Securinega alkaloids have attracted immense attention from the phytochemical, synthetic, and pharmacological communities owing to their structural diversity and intriguing biological activities. Predominantly found in the genera Flueggea, Phyllanthus, Margaritaria, and Zygogynum, these alkaloids display a remarkable range of molecular architectures derived from the monomeric tetracyclic core consisting of the α,β-γ,δ-unsaturated ester moiety and the tertiary alkyl amine group. Their biosynthetic elaboration through oxidation, rearrangement, and oligomerization gives rise to an extraordinary chemical diversity spanning monomeric, dimeric, trimeric, and even higher oligomeric forms with varying oxidation states. This chapter provides a comprehensive overview of the isolation and structure elucidation of securinega alkaloids and recent (2014-2025) discoveries related to their biosynthesis, chemical synthesis, and biological evaluations. Particular emphasis is placed on recent discoveries, including the synthesis of oxidized, rearranged, and dimerized congeners, and newly uncovered biosynthetic enzymes that illuminate the molecular logic underlying scaffold assembly. The chapter also summarizes emerging insights into their pharmacological properties, including cytotoxic, neurotropic, and anti-inflammatory activities. Collectively, these advances not only clarify the intricate biogenetic origins and chemical synthesis of the securinega family but also establish a foundation for future exploration of their chemical biology and potential therapeutic applications.
Marine natural products have attracted considerable attention owing to their diverse biological activities and unique structural features. Among them, the dragmacidin alkaloids represent a structurally intriguing family of marine-derived natural products. These alkaloids exhibit a wide range of biological activities, including anticancer and antimicrobial activities, which have stimulated significant interest from both the chemical and biological communities. Structurally, they are characterized by highly functionalized bisindole frameworks in which two indole units are connected via a piperazine, pyrazine, or pyrazinone ring, and can be classified into three categories based on the nature of the linking unit: (i) dragmacidin and dragmacidins A, B, C, I, J, and didebromodragmacidin, featuring a piperazine linker; (ii) dragmacidins D, E, and F, containing a pyrazinone linker; and (iii) dragmacidins G and H, incorporating a pyrazine linker. These structural features pose formidable challenges for chemical synthesis, and consequently, the dragmacidin family has served as an important platform for the development of new synthetic strategies. In this chapter, we provide a comprehensive overview of the dragmacidin alkaloids, focusing on their isolation, structural features, biological activities, and synthetic studies.
Natural products containing five-membered nitrogen heterocycles, such as imidazole, oxazole, and thiazole rings, belong to a significant class of naturally occurring heterocyclic alkaloids. These are widely distributed in terrestrial plants, animals, marine invertebrates, and microorganisms. The complexity and diversity of the molecular architectures, as well as the inherently promising biological activities, endow these alkaloids with ideal targets of chemical synthesis and potent application in the discovery of new drugs. In this review, the latest research on the occurrence, isolation, structural characterization, biological activity, chemical synthesis, and state-of-the-art synthetic biology of these imidazole-, oxazole-, and thiazole-containing natural products was summarized. All alkaloids were classified into the corresponding subgroups according to common structural features or biological origins, with a view to convenience and rationality.
Marine organisms are a valuable source of lead compounds for drug development, and basic research. This field has been active for nearly half a century. However, because of their unique structures and poor chemical stability, it is difficult to achieve a sustainable, large-scale supply of marine natural products and thus, their use in drug development is rare. Renieramycin was first reported in 1982 by Fricke and Faulkner as a trace secondary metabolite from the blue sponge Reniera sp. Dimeric 1,2,3,4-tetrahydroisoquinoline derivatives, such as renieramycins, have attracted attention as novel anticancer agents. Therefore, challenges related to chemical stability and transformations, as well as development of total syntheses were overcome. Several excellent reviews on renieramycin marine natural products have been published. Research in the renieramycin family has been developed based on the results of various previous studies on saframycin, an antibiotic discovered from the Actinomycete Streptomyces lavendulae No. 314. In this review, we will introduce from a new perspective the results of ongoing efforts in the medicinal chemistry. We will explore the discovery, chemical transformation, total synthesis, and structure-activity relationships of renieramycin marine natural products, highlighting unexpected findings that emerged during the research process.1.
The pyrazole and indazole alkaloids include two different but related groups of naturally occurring substances with interesting structural variations and their biological properties are obtained from the secondary metabolites. In the present book chapter we describe the chemistry and biology of these alkaloids, including their biosynthetic pathway, isolation, structural properties, and variety of biological effects. An overview of the separation and structural elucidation of pyrazole and indazole alkaloids from several natural sources is presented at the beginning, demonstrating the diversity of these molecules across the kingdoms of plants. We also look at synthetic approaches to these structures. The main focus is on the biological activities of pyrazole and indazole alkaloids, which include pharmacological activities such as antibacterial, anti-inflammatory, and anticancer properties. A thorough review of the relevant literature is presented, providing insight into the essential structural motifs that govern their interactions with biological targets. In addition, the possible medicinal uses of these alkaloids are examined, highlighting their importance in the search for new drugs. Thus, the present chapter provides a comprehensive analysis of pyrazole and indazole alkaloids with an emphasis on their chemical structures and biological activities. It serves as a valuable resource for professionals in pharmacology and drug development, offering insights into the potential therapeutic applications of these compounds. By describing the intricate relationship between the chemistry and biology of these alkaloids, the chapter contributes to the field of natural product chemistry and to the discovery and synthesis of new drugs and treatments. This synthesis of current knowledge furthers scientific understanding and underscores the importance of alkaloids in medical research and pharmaceutical innovation.
Natural products containing the hydroxylamine group are discussed. These include acyclic hydroxylamines, isoxazolidines, 1,2-oxazines, diketopiperazines, endocyclic hydroxylamines with larger ring sizes, N-hydroxy and N-methoxypyrroles, -indoles, -carbazoles and -carbolines, pyridones, other rings with an exocyclic hydroxylamine, O-acylhydroxylamines and compounds that may be regarded as unprecedented or having little precedent. Isolation, characterization, biosynthesis and synthesis are covered.
Indolactam alkaloids are a family of aromatic toxins produced by various actinobacteria and the cyanobacterium, Moorena producens. The best characterized examples include the teleocidins, lyngbyatoxins, olivoretins, blastmycetins, and pendolmycins, which share a nine-membered lactam core, comprised from l-tryptophanol and l-valine. Contact with indolactam alkaloids has been linked to severe dermatitis (swimmers itch), while accidental ingestion may lead to illness and fatalities. Indolactam alkaloids are also potent tumor promotors, due to their activation of protein kinase C isozymes. This chapter reviews the current literature on indolactam alkaloids, from their discovery in the early 1960s up to 2024. Topics covered include the isolation, structural elucidation, biosynthesis, bioactivity, and total synthesis of the indolactam alkaloid core.
The sarpagine-ajmaline type monoterpenoid indole alkaloids are among the most important groups of natural alkaloids, and the complex polycyclic and cage-like architectures present significant synthetic challenges. Because of their characteristic indole-fused azabicyclo[3.3.1]nonane structures and prominent biological activities, sarpagine-ajmaline related alkaloids have captured the attention of organic synthetic chemists for decades. In this chapter, the strategies employed in the synthesis of sarpagine-ajmaline related alkaloids are outlined, and the synthetic progress during the period of 2019-2023 is provided in detail. To provide potential targets for future synthetic endeavors, some sarpagine/ajmaline type alkaloids isolated in recent years with novel structures and biological activities are also summarized.
Naphthylisoquinoline alkaloids are a fascinating class of natural biaryl compounds. They show characteristic mono- and dimeric scaffolds, with chiral axes and stereogenic centers. Since the appearance of the last comprehensive overview on these secondary plant metabolites in this series in 1995, the number of discovered representatives has tremendously increased to more than 280 examples known today. Many novel-type compounds have meanwhile been discovered, among them naphthylisoquinoline-related follow-up products like e.g., the first seco-type (i.e., ring-opened) and ring-contracted analogues. As highlighted in this review, the knowledge on the broad structural chemodiversity of naphthylisoquinoline alkaloids has been decisively driven forward by extensive phytochemical studies on the metabolite pattern of Ancistrocladus abbreviatus from Coastal West Africa, which is a particularly "creative" plant. These investigations furnished a considerable number of more than 80-mostly new-natural products from this single species, with promising antiplasmodial activities and with pronounced cytotoxic effects against human leukemia, pancreatic, cervical, and breast cancer cells. Another unique feature of naphthylisoquinoline alkaloids is their unprecedented biosynthetic origin from polyketidic precursors and not, as usual for isoquinoline alkaloids, from aromatic amino acids-a striking example of biosynthetic convergence in nature. Furthermore, remarkable botanical results are presented on the natural producers of naphthylisoquinoline alkaloids, the paleotropical Dioncophyllaceae and Ancistrocladaceae lianas, including first investigations on the chemoecological role of these plant metabolites and their storage and accumulation in particular plant organs.
Morphinan alkaloids have attracted constant attention since the isolation of morphine by Sertürner in 1805. However, a group of 45 compounds possessing a complete ent-morphinan backbone can also be found in the literature. These compounds are related to the morphinandienone subgroup and display a substitution pattern which is different from the morphinans. In particular, these alkaloids could be substituted at position C-2 and C-8 either by a hydroxy function or a methoxy moiety. Four groups of ent-morphinan alkaloids can be proposed, the salutaridine, pallidine, cephasugine and erromangine series. Interestingly, the botanical distribution of the ent-morphinans is more widespread than for the morphinans and includes the Annonaceae, Berberidaceae, Euphorbiaceae, Fumariaceae, Hernandiaceae, Lauraceae, Menispermaceae, Monimiaceae, Papaveraceae, and Ranunculaceae families. To date, their exact mode of production remains elusive and their interplay with the biosynthetic pathway of other classes of benzyltetrahydroisoquinoline alkaloids, in particular aporphines, should be confirmed. Exploration of the biological and therapeutic potential of these compounds is limited to some areas, namely central nervous system (CNS), inflammation, cancer, malaria and viruses. Further studies should be conducted to identify the cellular/molecular targets in view of promoting these compounds as new scaffolds in medicinal chemistry.
Quinolizidine alkaloids isolated from various marine and terrestrial animals and plants are primarily composed of lupinine-, matrine-, and sparteine-type alkaloids. Matrine, phenanthroquinolizidines, bis-quinolizidines, and small molecules from amphibian skins are representative compounds of such alkaloids. Quinolizidine alkaloids harbor anticancer, antibacterial, antiinflammatory, antifibrosis, antiviral, and anti-arrhythmia. In this chapter, we comprehensively outline the biological activity and pharmacological action of quinolizidine alkaloids and discuss new avenues toward the discovery of novel and more efficient drugs based on these naturally occurring compounds. It is urgent for basic research and clinical practice to conduct more targeted comprehensive research based on the lead drugs of quinolizidine alkaloids with significant pharmacological activity.
The families of pyridoacridine, pyridoacridone, and pyrroloacridine alkaloids are fascinating classes of natural products that have attracted the attention of chemists for over 80 years. Since the first purification of a brightly colored molecule isolated from the sea anemone Calliactis parasitica in 1940, over 110 examples of these alkaloids have been reported from marine organisms. While the paucity of numbers of protons relative to carbons and nitrogens in these molecules presents challenges in structure solution, the chemist is rewarded by their bright pigmented colors and typically diverse biological activities. In the past, several authors have proposed biosynthetic relationships within the pyridoacridine family of alkaloids, formulating a family tree derived from the reaction of dopaminequinone and kynuramine to tie together over 75 alkaloids. Inclusion of two additional quinones, and one homologous diamine, building blocks, for which there is biomimetic synthesis support, is suggestive of a more expansive connected biogenesis that encompasses not only pyridoacridines, but also pyridoacridone, and pyrroloacridine alkaloids. This review covers the isolation, structure elucidation, and proposed biosynthesis and biogenesis of pyridoacridine, pyridoacridone and pyrroloacridine marine alkaloids published to the end of 2022. Biomimetic or bio-inspired syntheses of the compound classes are described and new biological activities reported since 2004 are updated.
The 2,5-diketopiperazine (DKP) motif is present in many biologically relevant, complex natural products. The cyclodipeptide substructure offers structural rigidity and stability to proteolysis that makes these compounds promising candidates for medical applications. Due to their fascinating molecular architecture, synthetic organic chemists have focused significant effort on the total synthesis of these compounds. This review covers many such efforts on the total synthesis of DKP containing complex alkaloid natural products.
This study involves aporphine alkaloids identified through 13C Nuclear Magnetic Resonance (NMR) spectroscopic data. For the present publication, articles were selected from several databases on aporphine alkaloids from 1994 to 2021. In this class, more than 700 compounds have been registered, with 221 were included in this section, among which 122 were characterized for the first time in the investigated period. The study also addresses their biosynthetic pathways, classifying substances according to their structural characteristics based on established literature. Furthermore, pharmacological activities related to the aporphine alkaloids highlighted in this section are also presented, giving an overview of the various applications of these compounds.
Quinoline and quinazoline alkaloids, two important classes of N-based heterocyclic compounds, have attracted scientific and popular interest worldwide since the 19th century. More than 600 compounds have been isolated from nature to date. To build on our two prior reviews, we reexamined the promising molecules described in previous reports and provided updated literature on novel quinoline and quinazoline alkaloids isolated over the past 5 years. This chapter reviews and discusses 205 molecules with a broad range of bioactivities, including antiparasitic and insecticidal, antibacterial and antifungal, cardioprotective, antiviral, anti-inflammatory, and other effects. This survey should provide new clues or possibilities for the discovery of new and better drugs from the original naturally occurring quinoline and quinazoline alkaloids.
The diterpenoid alkaloids are a family of extremely important natural products that have long been a research hotspot due to their myriad of intricate structures and diverse biological properties. This chapter systematically summarizes the past 11 years (2009-2019) of studies on the diterpenoid alkaloids, including the "so-called" atypical ones, covering the classification and biogenetic relationships, phytochemistry together with 444 new alkaloids covering 32 novel skeletons and the corrected structures, chemical reactions including conversion toward toxoids, synthetic studies, as well as biological activities. It should be noted that the synthetic studies, especially the total syntheses of various diterpenoid alkaloids, are for the first time reviewed in this treatise. This chapter, in combination with our four previous reviews in volumes 42, 59, 67, and 69, will present to the readers a more completed and updated profile of the diterpenoid alkaloids.
This review deals with the synthesis of naturally occurring alkaloids containing partially or completely saturated pyrimidine nuclei. The interest in these compounds is associated with their structural diversity, high biological activity and toxicity. The review is divided into four parts, each of which describes a number of synthetic methodologies toward structurally different naturally occurring alkaloids containing saturated cyclic six-membered amidine, guanidine, aminal and urea (thiourea) moieties, respectively. The development of various synthetic strategies for the preparation of these compounds has remarkably increased during the past few decades. This is primarily due to the fact that some of these compounds are isolated only in limited quantities, which makes it practically impossible to study their full structural characteristics and biological activity.
This chapter provides a short overview of the history of morphine since it's isolation by Sertürner in 1805. The biosynthesis of the title alkaloid as well as all total and formal syntheses of morphine and codeine published after 1996 are discussed in detail. The last section of this chapter provides a detailed overview of medicinally relevant derivatives of the title alkaloid.
