Crocetin and related oxygen diffusion-enhancing compounds: Review of chemical synthesis, pharmacology, clinical development, and novel therapeutic applications.

The current pandemic forced us to introspect and revisit our armamentarium of medicinal agents which could be life-saving in emergency situations. Oxygen diffusion-enhancing compounds represent one such class of potential therapeutic agents, particularly in ischemic conditions. As rewarding as the name suggests, these agents, represented by the most advanced and first-in-class molecule, trans-sodium crocetinate (TSC), are the subject of intense clinical investigation, including Phase 1b/2b clinical trials for COVID-19. Being a successor of a natural product, crocetin, TSC is being investigated for various cancers as a radiosensitizer owing to its oxygen diffusion enhancement capability. The unique properties of TSC make it a promising therapeutic agent for various ailments such as hemorrhagic shock, stroke, heart attack, among others. The present review outlines various (bio)synthetic strategies, pharmacological aspects, clinical overview and potential therapeutic benefits of crocetin and related compounds including TSC. The recent literature focusing on the delivery aspects of these compounds is covered as well to paint the complete picture to the curious reader. Given the potential TSC holds as a first-in-class agent, small- and/or macromolecular therapeutics based on the core concept of improved oxygen diffusion from blood to the surrounding tissues where it is needed the most, will be developed in future and satisfy the unmet medical need for many diseases and disorders.

Facile liquid-phase deposition synthesis of titania-coated magnetic sporopollenin for the selective capture of phosphopeptides.

Titania-grafted magnetic sporopollenin is synthesized by the liquid-phase deposition (LPD) technique, characterized by SEM, EDX, and nitrogen adsorption porosimetry, and used for the selective enrichment of phosphorylated peptides. The material is low cost because of easier availability of pollens and has rich surface chemistry which enables strong attachment of titania onto magnetic sporopollenin. The material shows higher selectivity of 1:1000 with ß-casein spiked in BSA. Higher sensitivity of 10 fmol is recorded for phosphopeptides from standard ß-casein digest. Twenty phosphorylated peptides are enriched from milk digest and four endogenous phosphopeptides from diluted human serum. The magnetic property of titania-coated magnetic sporopollenin facilitates the fast and effective isolation of phosphopeptides from complex mixtures through external magnet. The material is finally applied to tryptic digest of rat brain cell lysate for phosphopeptide enrichment where 2718 phosphopeptides are identified by using LC-MS/MS with C18 column. Titania-coated magnetic sporopollenin captures both mono-phosphorylated (2489) and multi-phosphorylated peptides (229) due to strong affinity of TiO2 with phosphates. TiO2-coated magnetic material also shows better enrichment efficiency in comparison to commercial TiO2. Graphical abstract.

Synthesis of methyl 4-dihydrotrisporate B and methyl trisporate B, morphogenetic factors of Zygomycetes fungi.

(9Z)-Methyl 4-dihydrotrisporate B and (9Z)-methyl trisporate B, pheromones of Zygomycetes fungi, have been synthesized using Stille cross-coupling from previously described cyclohexenone precursors. Conducting the coupling without protection groups allowed for a short and stereospecific synthesis route of the late trisporoids. Stability studies for both the compounds revealed (9Z)-methyl trisporate B to be very unstable against UV irradiation.

Synthesis of apo-13- and apo-15-lycopenoids, cleavage products of lycopene that are retinoic acid antagonists.

Consumption of the tomato carotenoid, lycopene, has been associated with favorable health benefits. Some of lycopene's biological activity may be due to metabolites resulting from cleavage of the lycopene molecule. Because of their structural similarity to the retinoic acid receptor (RAR) antagonist, ß-apo-13-carotenone, the "first half" putative oxidative cleavage products of the symmetrical lycopene have been synthesized. All transformations proceed in moderate to good yield and some with high stereochemical integrity allowing ready access to these otherwise difficult to obtain terpenoids. In particular, the methods described allow ready access to the trans isomers of citral (geranial) and pseudoionone, important flavor and fragrance compounds that are not readily available isomerically pure and are building blocks for many of the longer apolycopenoids. In addition, all of the apo-11, apo-13, and apo-15 lycopenals/lycopenones/lycopenoic acids have been prepared. These compounds have been evaluated for their effect on RAR-induced genes in cultured hepatoma cells and, much like ß-apo-13-carotenone, the comparable apo-13-lycopenone and the apo-15-lycopenal behave as RAR antagonists. Furthermore, molecular modeling studies demonstrate that the apo-13-lycopenone efficiently docked into the ligand binding site of RARα. Finally, isothermal titration calorimetry studies reveal that apo-13-lycopenone acts as an antagonist of RAR by inhibiting coactivator recruitment to the receptor.

Chemical vs. biotechnological synthesis of C13-apocarotenoids: current methods, applications and perspectives.

Apocarotenoids are natural compounds derived from the oxidative cleavage of carotenoids. Particularly, C13-apocarotenoids are volatile compounds that contribute to the aromas of different flowers and fruits and are highly valued by the Flavor and Fragrance industry. So far, the chemical synthesis of these terpenoids has dominated the industry. Nonetheless, the increasing consumer demand for more natural and sustainable processes raises an interesting opportunity for bio-production alternatives. In this regard, enzymatic biocatalysis and metabolically engineered microorganisms emerge as attractive biotechnological options. The present review summarizes promising bioengineering approaches with regard to chemical production methods for the synthesis of two families of C13-apocarotenoids: ionones/dihydroionones and damascones/damascenone. We discuss each method and its applicability, with a thorough comparative analysis for ionones, focusing on the production process, regulatory aspects, and sustainability.

A chain extension method for apocarotenoids; lycopene and lycophyll syntheses.

The novel C5 benzothiazolyl (BT) sulfone containing an acetal group was prepared as a building block for the chain-extension of apocarotenoids. The double Julia-Kocienski olefination of the BT-sulfone with C10 2,7-dimethyl-2,4,6-octatrienedial and deprotection of the resulting acetal groups efficiently produced C20 crocetin dial. The higher homologues of C30 and C40 apocarotenoids were prepared from C20 crocetin dial by the repeated application of the Julia-Kocienski olefination of the C5 BT-sulfone and hydrolysis. The scopes of the Julia-Kocienski olefination in the total synthesis of carotenoid natural products were evaluated using the C10+C20+C10 coupling protocol. The olefination was sensitive to the steric factor and bulky C10 ß-cyclogeranyl BT-sulfone was not able to react with C20 crocetin dial, however, lycopene and lycophyll were efficiently produced by the Julia-Kocienski olefination of C10 geranyl BT-sulfone and hydroxygeranyl BT-sulfone, in which protection of the hydroxyl group was not necessary.

Sulfone-mediated syntheses of crocetin derivatives: regioselectivity of highly functionalized building blocks.

New C5 sulfone building blocks containing a masked polar end group have been devised for the efficient synthesis of carotenoids with polar termini. Chemoselectivity or the regiochemical issue of the highly functionalized units has been carefully addressed depending on the soft or hard nature of electrophiles. These building blocks have been successfully applied to the syntheses of crocetin derivatives, crocetin dial and the novel crocetin dinitrile.

Synthesis and characterization of quantum dot nanoparticles bound to the plant volatile precursor of hydroxy-apo-10'-carotenal.

This study is focused on the synthesis and characterization of hydroxy-apo-10'-carotenal/quantum dot (QD) conjugates aiming at the in vivo visualization of ß-ionone, a carotenoid-derived volatile compound known for its important contribution to the flavor and aroma of many fruits, vegetables, and plants. The synthesis of nanoparticles bound to plant volatile precursors was achieved via coupling reaction of the QD to C27-aldehyde which was prepared from α-ionone via 12 steps in 2.4% overall yield. The formation of the QD-conjugate was confirmed by measuring its fluorescence spectrum to observe the occurrence of fluorescence resonance energy transfer.

Total synthesis of enantiopure pyrrhoxanthin: alternative methods for the stereoselective preparation of 4-alkylidenebutenolides.

A new stereocontrolled total synthesis of the configurationally labile C37 -norcarotenoid pyrrhoxanthin in enantiopure form has been completed. A highly stereoselective Horner-Wadsworth-Emmons (HWE) condensation of a C17-allylphosphonate and a C20-aldehyde was used as the last conjunctive step. Both a Sonogashira reaction to form the C17-phosphonate and the final HWE condensation proved to be compatible with the sensitive C7-C10 enyne E configuration. Regioselective (5-exo-dig) silver-promoted lactonization reactions of three alternative pent-2-en-4-ynoic acid precursors with increased complexity, including a fully functionalized C20-fragment, were explored for the preparation of the γ-alkylidenebutenolide fragment. This survey extends the existing methodologies for the preparation of oxygen-containing carotenoids (xanthophylls) and streamlines the synthesis of additional members of the C37-norcarotenoid butenolide family of natural products.

On the role of excitonic interactions in carotenoid-phthalocyanine dyads and implications for photosynthetic regulation.

In two recent studies, energy transfer was reported in certain phthalocyanine-carotenoid dyads between the optically forbidden first excited state of carotenoids (Car S(1)) and phthalocyanines (Pcs) in the direction Pc â†’ Car S(1) (Kloz et al., J Am Chem Soc 133:7007-7015, 2011) as well as in the direction Car S(1) â†’ Pc (Liao et al., J Phys Chem A 115:4082-4091, 2011). In this article, we show that the extent of this energy transfer in both directions is closely correlated in these dyads. This correlation and the additional observation that Car S(1) is instantaneously populated after Pc excitation provides evidence that in these compounds excitonic interactions can occur. Besides pure energy transfer and electron transfer, this is the third type of tetrapyrrole-carotenoid interaction that has been shown to occur in these model compounds and that has previously been proposed as a photosynthetic regulation mechanism. We discuss the implications of these models for photosynthetic regulation. The findings are also discussed in the context of a model in which both electronic states are disordered and in which the strength of the electronic coupling determines whether energy transfer, excitonic coupling, or electron transfer occurs.

UVA photoprotective properties of an artificial carotenylflavonoid hybrid molecule.

Carotenoids and flavonoids represent two classes of natural antioxidants, a biological activity, which is determined by their chemical structure. To combine their antioxidant properties, a dual functional carotenylflavonoid hybrid molecule was synthesized. The antioxidant activity of this compound was tested in human dermal fibroblasts exposed to UVA irradiation. Test parameters were hemeoxygenase-1 (HO-1) expression, malondialdehyde (MDA), and reactive oxygen species (ROS) formation and cell viability. For comparison, the substructure components of the carotenylflavonoid, 4-hydroxyflavone and 11'-apo-ß-carotenylbenzene, were also tested. Incubation of cells with the carotenylflavonoid and 11'-apo-ß-carotenylbenzene attenuated UVA-induced HO-1 expression. In the MDA assay, the carotenylflavonoid and 11'-apo-ß-carotenylbenzene were moderately effective at low concentrations. At higher concentrations, the compound provoked an increase of MDA, which was confirmed by the H(2)DCF-DA assay measuring ROS formation. 4-Hydroxyflavone moderately inhibited the formation of MDA at all levels that were tested. The study showed that the carotenylflavonoid counteracts UVA-induced HO-1 expression. However, a photoprotection against lipid oxidation, ROS formation, and cell toxicity could not be proven in the experimental setting.

Stereoselective synthesis by olefin metathesis and characterization of η-carotene (7,8,7',8'-tetrahydro-ß,ß-carotene).

The purported structure of the elusive η-carotene (7,8,7',8'-tetrahydro-ß,ß-carotene), a natural C(40) carotenoid first detected in the berries of Lonicera japonica and in citrus fruits sixty years ago, has been synthesized by olefin cross-metathesis/dimerization of a C(21) polyene derived from trans-7,8-dihydroretinal, thus allowing the full characterization of this highly unstable natural product.

Hydrophilic carotenoids: recent progress.

Carotenoids are substantially hydrophobic antioxidants. Hydrophobicity is this context is rather a disadvantage, because their utilization in medicine as antioxidants or in food chemistry as colorants would require some water dispersibility for their effective uptake or use in many other ways. In the past 15 years several attempts were made to synthetize partially hydrophilic carotenoids. This review compiles the recently synthetized hydrophilic carotenoid derivatives.

Dicyano and pyridine derivatives of ß-carotene: synthesis and vibronic, electronic, and photophysical properties.

Density functional theory and time-dependent density functional theory calculations provide pictures of the molecular orbitals involved in the ground and excited states of two cyano derivatives of 8'-apo-ß-caroten-8'-al synthesized via an acid-base-catalyzed Knoevenagel condensation reaction. Population analysis shows that the symmetry-allowed transition, S(0) ((1)A(g)) → S(2) ((1)B(u)) based on the C(2h) symmetry is a HOMO (highest occupied molecular orbital) to LUMO (lowest unoccupied molecular orbital) π → π* transition with electron densities located mostly on the polyene chain. Calculated and actual steady-state absorption spectra show similar features with low-energy peak maxima between 550 and 600 nm.

Fluorinated retinoids and carotenoids.

Methods of preparing fluorinated retinoids with labels located on odd-numbered carbons as well on even-numbered carbons and those containing trifluoromethyl groups are reviewed. The use of such retinoids in studies of protein-bound species is summarized, including the application of (19)F NMR spectroscopy for elucidating the mechanism of cis/trans isomerization, restricted rotation within the protein binding pocket, and identification of specific protein-substrate interactions. The fluorine label was also useful for wavelength attenuation of protein-bound species (including formation of NIR absorbing pigments) and for other unique applications. The more limited studies available on fluorinated carotenoids are also reviewed.

Seco-type ß-Apocarotenoid Generated by ß-Carotene Oxidation Exerts Anti-inflammatory Effects against Activated Macrophages.

ß-Apocarotenoids are the cleavage products of ß-carotene. They are found in plants, carotenoid-containing foods, and animal tissues. However, limited information is available regarding the health benefits of ß-apocarotenoids. Here, we prepared seco-type ß-apocarotenoids through the chemical oxidation of ß-carotene and investigated their anti-inflammatory effects against activated macrophages. Oxidation of ß-carotene with potassium permanganate produced seco-ß-apo-8'-carotenal, in which one end-group formed an "open" ß-ring and the other was cleaved at the C-7',8' position. In lipopolysaccharide-stimulated murine macrophage-like RAW264.7 cells, seco-ß-apo-8'-carotenal inhibited the secretion and mRNA expression of inflammatory mediators such as nitric oxide, interleukin (IL)-6 and IL-1ß, and monocyte chemoattractant protein-1. Furthermore, seco-ß-apo-8'-carotenal suppressed phosphorylation of c-Jun N-terminal kinase and the inhibitor of nuclear factor (NF)-κB as well as the nuclear accumulation of NF-κB p65. Notably, since seco-ß-apo-8'-carotenal exhibited remarkable anti-inflammatory activity compared with ß-apo-8'-carotenal, its anti-inflammatory action could depend on the opened ß-ring structure. These results suggest that seco-ß-apo-8'-carotenal has high potential for the prevention of inflammation-related diseases.

Stereoretentive Suzuki-Miyaura coupling of haloallenes enables fully stereocontrolled access to (-)-peridinin.

Stimulated by the substantial challenge of synthesizing the complex and sensitive stereogenic allene-containing core of (-)-peridinin, the first stereocontrolled coupling of haloallenes with boronic acids has been achieved. This new method and the principles that emerged during its development stand to enable the more efficient and flexible preparation of a wide range of natural products, pharmaceuticals, and intermediates that possess a stereogenic allene motif. This new reaction was harnessed to achieve the first completely stereocontrolled total synthesis of (-)-peridinin. This synthesis was accomplished using only one reaction iteratively to assemble four fully functionalized building blocks with complete stereoretention at each initial halide or boron-bearing carbon. This synthesis elevates the capacity of the iterative cross-coupling strategy to an unprecedented benchmark. Moreover, the efficient and highly modular nature of this synthesis promises to enable systematic dissection of the heretofore enigmatic structure/function relationships that underlie the protein-like antilipoperoxidant activities of this remarkable small molecule natural product.

Syntheses of ylidenbutenolide-modified derivatives of peridinin and their stereochemical and spectral characteristics.

Peridinin is a light-harvesting carotenoid found in oceanic photosynthetic organisms. It possesses a unique gamma-ylidenbutenolide function and engages in energy transfer to chlorophyll a with very high (>90%) efficiency. In order to examine the relationship between the unique structure of peridinin and its facility in carrying out energy transfer, we have synthesized two different ylidenbutenolide-modified derivatives of peridinin. In this communication, the details of the syntheses are described as are the stereochemical and spectral characteristics of the derivatives; the novel ylidenbutenolide functional group stabilizes the molecule and maintains the conjugated pi-electron system in an all-trans configuration.

Carotenoids and related polyenes, part 12. First total synthesis and absolute configuration of 3'-deoxycapsanthin and 3,4-didehydroxy-3'-deoxycapsanthin.

The synthesis of 3'-deoxycapsanthin (1) and 3,4-didehydroxy-3'-deoxycapsanthin (2), carotenoids of paprika, has been achieved by employing Lewis acid-promoted regio- and stereoselective rearrangement of the C(15)-epoxy dienal 5a. The absolute stereochemistry of the newly formed C-5 chiral center of rearrangement product 6a was determined to be (R) from its alternative synthesis derived from (+)-(R)-camphonanic acid (11).