Magnesiate addition/ring-expansion strategy to access the 6-7-6 tricyclic core of hetisine-type C20-diterpenoid alkaloids

A synthetic strategy to access the fused 6–7–6 tricyclic core of hetisine-type C20-diterpenoid alkaloids is reported. This strategy employs a Diels–Alder cycloaddition to assemble a fused bicyclic anhydride intermediate, which is elaborated to a vinyl lactone-acetal bearing an aromatic ring in five steps. Aromatic iodination is followed by magnesium–halogen exchange with a trialkyl magnesiate species, which undergoes intramolecular cyclization. Subsequent oxidation provides the desired 6–7–6 tricyclic diketoaldehyde, with carbonyl groups at all three positions for eventual C–N bond formation and subsequent elaboration

Circulating microRNAs in sera correlate with soluble biomarkers of immune activation but do not predict mortality in ART treated individuals with HIV-1 infection: A case control study

Introduction: The use of anti-retroviral therapy (ART) has dramatically reduced HIV-1 associated morbidity and mortality. However, HIV-1 infected individuals have increased rates of morbidity and mortality compared to the non-HIV-1 infected population and this appears to be related to end-organ diseases collectively referred to as Serious Non-AIDS Events (SNAEs). Circulating miRNAs are reported as promising biomarkers for a number of human disease conditions including those that constitute SNAEs. Our study sought to investigate the potential of selected miRNAs in predicting mortality in HIV-1 infected ART treated individuals. Materials and Methods: A set of miRNAs was chosen based on published associations with human disease conditions that constitute SNAEs. This case: control study compared 126 cases (individuals who died whilst on therapy), and 247 matched controls (individuals who remained alive). Cases and controls were ART treated participants of two pivotal HIV-1 trials. The relative abundance of each miRNA in serum was measured, by RTqPCR. Associations with mortality (all-cause, cardiovascular and malignancy) were assessed by logistic regression analysis. Correlations between miRNAs and CD4+ T cell count, hs-CRP, IL-6 and D-dimer were also assessed. Results: None of the selected miRNAs was associated with all-cause, cardiovascular or malignancy mortality. The levels of three miRNAs (miRs -21, -122 and -200a) correlated with IL-6 while miR-21 also correlated with D-dimer. Additionally, the abundance of miRs -31, -150 and -223, correlated with baseline CD4+ T cell count while the same three miRNAs plus miR- 145 correlated with nadir CD4+ T cell count. Discussion: No associations with mortality were found with any circulating miRNA studied. These results cast doubt onto the effectiveness of circulating miRNA as early predictors of mortality or the major underlying diseases that contribute to mortality in participants treated for HIV-1 infection

Development and Validation of a Risk Score for Chronic Kidney Disease in HIV Infection Using Prospective Cohort Data from the D:A:D Study

Ristola M. on työryhmien DAD Study Grp ; Royal Free Hosp Clin Cohort ; INSIGHT Study Grp ; SMART Study Grp ; ESPRIT Study Grp jäsen.Background Chronic kidney disease (CKD) is a major health issue for HIV-positive individuals, associated with increased morbidity and mortality. Development and implementation of a risk score model for CKD would allow comparison of the risks and benefits of adding potentially nephrotoxic antiretrovirals to a treatment regimen and would identify those at greatest risk of CKD. The aims of this study were to develop a simple, externally validated, and widely applicable long-term risk score model for CKD in HIV-positive individuals that can guide decision making in clinical practice. Methods and Findings A total of 17,954 HIV-positive individuals from the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study with >= 3 estimated glomerular filtration rate (eGFR) values after 1 January 2004 were included. Baseline was defined as the first eGFR > 60 ml/min/1.73 m2 after 1 January 2004; individuals with exposure to tenofovir, atazanavir, atazanavir/ritonavir, lopinavir/ritonavir, other boosted protease inhibitors before baseline were excluded. CKD was defined as confirmed (>3 mo apart) eGFR In the D:A:D study, 641 individuals developed CKD during 103,185 person-years of follow-up (PYFU; incidence 6.2/1,000 PYFU, 95% CI 5.7-6.7; median follow-up 6.1 y, range 0.3-9.1 y). Older age, intravenous drug use, hepatitis C coinfection, lower baseline eGFR, female gender, lower CD4 count nadir, hypertension, diabetes, and cardiovascular disease (CVD) predicted CKD. The adjusted incidence rate ratios of these nine categorical variables were scaled and summed to create the risk score. The median risk score at baseline was -2 (interquartile range -4 to 2). There was a 1: 393 chance of developing CKD in the next 5 y in the low risk group (risk score = 5, 505 events), respectively. Number needed to harm (NNTH) at 5 y when starting unboosted atazanavir or lopinavir/ritonavir among those with a low risk score was 1,702 (95% CI 1,166-3,367); NNTH was 202 (95% CI 159-278) and 21 (95% CI 19-23), respectively, for those with a medium and high risk score. NNTH was 739 (95% CI 506-1462), 88 (95% CI 69-121), and 9 (95% CI 8-10) for those with a low, medium, and high risk score, respectively, starting tenofovir, atazanavir/ritonavir, or another boosted protease inhibitor. The Royal Free Hospital Clinic Cohort included 2,548 individuals, of whom 94 individuals developed CKD (3.7%) during 18,376 PYFU (median follow-up 7.4 y, range 0.3-12.7 y). Of 2,013 individuals included from the SMART/ESPRIT control arms, 32 individuals developed CKD (1.6%) during 8,452 PYFU (median follow-up 4.1 y, range 0.6-8.1 y). External validation showed that the risk score predicted well in these cohorts. Limitations of this study included limited data on race and no information on proteinuria. Conclusions Both traditional and HIV-related risk factors were predictive of CKD. These factors were used to develop a risk score for CKD in HIV infection, externally validated, that has direct clinical relevance for patients and clinicians to weigh the benefits of certain antiretrovirals against the risk of CKD and to identify those at greatest risk of CKD.Peer reviewe

Site-Selective Cross-Coupling of Polyhalogenated Arenes and Heteroarenes with Identical Halogen Groups

Methods to functionalize arenes and heteroarenes in a site-selective manner are highly sought after for rapidly constructing value-added molecules of medicinal, agrochemical, and materials interest. One effective approach is the site-selective cross-coupling of polyhalogenated arenes bearing multiple, but identical, halogen groups. Such cross-coupling reactions have proven to be incredibly effective for site-selective functionalization. However, they also present formidable challenges due to the inherent similarities in the reactivities of the halogen substituents. In this Review, we discuss strategies for site-selective cross-couplings of polyhalogenated arenes and heteroarenes bearing identical halogens, beginning first with an overview of the reaction types that are more traditional in nature, such as electronically, sterically, and directing-group-controlled processes. Following these examples is a description of emerging strategies, which includes ligand- and additive/solvent-controlled reactions as well as photochemically initiated processes

Transition Metal‐Mediated C−C Single Bond Cleavage: Making the Cut in Total Synthesis

Transition-metal-mediated cleavage of C-C single bonds can enable entirely new retrosynthetic disconnections in the total synthesis of natural products. Given that C-C bond cleavage inherently alters the carbon framework of a compound, and that, under transition-metal catalysis, the generated organometallic or radical intermediate is primed for further complexity-building reactivity, C-C bond-cleavage events have the potential to drastically and rapidly remodel skeletal frameworks. The recent acceleration of the use of transition-metal-mediated cleavage of C-C single bonds in total synthesis can be ascribed to a communal recognition of this fact. In this Review, we highlight ten selected total syntheses from 2014 to 2019 that illustrate how transition-metal-mediated cleavage of C-C single bonds at either the core or the periphery of synthetic intermediates can streamline synthetic efforts

C-C Bond Cleavage of α-Pinene Derivatives Prepared from Carvone as a General Strategy for Complex Molecule Synthesis.

The preparation of complex molecules (e.g., biologically active secondary metabolites) remains an important pursuit in chemical synthesis. By virtue of their sophisticated architectures, complex natural products inspire total synthesis campaigns that can lead to completely new ways of building molecules. In the twentieth century, one such paradigm which emerged was the use of naturally occurring "chiral pool terpenes" as starting materials for total synthesis. These inexpensive and naturally abundant molecules provide an easily accessed source of enantioenriched material for the enantiospecific preparation of natural products. The most common applications of chiral pool terpenes are in syntheses where their structure can, entirely or largely, be superimposed directly onto a portion of the target structure. Less straightforward uses, where the structure of the starting chiral pool terpene is not immediately evident in the structure of the target, can be more challenging to implement. Nevertheless, these "nonintuitive" approaches illustrate the ultimate promise of chiral pool-based strategies: that any single chiral pool terpene could be applied to syntheses of an indefinite number of structurally diverse complex synthetic targets.By definition, such strategies require carefully orchestrated sequences of C-C bond forming and C-C cleaving reactions which result in remodeling of the terpene architecture. The combination of traditional rearrangement chemistry and transition-metal-catalyzed C-C cleavage methods, the latter of which were primarily developed in the early twenty-first century, provide a rich and powerful toolbox for implementing this remodeling approach. In this Account, we detail our efforts to use a variety of C-C cleavage tactics in the skeletal remodeling of carvone, a chiral pool terpene. This skeletal remodeling strategy enabled the reorganization of the carvone scaffold into synthetic intermediates with a variety of carboskeletons, which we, then, leveraged for the total syntheses of structurally disparate terpene natural products.We begin by describing our initial investigations into various, mechanistically distinct C-C cleavage processes involving cyclobutanols synthesized from carvone. These initial studies showcased how electrophile-mediated semipinacol rearrangements of these cyclobutanols can lead to [2.2.1]bicyclic intermediates, and how Rh- and Pd-catalyzed C-C cleavage can lead to a variety of densely functionalized cyclohexenes pertinent to natural product synthesis. We, then, present several total syntheses using these synthetic intermediates, beginning with the bridged, polycyclic sesquiterpenoid longiborneol, which was synthesized from a carvone-derived [2.2.1]bicycle following a key semipinacol rearrangement. Next, we discuss how several members of the macrocyclic phomactin family were synthesized from a cyclohexene derivative prepared through a Rh-catalyzed C-C cleavage reaction. Finally, we describe our synthesis of the marine diterpene xishacorene B, which was prepared using a key Pd-catalyzed C-C cleavage/cross-coupling that facilitated the assembly of the core [3.3.1]bicycle that is resident in the natural product structure

A pyrone remodeling strategy to access diverse heterocycles: Application to the synthesis of fascaplysin natural products

The synthesis of diverse N-fused heterocycles, including the pyrido[1,2-a]indole scaffold, using an efficient pyrone remodeling strategy is described. The pyrido[1,2-a]indole core was demonstrated to be a versatile scaffold that can be site-selectively functionalized. The utility of this novel annulation strategy was showcased in a concise formal synthesis of three fascaplysin congeners

Transition Metal‐Mediated C−C Single Bond Cleavage: Making the Cut in Total Synthesis

Transition-metal-mediated cleavage of C-C single bonds can enable entirely new retrosynthetic disconnections in the total synthesis of natural products. Given that C-C bond cleavage inherently alters the carbon framework of a compound, and that, under transition-metal catalysis, the generated organometallic or radical intermediate is primed for further complexity-building reactivity, C-C bond-cleavage events have the potential to drastically and rapidly remodel skeletal frameworks. The recent acceleration of the use of transition-metal-mediated cleavage of C-C single bonds in total synthesis can be ascribed to a communal recognition of this fact. In this Review, we highlight ten selected total syntheses from 2014 to 2019 that illustrate how transition-metal-mediated cleavage of C-C single bonds at either the core or the periphery of synthetic intermediates can streamline synthetic efforts