aspects, natural products possessing an individual alkaloid scaffold, as well as the mechanism of action of drugs and leads, are also discussed in this review.

Marine organisms have been found to be a very rich source of bioactive molecules. Among marine organisms, sponges have been proven to be excellent producers of secondary metabolites. More than 5,300 compounds have been isolated from sponges with around 200 new molecules reported each year. Bromopyrrole alkaloids constitute a family of exclusively marine alkaloids and represent a fascinating example of the large variety of compounds formed by marine sponges which exhibit different biological activities such as antifeedent, anti-biofilm, anticancer, antiinflammatory, antimicrobial, immunomodulatory, analgesic, antiserotonergic, antiangiogenic, antihistaminic, chitinase inhibitor and actimyosin ATPase activator. More than 140 derivatives with different structures and biological activities, have been isolated from more than 20 different sponges. Most of these alkaloids share a key building block, pyrrole-imidazole with oroidin being their underlying structural motif. In this review detailed account of isolation and medicinal application of marine bromopyrrole alkaloids and their synthetic derivatives are discussed.

The subject of chemosystematics has provided insight to both botanical classification and drug development. However, degrees of subjectivity in botanical classifications and limited understanding of the evolution of chemical characters and their biosynthetic pathways has often hampered such studies. In this review an approach of taking phylogenetic classification into account in evaluating colchicine and related phenethylisoquinoline alkaloids from the family Colchicaceae will be applied. Following on the trends of utilizing evolutionary reasoning in inferring mechanisms in eg. drug resistance in cancer and infections, this will exemplify how thinking about evolution can influence selection of plant material in drug lead discovery, and how knowledge about phylogenetic relationships may be used to evaluate predicted biosynthetic pathways.