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.

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.

A Relational Framework for Engaging Latino Sexual Minority Men in Sexual and Behavioral Health Research.

Latino sexual minority men (LSMM) experience sexual and behavioral health disparities. Yet, LSMM are underrepresented in sexual and behavioral health research, creating scientific inequity. There is, therefore, a need to identify the barriers and facilitators to LSMM's participation in sexual and behavioral health research, which is the gap that the current study sought to fill. We interviewed LSMM (n = 28; age 18-40, 57% US born) and key informants (n = 10) regarding LSMM's barriers and facilitators to participating in sexual and behavioral health research and suggestions for increasing participation. The research team coded the data via thematic analysis. We found that relational factors are central to understanding LSMM's participation in sexual and behavioral health research. Some relational experiences (e.g., interpersonal stigma) interfered with participation, whereas others (e.g., altruistic desires to contribute to community well-being) facilitated participation. The findings are consolidated within a new relational framework for understanding LSMM's participation in sexual and behavioral health research. Study findings highlight the centrality of relational factors in influencing LSMM's participation in sexual and behavioral health research. Relational factors can be used to inform the development of culturally relevant recruitment strategies to improve representation of LSMM in sexual and behavioral health research. Implementing these recommendations may address scientific inequity, whereby LSMM are disproportionately impacted by sexual and behavioral health concerns yet underrepresented in related research.

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.

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.

Insomnia, Health, and Health-related Quality of Life in an Urban Clinic Sample of People Living with HIV/AIDS.

OBJECTIVE/BACKGROUND: Insomnia is a prevalent and interfering comorbidity of HIV infection. Nearly 70% of people living with HIV/AIDS (PLWHA) experience symptoms of insomnia and associated distress. The current study examined the mechanisms of insomnia in HIV health status and health-related quality of life and explored behavioral pathways to explain relationships. PARTICIPANTS: Participants (N = 103) were active patients in an HIV clinic located within a nonprofit, tertiary care hospital in a large, urban city in the Southeast United States. METHODS: Participants completed a clinical sleep interview and self-report assessments for adherence to antiretroviral medication, depression (PHQ-9), quality of life (ACTG-QOL), and relevant covariates. Viral load and CD4 were obtained via medical chart review. RESULTS: Insomnia affected 67% of the clinic sample. Insomnia symptoms were directly associated with poorer health-related quality of life (p<.001). Greater insomnia symptoms were also significantly associated with greater depressive symptoms [b =.495, S.E. =.061], poorer medication adherence [b = -.912, S.E. =.292], and worse health status measured by absolute CD4 count [b = -.011, S.E. =.005]. CONCLUSIONS: In this sample of PLWHA, insomnia was associated with poorer health-related quality of life and worse health status. Future research and practice should consider insomnia treatment for this population, as it could improve overall health and well-being.

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).

On the regiochemical differences between Pd-catalyzed heterocyclization-allylation and -arylation reactions of alkynylbenzamides: preparation of 4-allyl-isochromen-1-imines and computational study.

The Pd(0)-catalyzed cyclization-allylation reactions of 2-alkynylbenzamides proceed with high regioselectivity to afford the 6-endo-cyclization-derived products 4-allyl-isochromen-1-imines. DFT calculations have been performed on this and the related arylation reaction, that has been reported to afford the products corresponding to an exo-cyclization under similarly Pd(0)-catalyzed conditions. Under the reaction conditions, these cyclizations are presumed to be triggered by activation of the C-C triple bond with either an allyl- or an aryl palladium complex, generated by oxidative addition of an allyl- or aryl halide to the Pd(0) catalyst. For reactions promoted by allylpalladium species, calculations predict a reversible cyclization, followed by a regioselectivity-determining endo-selective reductive elimination. In contrast, according to calculations, the corresponding arylations would proceed through irreversible exo-selective cyclization and reductive elimination steps. These predictions are consistent with the experimental observations. The divergent regiochemical outcome appears to have its origin in the differences caused on the intermediate palladium complexes by the groups derived from the coupling agents (allyl or aryl) and by the reaction conditions (solvent and ligands) through a subtle interplay of polarity and coordinative effects.

Exploiting the Multidentate Nature of Chiral Disulfonimides in a Multicomponent Reaction for the Asymmetric Synthesis of Pyrrolo[1,2-a]indoles: A Remarkable Case of Enantioinversion.

A new multicomponent coupling reaction for the enantioselective synthesis of pyrrolo[1,2-a]indoles under the catalysis of a chiral disulfonimide is described. The high specificity of the reaction is a consequence of the multidentate character of the Brønsted acid catalyst. Insights from DFT calculations helped explain the unexpected high enantioselectivity observed with the simplest 3,3'-unsubstituted binaphthyl catalyst as a result of transition-state stabilization by a network of cooperative noncovalent interactions. The remarkable enantioinversion resulting from the simple introduction of substituents at 3- and 3'-positions, the first reported example of this phenomenon in the context of binaphthalene-derived Brønsted acid catalysis, was instead attributed to destabilizing steric interactions.

Stereoselective [3+2] Carbocyclization of Indole-Derived Imines and Electron-Rich Alkenes: A Divergent Synthesis of Cyclopenta[b]indole or Tetrahydroquinoline Derivatives.

An unprecedented stereoselective [3+2] carbocyclization reaction of indole-2-carboxaldehydes, anilines, and electron-rich alkenes to obtain cyclopenta[b]indoles is disclosed. This pathway is different from the well-established Povarov reaction: the formal [4+2] cycloaddition involving the same components, which affords tetrahydroquinolines. Moreover, by simply changing the Brønsted acid catalyst, this multicomponent coupling process could be divergently directed towards the conventional Povarov pathway to produce tetrahydroquinolines or to the new pathway (anti-Povarov) to generate cyclopenta[b]indoles. Supported by computational studies, a stepwise Mannich/Friedel-Crafts cascade is proposed for the new anti-Povarov reaction, whereas a concerted [4+2] cycloaddition mechanism is proposed for the Povarov reaction.

Synthesis of labile all-trans-7,8,7',8'-bis-acetylenic carotenoids by bi-directional Horner-Wadsworth-Emmons condensation.

A new stereoselective synthesis of the C40-bis-acetylenic carotenoids all-trans-(3R,3'R)-alloxanthin and all-trans-3,4,7,8,3',4',7',8'-octadehydro-ß,ß-carotene, both compounds featuring a stereochemically labile C7-C10 enyne, based on a bi-directional Horner-Wadsworth-Emmons (HWE) reaction of a C15-phosphonate and a central C10-dialdehyde, is reported. The triene unit of the latter fragment was synthesized using the acyclic metathesis/dimerization reaction.

Total synthesis and structural revision of (+)-cristatumin C.

Naturally occurring (+)-cristatumin C, a bis-pyrrolidinoindoline diketopiperazine alkaloid isolated from Eurotium cristatum EN-220, is the 2R,3R,11S,15R,2'R,3'R,11'S,15'S enantiomer, as confirmed by total synthesis.

Silicon particles as trojan horses for potential cancer therapy.

BACKGROUND: Porous silicon particles (PSiPs) have been used extensively as drug delivery systems, loaded with chemical species for disease treatment. It is well known from silicon producers that silicon is characterized by a low reduction potential, which in the case of PSiPs promotes explosive oxidation reactions with energy yields exceeding that of trinitrotoluene (TNT). The functionalization of the silica layer with sugars prevents its solubilization, while further functionalization with an appropriate antibody enables increased bioaccumulation inside selected cells. RESULTS: We present here an immunotherapy approach for potential cancer treatment. Our platform comprises the use of engineered silicon particles conjugated with a selective antibody. The conceptual advantage of our system is that after reaction, the particles are degraded into soluble and excretable biocomponents. CONCLUSIONS: In our study, we demonstrate in particular, specific targeting and destruction of cancer cells in vitro. The fact that the LD50 value of PSiPs-HER-2 for tumor cells was 15-fold lower than the LD50 value for control cells demonstrates very high in vitro specificity. This is the first important step on a long road towards the design and development of novel chemotherapeutic agents against cancer in general, and breast cancer in particular.

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.