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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Synthesis of Symmetrical and Nonsymmetrical Polyenes by Iterative and Bidirectional Palladium-Catalyzed Cross-Coupling Reactions.

Bifunctional unsaturated reagents designed to undergo palladium-catalyzed cross-coupling reactions with complementary polyenyl connective fragments are highly useful for the undoubtedly challenging synthesis of polyenes. The current toolkit of building blocks for the bidirectional formation of Csp2 -Csp2 single bonds of polyenes includes homo-bisfunctionalized reagents with equal or unequal reactivity (due to steric and/or electronic factors), and hetero-bisfunctionalized counterparts containing either two different nucleophiles, two electrophiles or one of these functionalities and a latent nucleophile that can be unmasked when desired. The combination of these bifunctional linchpin reagents using tactics that modulate the reactivity of each terminus in order to achieve the required connection have streamlined the synthesis of polyenes of great complexity using (iterative) cross-coupling methods for Csp2 -Csp2 bond formation. Reaction conditions for the Pd-catalyzed cross-coupling reactions are mild and functional-group-tolerant, and therefore these protocols allow to construct the polyene structures using shorter unsaturated reactants with the desired geometries, since in general the products preserve the stereochemical information of the connected cross-coupling partners.

Synthesis of C11-to-C14 methyl-shifted all-trans-retinal analogues and their activities on human aldo-keto reductases.

Human aldo-keto reductases (AKRs) are enzymes involved in the reduction, among other substrates, of all-trans-retinal to all-trans-retinol (vitamin A), thus contributing to the control of the levels of retinoids in organisms. Structure-activity relationship studies of a series of C11-to-C14 methyl-shifted (relative to natural C13-methyl) all-trans-retinal analogues as putative substrates of AKRs have been reported. The synthesis of these retinoids was based on the formation of a C10-C11 single bond of the pentaene skeleton starting from a trienyl iodide and the corresponding dienylstannanes and dienylsilanes, using the Stille-Kosugi-Migita and Hiyama-Denmark cross-coupling reactions, respectively. Since these reagents differ by the location and presence of methyl groups at the dienylorganometallic fragment, the study also provided insights into the ability of the different positional isomers to undergo cross-coupling and the sensitivity of these processes to steric hindrance. The resulting C11-to-C14 methyl-shifted all-trans-retinal analogues were found to be active substrates when tested with AKR1B1 and AKR1B10 enzymes, although relevant differences in substrate specificities were noted. For AKR1B1, all analogues exhibited higher catalytic efficiency (kcat/Km) than parent all-trans-retinal. In addition, only all-trans-11-methylretinal, the most hydrophobic derivative, showed a higher value of kcat/Km = 106 000 ± 23 200 mM-1 min-1 for AKR1B10, which is in fact the highest value from all known retinoid substrates of this enzyme. The novel structures, identified as efficient AKR substrates, may serve in the design of selective inhibitors with potential pharmacological interest.

Bidirectional Hiyama-Denmark Cross-Coupling Reactions of Bissilyldeca-1,3,5,7,9-pentaenes for the Synthesis of Symmetrical and Non-Symmetrical Carotenoids.

The construction of the carotenoid skeleton by Pd-catalyzed Csp2 -Csp2 cross-coupling reactions of symmetrical and non-symmetrical 1,10-bissilyldeca-1,3,5,7,9-pentaenes and the corresponding complementary alkenyl iodides has been developed. Reaction conditions for these bidirectional and orthogonal Hiyama-Denmark cross-coupling reactions of bisfunctionalized pentaenes are mild and the carotenoid products preserve the stereochemical information of the corresponding oligoene partners. The carotenoids synthesized in this manner include ß,ß-carotene and (3R,3'R)-zeaxanthin (symmetrical) as well as 9-cis-ß,ß-carotene, 7,8-dihydro-ß,ß-carotene and ß-cryptoxanthin (non-symmetrical).

Deciphering the Origin of Enantioselectivity on the Cis-Cyclopropanation of Styrene with Enantiopure Di-chloro,Di-gold(I)-SEGPHOS Carbenoids Generated from Propargylic Esters.

The stereoselective synthesis of cis-disubstituted cyclopropanes by the Au(I)/PPh3-catalyzed cycloaddition of propargylic esters and styrene has been studied using density functional theory calculations. The computed mechanistic scheme involves the rate-limiting 1,2-rearrangement of the propargylic ester with the π-coordinated gold complex, followed by the (2 + 1)-cheletropic reaction of styrene with the alkenyl-Au(I) carbene intermediate to afford the cis-disubstituted cyclopropane derivative in a high cis/trans diastereomeric ratio. With a ( R)-di-chloro,di-gold-DTBM-SEGPHOS complex as the catalyst, computations are consistent with a rate-determining (2 + 1)-cheletropic reaction, in which facial discrimination is proposed to result from a combination of subtle steric and electronic effects in the SiRe facial approach transition structure, which favor the formation of the cis-cyclopropane diastereomer of 1 R,2 S absolute configuration, as experimentally observed.

Reduced adiponectin expression after high-fat diet is associated with selective up-regulation of ALDH1A1 and further retinoic acid receptor signaling in adipose tissue.

Adiponectin is an adipocyte-derived adipokine with potent antidiabetic, anti-inflammatory, and antiatherogenic activity. Long-term, high-fat diet results in gain of body weight, adiposity, further inflammatory-based cardiovascular diseases, and reduced adiponectin secretion. Vitamin A derivatives/retinoids are involved in several of these processes, which mainly take place in white adipose tissue (WAT). In this study, we examined adiponectin expression as a function of dietary high-fat and high-vitamin A conditions in mice. A decrease of adiponectin expression in addition to an up-regulation of aldehyde dehydrogenase A1 (ALDH1A1), retinoid signaling, and retinoic acid response element signaling was selectively observed in WAT of mice fed a normal-vitamin A, high-fat diet. Reduced adiponectin expression in WAT was also observed in mice fed a high-vitamin A diet. Adipocyte cell culture revealed that endogenous and synthetic retinoic acid receptor (RAR)α- and RARγ-selective agonists, as well as a synthetic retinoid X receptor agonist, efficiently reduced adiponectin expression, whereas ALDH1A1 expression only increased with RAR agonists. We conclude that reduced adiponectin expression under high-fat dietary conditions is dependent on 1) increased ALDH1A1 expression in adipocytes, which does not increase all-trans-retinoic acid levels; 2) further RAR ligand-induced, WAT-selective, increased retinoic acid response element-mediated signaling; and 3) RAR ligand-dependent reduction of adiponectin expression.-Landrier, J.-F., Kasiri, E., Karkeni, E., Mihály, J., Béke, G., Weiss, K., Lucas, R., Aydemir, G., Salles, J., Walrand, S., de Lera, A. R., Rühl, R. Reduced adiponectin expression after high-fat diet is associated with selective up-regulation of ALDH1A1 and further retinoic acid receptor signaling in adipose tissue.

9-cis-13,14-Dihydroretinoic Acid Is an Endogenous Retinoid Acting as RXR Ligand in Mice.

The retinoid X receptors (RXRs) are ligand-activated transcription factors which heterodimerize with a number of nuclear hormone receptors, thereby controlling a variety of (patho)-physiological processes. Although synthetic RXR ligands are developed for the treatment of various diseases, endogenous ligand(s) for these receptors have not been conclusively identified. We show here that mice lacking cellular retinol binding protein (Rbp1-/-) display memory deficits reflecting compromised RXR signaling. Using HPLC-MS and chemical synthesis we identified in Rbp1-/- mice reduced levels of 9-cis-13,14-dihydroretinoic acid (9CDHRA), which acts as an RXR ligand since it binds and transactivates RXR in various assays. 9CDHRA rescues the Rbp1-/- phenotype similarly to a synthetic RXR ligand and displays similar transcriptional activity in cultured human dendritic cells. High endogenous levels of 9CDHRA in mice indicate physiological relevance of these data and that 9CDHRA acts as an endogenous RXR ligand.

Lineage-specific duplication of amphioxus retinoic acid degrading enzymes (CYP26) resulted in sub-functionalization of patterning and homeostatic roles.

BACKGROUND: During embryogenesis, tight regulation of retinoic acid (RA) availability is fundamental for normal development. In parallel to RA synthesis, a negative feedback loop controlled by RA catabolizing enzymes of the cytochrome P450 subfamily 26 (CYP26) is crucial. In vertebrates, the functions of the three CYP26 enzymes (CYP26A1, CYP26B1, and CYP26C1) have been well characterized. By contrast, outside vertebrates, little is known about CYP26 complements and their biological roles. In an effort to characterize the evolutionary diversification of RA catabolism, we studied the CYP26 genes of the cephalochordate amphioxus (Branchiostoma lanceolatum), a basal chordate with a vertebrate-like genome that has not undergone the massive, large-scale duplications of vertebrates. RESULTS: In the present study, we found that amphioxus also possess three CYP26 genes (CYP26-1, CYP26-2, and CYP26-3) that are clustered in the genome and originated by lineage-specific duplication. The amphioxus CYP26 cluster thus represents a useful model to assess adaptive evolutionary changes of the RA signaling system following gene duplication. The characterization of amphioxus CYP26 expression, function, and regulation by RA signaling demonstrated that, despite the independent origins of CYP26 duplicates in amphioxus and vertebrates, they convergently assume two main roles during development: RA-dependent patterning and protection against fluctuations of RA levels. Our analysis suggested that in amphioxus RA-dependent patterning is sustained by CYP26-2, while RA homeostasis is mediated by CYP26-1 and CYP26-3. Furthermore, comparisons of the regulatory regions of CYP26 genes of different bilaterian animals indicated that a CYP26-driven negative feedback system was present in the last common ancestor of deuterostomes, but not in that of bilaterians. CONCLUSIONS: Altogether, this work reveals the evolutionary origins of the RA-dependent regulation of CYP26 genes and highlights convergent functions for CYP26 enzymes that originated by independent duplication events, hence establishing a novel selective mechanism for the genomic retention of gene duplicates.

Synthesis of the octahydronaphthalene core of nahuoic acid A via a B(C6F5)3-catalyzed intramolecular Diels-Alder (IMDA) reaction.

Model tetraenal 9b underwent intramolecular Diels-Alder cycloaddition in CH2Cl2 at -10 °C under catalysis by the bulky Lewis acid B(C6F5)3 to deliver as major components the cis-fused angularly-methylated octahydronaphthalene products, which are formed through the alternative exo orientations of the reacting moieties. One of these diastereomers features the relative and absolute configuration present in the core of nahuoic acid A, a natural product that acts as a cofactor-competitive inhibitor of the lysine methyl transferase SETD8. By contrast, catalysis of the reaction by Me2AlCl at -40 °C selectively afforded the trans-fused isomer resulting from the Re-endo orientation.