Human nutritional relevance and suggested nutritional guidelines for vitamin A5/X and provitamin A5/X.

In the last century, vitamin A was identified that included the nutritional relevant vitamin A1 / provitamin A1, as well as the vitamin A2 pathway concept. Globally, nutritional guidelines have focused on vitamin A1 with simplified recommendations and calculations based solely on vitamin A. The vitamin A / provitamin A terminology described vitamin A with respect to acting as a precursor of 11-cis-retinal, the chromophore of the visual pigment, as well as retinoic acid(s), being ligand(s) of the nuclear hormone receptors retinoic acid receptors (RARs) α, ß and γ. All-trans-retinoic acid was conclusively shown to be the endogenous RAR ligand, while the concept of its isomer 9-cis-retinoic acid, being "the" endogenous ligand of the retinoid-X receptors (RXRs), remained inconclusive. Recently, 9-cis-13,14-dihydroretinoic acid was conclusively reported as an endogenous RXR ligand, and a direct nutritional precursor was postulated in 2018 and further confirmed by Rühl, Krezel and de Lera in 2021. This was further termed vitamin A5/X / provitamin A5/X. In this review, a new vitamin A5/X / provitamin A5/X concept is conceptualized in parallel to the vitamin A(1) / provitamin A(1) concept for daily dietary intake and towards dietary guidelines, with a focus on the existing national and international regulations for the physiological and nutritional relevance of vitamin A5/X. The aim of this review is to summarize available evidence and to emphasize gaps of knowledge regarding vitamin A5/X, based on new and older studies and proposed future directions as well as to stimulate and propose adapted nutritional regulations.

State-of-the-art methodological investigation of carotenoid activity and metabolism - from organic synthesis via metabolism to biological activity - exemplified by a novel retinoid signalling pathway.

Carotenoids are the most abundant lipophilic secondary plant metabolites and their dietary intake has been related to a large number of potential health benefits relevant for humans, including even reduced total mortality. An important feature is their potential to impact oxidative stress and inflammatory pathways, by interacting with transcription factors. For example, they may act as precursors of bioactive derivatives activating nuclear hormone receptor mediated signalling. These bioactive derivatives, originating e.g. from ß-carotene, i.e. retinoids / vitamin A, can activate the nuclear hormone receptors RARs (retinoic acid receptors). Due to new analytical insights, various novel metabolic pathways were recently outlined to be mediated via distinct nuclear hormone receptor activating pathways that were predicted and further confirmed. In this article, we describe old and novel metabolic pathways from various carotenoids towards novel ligands of alternative nuclear hormone receptors. However, to fully elucidate these pathways, a larger array of techniques and tools, starting from organic synthesis, lipidomics, reporter models, classical in vitro and in vivo models and further omics-approaches and their statistical evaluation are needed to comprehensively and conclusively study this topic. Thus, we further describe state-of-the-art techniques from A to Ω elucidating carotenoid biological mediated activities and describe in detail required materials and methods needed - in practical protocol form - for the various steps of carotenoid investigations.

Carotenoid metabolites, their tissue and blood concentrations in humans and further bioactivity via retinoid receptor-mediated signalling.

Many epidemiological studies have emphasised the relation between carotenoid dietary intake and their circulating concentrations and beneficial health effects, such as lower risk of cardiometabolic diseases and cancer. However, there is dispute as to whether the attributed health benefits are due to native carotenoids or whether they are instead induced by their metabolites. Several categories of metabolites have been reported, most notably involving (a) modifications at the cyclohexenyl ring or the polyene chain, such as epoxides and geometric isomers, (b) excentric cleavage metabolites with alcohol-, aldehyde- or carboxylic acid-functional groups or (c) centric cleaved metabolites with additional hydroxyl, aldehyde or carboxyl functionalities, not counting their potential phase-II glucuronidated / sulphated derivatives. Of special interest are the apo-carotenoids, which originate in the intestine and other tissues from carotenoid cleavage by ß-carotene oxygenases 1/2 in a symmetrical / non-symmetrical fashion. These are more water soluble and more electrophilic and, therefore, putative candidates for interactions with transcription factors such as NF-kB and Nrf2, as well as ligands for RAR-RXR nuclear receptor interactions. In this review, we discuss in vivo detected apo-carotenoids, their reported tissue concentrations, and potential associated health effects, focusing exclusively on the human situation and based on quantified / semi-quantified carotenoid metabolites proven to be present in humans.

Bispyrrolidinoindoline Epi(poly)thiodioxopiperazines (BPI-ETPs) and Simplified Mimetics: Structural Characterization, Bioactivities, and Total Synthesis.

Within the 2,5-dioxopiperazine-containing natural products generated by "head-to-tail" cyclization of peptides, those derived from tryptophan allow further structural diversification due to the rich chemical reactivity of the indole heterocycle, which can generate tetracyclic fragments of hexahydropyrrolo[2,3-b]indole or pyrrolidinoindoline skeleton fused to the 2,5-dioxopiperazine. Even more complex are the dimeric bispyrrolidinoindoline epi(poly)thiodioxopiperazines (BPI-ETPs), since they feature transannular (poly)sulfide bridges connecting C3 and C6 of their 2,5-dioxopiperazine rings. Homo- and heterodimers composed of diastereomeric epi(poly)thiodioxopiperazines increase the complexity of the family. Furthermore, putative biogenetically generated downstream metabolites with C11 and C11'-hydroxylated cores, as well as deoxygenated and/or oxidized side chain counterparts, have also been described. The isolation of these complex polycyclic tryptophan-derived alkaloids from the classical sources, their structural characterization, the description of the relevant biological activities and putative biogenetic routes, and the synthetic efforts to generate and confirm their structures and also to prepare and further evaluate structurally simple analogs will be reported.

Total Synthesis of the Proposed Structure of (-)-Novofumigatamide, Isomers Thereof, and Analogues. Part I.

The total synthesis of the suggested structure of (-)-novofumigatamide, a natural product containing a C3-reverse prenylated N-acetyl-exo-hexahydropyrrolo[2,3-b]indole motif fused to a 10-membered ring lactam, was achieved using the macrolactam formation in advance of a diastereoselective bromocyclization and reverse prenylation steps. Since the NMR data of the synthetic sample did not match those of the natural product, the endo-bromo precursor of a N-Boc analogue and additional diastereomers derived from l-Trp were also synthesized. Five alternative synthetic routes, which differed in the order of final key steps used for the construction of the 10-membered ring lactam and the hexahydropyrrolo[2,3-b]indole framework within the polycyclic skeleton and also in the amide bond selected for the ring-closing of the macrolactam, were thoroughly explored. Much to our dismay, the lack of spectroscopic correlations between the proposed structure of natural (-)-novofumigatamide and the synthetic products suggested a different connectivity between the atoms. Additional synthetic efforts to assemble alternative structures of the natural product and isomers thereof (see accompanying paper; DOI: 10.1021/acs.joc.2c01228) further highlighted the frustrating endeavors toward the identification of a natural product.

Puzzling Out the Structure of Novofumigatamide: Total Synthesis of Constitutional Isomers. Part II.

The total synthesis of several constitutional isomers showing a different connectivity of the macrolactam ring with the hexahydropyrrolo[2,3-b]indole core, as well as those arising from the positional exchange of the valine and the anthranilate units of the structure originally proposed for (-)-novofumigatamide, has been carried out. The constitutional isomers with 12-membered ring macrolactam connected with the pyrroloindoline framework through the indole nitrogen, and the acetyl group at the pyrrole nitrogen, of endo relative configuration, were prepared through the condensation between the tryptophan and valine edges derived from l- or d-tryptophan and l-valine amino acids. The corresponding exo products are highly unstable structures difficult to isolate and characterize. A second group of isomeric structures synthesized considered the positional exchange between the valine and the anthranilate residues within the macrolactam ring in the originally proposed macrocyclic structure. Comparison of the spectroscopic data allowed us to discard these alternative structures for the natural product.

Stereoselective Synthesis of Bisfuranoxide (Aurochrome, Auroxanthin) and Monofuranoxide (Equinenone 5',8'-Epoxide) Carotenoids by Double Horner-Wadsworth-Emmons Reaction.

The stereoselective synthesis of C40-all-trans-carotenoids with the formal hexahydrobenzofuran skeletons aurochrome, auroxanthin, and equinenone-5',8'-epoxide is reported. The synthesis is based on a one-pot or stepwise double Horner-Wadsworth-Emmons (HWE) reaction of a terminal enantiopure C15-5,6-epoxycyclohexadienylphosphonate and a central C10-trienedial. The ring expansion of the epoxycyclohexadienylphosphonate, generated by a Stille cross-coupling reaction, to the hexahydrobenzofuran skeleton was promoted by the reaction conditions of the HWE reaction prior to double-bond formation.

Synergistic Antitumoral Effect of Epigenetic Inhibitors and Gemcitabine in Pancreatic Cancer Cells.

Epigenetic modifications could drive some of the molecular events implicated in proliferation, drug resistance and metastasis of pancreatic ductal adenocarcinoma (PDAC). Thus, epigenetic enzyme inhibitors could be the key to revert those events and transform PDAC into a drug-sensitive tumor. We performed a systematic study with five different epigenetic enzyme inhibitors (1, UVI5008, MS275, psammaplin A, and BIX01294) targeting either Histone Deacetylase (HDAC) 1 or 1/4, DNA methyltransferase 3a (DNMT3a), Euchromatic histone lysine methyltransferase 2 (EHMT2), or Sirtuin 1 (SIRT1), as well as one drug that restores the p53 function (P53R3), in three different human PDAC cell lines (SKPC-1, MIA PaCa-2, and BxPC-3) using 2D and 3D cell cultures. The synergistic effect of these antitumoral drugs with gemcitabine was tested and the most efficient combinations were characterized by RNA-seq. The inhibition of HDAC1/4 (MS275), HDAC1/4/SIRT1/DNMT3a (UVI5008) or EHMT2 (BIX01294) induced a significant reduction on the cell viability, even in gemcitabine-resistance cells. The combination of UVI5008 or MS275 with gemcitabine induced a synergistic effect at low concentration and the RNA-Seq analysis revealed some synergy candidate genes as potential biomarkers. Reverting aberrant epigenetic modifications in combination with gemcitabine offers an alternative treatment for PDAC patients, with an important reduction of the therapeutic dose.

Chemical synthesis in competition with global genome mining and heterologous expression for the preparation of dimeric tryptophan-derived 2,5-dioxopiperazines.

Covering: up to the end of 2021Within the 2,5-dioxopiperazines-containing natural products, those generated from tryptophan allow further structural diversification due to the rich chemical reactivity of the indole heterocycle. The great variety of natural products, ranging from simple dimeric bispyrrolidinoindoline dioxopiperazines and tryptophan-derived dioxopiperazine/pyrrolidinoindoline dioxopiperazine analogs to complex polycyclic downstream metabolites containing transannular connections between the subunits, will be covered. These natural products are constructed by Nature using hybrid polyketide synthase (PKS) and nonribosomal peptide synthetase (NRPS) assembly lines. Mining of microbial genome sequences has more recently allowed the study of the metabolic routes and the discovery of their hidden biosynthetic potential. The competition (ideally, also the combined efforts) between their isolation from the cultures of the producing microorganisms after global genome mining and heterologous expression and the synthetic campaigns, has more recently allowed the successful generation and structural confirmation of these natural products. Their biological activities as well as their proposed biogenetic routes and computational studies on biogenesis will also be covered.

Retinoic acid receptor beta protects striatopallidal medium spiny neurons from mitochondrial dysfunction and neurodegeneration.

Retinoic acid is a powerful regulator of brain development, however its postnatal functions only start to be elucidated. We show that retinoic acid receptor beta (RARß), is involved in neuroprotection of striatopallidal medium spiny neurons (spMSNs), the cell type affected in different neuropsychiatric disorders and particularly prone to degenerate in Huntington disease (HD). Accordingly, the number of spMSNs was reduced in the striatum of adult Rarß-/- mice, which may result from mitochondrial dysfunction and neurodegeneration. Mitochondria morphology was abnormal in mutant mice whereas in cultured striatal Rarß-/- neurons mitochondria displayed exacerbated depolarization, and fragmentation followed by cell death in response to glutamate or thapsigargin-induced calcium increase. In vivo, Rarß-/- spMSNs were also more vulnerable to the mitochondrial toxin 3-nitropropionic acid (3NP), known to induce HD symptoms in human and rodents. In contrary, an RARß agonist, AC261066, decreased glutamate-induced toxicity in primary striatal neurons in vitro, and diminished mitochondrial dysfunction, spMSN cell death and motor deficits induced in wild type mice by 3NP. We demonstrate that the striatopallidal pathway is compromised in Rarß-/- mice and associated with HD-like motor abnormalities. Importantly, similar motor abnormalities and selective reduction of spMSNs were induced by striatal or spMSN-specific inactivation of RARß, further supporting a neuroprotective role of RARß in postnatal striatum.

An alternative, zeaxanthin epoxidase-independent abscisic acid biosynthetic pathway in plants.

Abscisic acid (ABA) is an important carotenoid-derived phytohormone that plays essential roles in plant response to biotic and abiotic stresses as well as in various physiological and developmental processes. In Arabidopsis, ABA biosynthesis starts with the epoxidation of zeaxanthin by the ABA DEFICIENT 1 (ABA1) enzyme, leading to epoxycarotenoids; e.g., violaxanthin. The oxidative cleavage of 9-cis-epoxycarotenoids, a key regulatory step catalyzed by 9-CIS-EPOXYCAROTENOID DIOXYGENASE, forms xanthoxin, which is converted in further reactions mediated by ABA DEFICIENT 2 (ABA2), ABA DEFICIENT 3 (ABA3), and ABSCISIC ALDEHYDE OXIDASE 3 (AAO3) into ABA. By combining genetic and biochemical approaches, we unravel here an ABA1-independent ABA biosynthetic pathway starting upstream of zeaxanthin. We identified the carotenoid cleavage products (i.e., apocarotenoids, ß-apo-11-carotenal, 9-cis-ß-apo-11-carotenal, 3-OH-ß-apo-11-carotenal, and 9-cis-3-OH-ß-apo-11-carotenal) as intermediates of this ABA1-independent ABA biosynthetic pathway. Using labeled compounds, we showed that ß-apo-11-carotenal, 9-cis-ß-apo-11-carotenal, and 3-OH-ß-apo-11-carotenal are successively converted into 9-cis-3-OH-ß-apo-11-carotenal, xanthoxin, and finally into ABA in both Arabidopsis and rice. When applied to Arabidopsis, these ß-apo-11-carotenoids exert ABA biological functions, such as maintaining seed dormancy and inducing the expression of ABA-responsive genes. Moreover, the transcriptomic analysis revealed a high overlap of differentially expressed genes regulated by ß-apo-11-carotenoids and ABA, suggesting that ß-apo-11-carotenoids exert ABA-independent regulatory activities. Taken together, our study identifies a biological function for the common plant metabolites, ß-apo-11-carotenoids, extends our knowledge about ABA biosynthesis, and provides new insights into plant apocarotenoid metabolic networks.

On the rearrangements of biologically-relevant vinyl allene oxides to cis-cyclopentenones, ketols, and Favorskii-type carboxylic acids.

In addition to stereodefined cis-cyclopentenones, the rearrangement of naturally-occurring vinyl allene oxides can provide ketols, cyclopropylcarbinols, and Favorskii-type bis-(Z)-but-2-en-1-yl acetic acids. These processes have been studied by DFT computations using (Z)-but-1-en-1-yl allene oxides as model systems. Prior studies on the stepwise cascade process starting from (Z)-but-1-en-1-yl allene oxides established as key steps the ring opening of the oxirane to give oxidopentadienyl biradicals, and their isomerization through formation of alkenylcyclopropanone intermediates prior to the conrotatory electrocyclic ring closure to cis-configured cyclopentenones. Under neutral or under acidic conditions, the corresponding ketols and cyclopropylcarbinols have been computationally characterized as resulting from SN2, SN1 and SN1'-type processes, showing that the rearrangement of vinyl allene oxides is pH-dependent. Moreover, stereoconvergent base-induced Favorskii-type rearrangements to provide bis-(Z)-but-1-en-1-yl substituted acetic acids have also been justified. Since the model system captures the structural features of the vinyl allene oxides of biological relevance, our computations provide the most comprehensive overview of the complex reactivity of these natural species.

Vitamin A5/X controls stress-adaptation and prevents depressive-like behaviors in a mouse model of chronic stress.

9-cis-13,14-dihydroretinoic acid (9CDHRA), acts as an endogenous ligand of the retinoid X receptors (RXRs), and is an active form of a suggested new vitamin, vitamin A5/X. Nutritional-relevance of this pathway as well as its detailed role in vertebrate physiology, remain largely unknown. Since recent GWAS data and experimental studies associated RXR-mediated signaling with depression, we explored here the relevance of RXR and vitamin A5/X-mediated signaling in the control of stress adaptation and depressive-like behaviors in mice. We found that compromised availability of 9CDHRA in Rbp1-/- mice was associated with increased despair in the forced swim and anhedonia in the sucrose preference test. 9CDHRA similarly to synthetic RXR agonist, BMS649, normalized despair behaviors in Rbp1-/- but not Rxrγ-/- mice, supporting involvement of RXR signaling in anti-despair activity of these ligands. Importantly, similarly to BMS649, the 9CDHRA and its nutritional-precursor, 9-cis-13,14-dihydroretinol (vitamin A5/X alcohol), prevented development of depressive-like behaviors in mice exposed to chronic social defeat stress, revealing the beneficial role of RXRs and its endogenous ligand in stress adaptation process. These data point to the need for relevant nutritional, biochemical and pharmacological studies of this signaling pathway in human, both in physiological conditions and in pathologies of stress-related disorders.

Palladium-Catalyzed Aminocyclization-Coupling Cascades: Preparation of Dehydrotryptophan Derivatives and Computational Study.

Dehydrotryptophan derivatives have been prepared by palladium-catalyzed aminocyclization-Heck-type coupling cascades starting from o-alkynylaniline derivatives and methyl α-aminoacrylate. Aryl, alkyl (primary, secondary, and tertiary), and alkenyl substituents have been introduced at the indole C-2 position. Further variations at the indole benzene ring, as well as the C-2-unsubstituted case, have all been demonstrated. In the case of C-2 aryl substitution, the preparation of the o-alkynylaniline substrate by Sonogashira coupling and the subsequent cyclization-coupling cascade have been performed in a one-pot protocol with a single catalyst. DFT calculations have revealed significant differences in the reaction profiles of these reactions relative to those involving methyl acrylate or methacrylate, and between the reactions of the free anilines and their corresponding carbamates. Those calculations suggest that the nature of the alkene and of the acid HX released in the HX/alkene exchange step that precedes C-C bond formation could be responsible for the experimentally observed differences in reaction efficiencies.

Total Synthesis of Homo- and Heterodimeric Bispyrrolidinoindoline Dioxopiperazine Natural Products.

Total synthesis and structural confirmation of homo- and heterodimeric bispyrrolidinoindoline dioxopiperazine alkaloids isolated from fungi and bacteria, namely, ditryptoleucine A, ditryptoleucine B (11), the N,N'-bis-demethylated analogue (+)-12, (-)-dibrevianamide F (13), (-)-SF-5280-451 (14), tetratryptomycin A (15), (-)-tryprophenaline (17), and (-)-SF-5280-415 (18), has been carried out starting from the corresponding bispyrrolidinoindolines derived from tryptophan. Our efforts to synthesize all possible diastereomers of the natural ditryptoleucine isolates uncovered structural factors that determine the rate and efficiency of dioxopiperazine ring formation, leading in some cases to mixtures of diastereomers by concomitant epimerization, to the formation of their putative monomeric dioxopiperazine dipeptide biogenetic precursors, and to the alternative formation of a dimer with a fused 1,3,5-triazepan-6-one heterocycle.

Vitamin A5/X, a New Food to Lipid Hormone Concept for a Nutritional Ligand to Control RXR-Mediated Signaling.

Vitamin A is a family of derivatives synthesized from carotenoids acquired from the diet and can be converted in animals to bioactive forms essential for life. Vitamin A1 (all-trans-retinol/ATROL) and provitamin A1 (all-trans-ß,ß-carotene/ATBC) are precursors of all-trans-retinoic acid acting as a ligand for the retinoic acid receptors. The contribution of ATROL and ATBC to formation of 9-cis-13,14-dihydroretinoic acid (9CDHRA), the only endogenous retinoid acting as retinoid X receptor (RXR) ligand, remains unknown. To address this point novel and already known retinoids and carotenoids were stereoselectively synthesized and administered in vitro to oligodendrocyte cell culture and supplemented in vivo (orally) to mice with a following high-performance liquid chromatography-mass spectrometry (HPLC-MS)/UV-Vis based metabolic profiling. In this study, we show that ATROL and ATBC are at best only weak and non-selective precursors of 9CDHRA. Instead, we identify 9-cis-13,14-dihydroretinol (9CDHROL) and 9-cis-13,14-dihydro-ß,ß-carotene (9CDHBC) as novel direct nutritional precursors of 9CDHRA, which are present endogenously in humans and the human food chain matrix. Furthermore, 9CDHROL displayed RXR-dependent promnemonic activity in working memory test similar to that reported for 9CDHRA. We also propose that the endogenous carotenoid 9-cis-ß,ß-carotene (9CBC) can act as weak, indirect precursor of 9CDHRA via hydrogenation to 9CDHBC and further metabolism to 9CDHROL and/or 9CDHRA. In summary, since classical vitamin A1 is not an efficient 9CDHRA precursor, we conclude that this group of molecules constitutes a new class of vitamin or a new independent member of the vitamin A family, named "Vitamin A5/X".

Correction: Natural polyenic macrolactams and polycyclic derivatives generated by transannular pericyclic reactions: optimized biogenesis challenging chemical synthesis.

Correction for 'Natural polyenic macrolactams and polycyclic derivatives generated by transannular pericyclic reactions: optimized biogenesis challenging chemical synthesis' by Rosana Alvarez et al., Nat. Prod. Rep., 2021, DOI: 10.1039/d0np00050g.

From carotenoid intake to carotenoid blood and tissue concentrations - implications for dietary intake recommendations.

There is uncertainty regarding carotenoid intake recommendations, because positive and negative health effects have been found or are correlated with carotenoid intake and tissue levels (including blood, adipose tissue, and the macula), depending on the type of study (epidemiological vs intervention), the dose (physiological vs supraphysiological) and the matrix (foods vs supplements, isolated or used in combination). All these factors, combined with interindividual response variations (eg, depending on age, sex, disease state, genetic makeup), make the relationship between carotenoid intake and their blood/tissue concentrations often unclear and highly variable. Although blood total carotenoid concentrations <1000 nmol/L have been related to increased chronic disease risk, no dietary reference intakes (DRIs) exist. Although high total plasma/serum carotenoid concentrations of up to 7500 nmol/L are achievable after supplementation, a plateauing effect for higher doses and prolonged intake is apparent. In this review and position paper, the current knowledge on carotenoids in serum/plasma and tissues and their relationship to dietary intake and health status is summarized with the aim of proposing suggestions for a "normal," safe, and desirable range of concentrations that presumably are beneficial for health. Existing recommendations are likewise evaluated and practical dietary suggestions are included.

Topical Vitamin D Receptor Antagonist/Partial-Agonist Treatment Induces Epidermal Hyperproliferation via RARγ Signaling Pathways.

Vitamin D and A derivatives are well-known endogenous substances responsible for skin homeostasis. In this study we topically treated shaved mouse skin with a vitamin D agonist (MC903) or vitamin D antagonist/partial agonist (ZK159222) and compared the changes with acetone (control treatment) treatment for 14 days. Topical treatment with ZK159222 resulted in increased expression of genes involved in retinoic acid synthesis, increased retinoic acid concentrations and increased expression of retinoid target genes. Clustering the altered genes revealed that heparin-binding epidermal growth factor-like growth factor, the main driver of epidermal hyperproliferation, was increased via RARγ-mediated pathways, while other clusters of genes were mainly decreased which were comparable to the changes seen upon activation of the RARα-mediated pathways. In summary, we conclude that epidermal hyperproliferation of mouse skin in response to a topically administered vitamin D receptor antagonist/partial agonist (ZK159222) is induced via increased retinoic acid synthesis, retinoic acid levels and increased RARγ-mediated pathways.

Natural polyenic macrolactams and polycyclic derivatives generated by transannular pericyclic reactions: optimized biogenesis challenging chemical synthesis.

Covering from 1992 to the end of 2020-11-20.Genetically-encoded polyenic macrolactams, which are constructed by Nature using hybrid polyketide synthase/nonribosomal peptide synthase (PKSs/NRPSs) assembly lines, are part of the large collection of natural products isolated from bacteria. Activation of cryptic (i.e., silent) gene clusters in these microorganisms has more recently allowed to generate and eventually isolate additional members of the family. Having two unsaturated fragments separated by short saturated chains, the primary macrolactam is posited to undergo transannular reactions and further rearrangements thus leading to the generation of a structurally diverse collection of polycyclic (natural) products and oxidized derivatives. The review will cover the challenges that scientists face on the isolation of these unstable compounds from the cultures of the producing microorganisms, their structural characterization, biological activities, optimized biogenetic routes, as well as the skeletal rearrangements of the primary structures of the natural macrolactams derived from pericyclic reactions of the polyenic fragments. The efforts of the synthetic chemists to emulate Nature on the successful generation and structural confirmation of these natural products will also be reported.