Current Topics in Medicinal Chemistry - Volume 13, Issue 17, 2013

A four-step approach for the synthesis of dihydroxylated piperidine, quinolizidine and indolizidine systems is described employing α,β-unsaturated diazoketones as versatile building blocks. Unsaturated diazoketones were readily prepared from a Horner-Wadsworth-Emmons reaction between a diazophosphonate and amino-aldehydes. The strategy employs an asymmetric dihydroxylation reaction as the key step and is simple and straightforward enough to be extended to other nitrogen heterocycles.

In order to overcome the significant side effects and the acquired resistance of platinum-based anticancer drugs, great efforts have been devoted to designing new platinum compounds or non-platinum transition metal anticancer complexes with improved pharmacological properties and a broader range of antitumor activity. Among them, the new complexes based on natural alkaloid and their derivatives provide a novel approach to potential (pro-)drugs. This review was mainly focused on the recent progresses of alkaloid-metal based anticancer agents, including metal complexes of natural or synthetic alkaloids, liriodenine, β-carboline, and quinolinoline as anticancer agents, their in vitro anticancer activities and primary action mechanism. Additionally, the future development of hybrid alkaloid and its derivatives metal complexes as anticancer drugs was discussed, which might hold a promise for overcoming multidrug resistance (MDR).

Aporphinoid alkaloids, which encompass a large number of complicated structures, are an important group of natural products. The anticancer activity of aporphinoid alkaloids has become a hot pharmaceutical research area in recent years. Recent studies on the anticancer activity of these compounds are reviewed. The structure activity relationships (SARs) and anticancer mechanisms of aporphinoid alkaloids, as well as simple aporphine, oxoaporphine, dehydroaporphine and dimeric aporphine, have been summarized. The presence of a 1,2-methylenedioxy group and methylation of nitrogen are key features to the cytotoxicity of aporphinoid alkaloids. Oxidation and dehydrogenation of C7 could improve the anticancer activity. The contributions of chirality of hydrogen at C6a and the substitution pattern of other positions about aporphinoid alkaloids for anticancer activity remain unknown. Induced cancer cells apoptosis, prevention of cell proliferation, DNA topoisomerase inhibition, reducing the drug-resistant cellular side population (SP) or cancer stem cells (CSCs) and inhibition of epidermal growth factor receptor (EGFR) tyrosine kinase seem to play important roles in the molecular mechanisms of anticancer activity about aporphinoid alkaloids.

In this study, antidepressant-like effects of intra-cerebroventricularly administration of oxoisoaporphine derivatives in post stroke-depressive like behavior were examined through despair swimming and tail suspension models. For this aim, acute ischemic stroke was induced by bilateral common carotid arteries occlusion which significantly changed the normal behaviors of male balb/c mice. We performed stroke-induced anhedonia test as a key result of post strokedepressive like behavior by determination of sucrose consumption. Results show that some 2,3-dihydro- and oxoisoaporphine derivatives modified the abnormality in the behaviors through decreasing in the immobility time in tail suspension and despair swimming models and increasing in the swimming and climbing times in despair swimming model. We concluded that these alkaloids showed antidepressant actions and therefore can be used for treatment of post strokedepressive like behavior in acute ischemic stroke patients.

High molecular diversity of natural products (NPs) can provide a solution for many serious medicinal conditions. Frequently attributed with strong and useful biological/pharmacological properties, NPs may be directly applied in therapy, or could serve as templates for future drugs. As pain is a major symptom in many illnesses, and can significantly interfere with a person's quality of life and general functioning, pain-killing potential is certainly among the most highly valued features of any newly discovered, potentially pharmacologically useful molecule. Inspired by the fact that some of the most famous and powerful analgesic/antinociceptive agents are natural (plant) alkaloids (e.g. codeine, morphine), or are derived from them (oxycodone), herein we have tried to systematize recent findings (accumulated during the last decade) on molecular structure, mechanism of antinociceptive/analgesic action and synthesis of pain-killing alkaloids. In other words, this review tries to find out whether it is possible to give a general answer to the following questions: Which (new) structures are active? How can we obtain them? What do they do to the organism? How do they do that (structureactivity relationship)? And what can we do to them to make them better (i.e. could they be used as potential leads for new antinociceptive drugs)?

A great number of alkaloids exhibit high potential in cancer research. Some of them are anticancer drugs with well-defined clinical uses, exerting their action on microtubules dynamics or DNA replication and topology. On the other hand, mitochondria have been recognized as an essential organelle in the establishment of tumor characteristics, especially the resistance to cell death, high proliferative capacity and adaptation to unfavorable cellular environment. Interestingly, many alkaloids exert their anticancer activities affecting selectively some functions of the tumor mitochondria by 1) modulating OXPHOS and ADP/ATP transport, 2) increasing ROS levels and mitochondrial potential dissipation by crosstalk between endoplasmic reticulum (ER) and mitochondria, 3) inducing mitochondria-dependent apoptosis and autophagy, 4) inhibiting mitochondrial metabolic pathways and 5) by alteration of the morphology and biogenesis of this organelle. These antecedents show the relevance of developing research about the effects of alkaloids on functions controlled by tumor mitochondria, offering an attractive target for the design of new alkaloid derivatives, considering organelle- specific delivery strategies. This review describes mitochondria as a central component in the anticancer action of a set of alkaloids, in a way to illustrate the importance of this organelle in medicinal chemistry.

Alkaloids are interesting groups of natural products with important biological properties, but naturally available alkaloids are insufficient for biological studies. Therefore, the demand for higher amounts of alkaloids made research community to synthesize alkaloids by innovative techniques. The importance of asymmetric reactions for scientific community to obtain enantiomerically pure compounds with good yield and diastereomeric excess (de) or enantiomeric excess (ee) by different strategies of asymmetric induction is emphasized in this review. In addition, importance have been given to discuss on biologically important alkaloids, their skeleton synthesis, intermediates and total synthesis with different strategies mainly based on chiral auxiliaries, chiral reagents and chiral metal ligand based catalysts.

Argemone mexicana L. (Papaveraceae), accumulates benzylisoquinoline alkaloids, (BIA) derived from tyrosine. Although it was originated in the western region of the USA-Mexico border, it has spread to tropical and subtropical areas around the world. Today, it is used to treat different ailments, given to its antimicrobial, antiparasitic, antimalarial, pesticide, cytotoxic and neurological properties. These effects are related to the presence of different types of BIA’s, such as benzophenanthridines (sanguinarine, chelerythrine), protoberberines (berberine) and protopines (protopine, allocryptopine). This review covers the historical medicinal uses of A. mexicana, as well as its current applications. The chemical bases of such effects are discussed in relation to the occurrence of the different types of alkaloids. The biochemical process involved in the synthesis of these types of alkaloids is also described.

Cyclopamine is a naturally occurring steroidal alkaloid that attenuates the Hedgehog signaling pathway by inhibiting the Smoothened receptor. The Hedgehog pathway plays an important role in many human cancers. Cyclopamine has served as a pivotal tool compound in elucidating the pharmacological effect of the Hedgehog signaling pathway, however, due to its poor solubility, stability, and moderate activity, its clinical development has been impeded. Significant efforts were made to overcome the shortcomings of cyclopamine, giving which results cultivated in the identification of IPI- 926, a derivative of cyclopamine, which proceeded to clinical trials.