Driven by the ever-increasing pace of drug discovery and the need to push the boundaries of unexplored chemical space, medicinal chemists are routinely turning to unusual strained bioisosteres such as bicyclo[1.1.1]pentane, azetidine, and cyclobutane to modify their lead compounds. Too often, however, the difficulty of installing these fragments surpasses the challenges posed even by the construction of the parent drug scaffold. This full account describes the development and application of a general strategy where spring-loaded, strained C–C and C–N bonds react with amines to allow for the “any-stage” installation of small, strained ring systems. In addition to the functionalization of small building blocks and late-stage intermediates, the methodology has been applied to bioconjugation and peptide labeling. For the first time, the stereospecific strain-release “cyclopentylation” of amines, alcohols, thiols, carboxylic acids, and other heteroatoms is introduced. This report describes the development, synthesis, scope of reaction, bioconjugation, and synthetic comparisons of four new chiral “cyclopentylation” reagents.

Negative impacts of endophyte-infected Lolium arundinaceum (Darbyshire) (tall fescue) are responsible for over $2 billion in losses to livestock producers annually. While the influence of endophyte-infected tall fescue has been studied for decades, mitigation methods have not been clearly elucidated. Isoflavones found in Trifolium pratense (red clover) have been the subject of recent research regarding tall fescue toxicosis mitigation. Therefore, the aim of this study was to determine the effect of ergovaline and red clover isoflavones on rumen microbial populations, fiber degradation, and volatile fatty acids (VFA) in an in vitro system. Using a dose of 1.10 mg × L-1, endophyte-infected or endophyte-free tall fescue seed was added to ANKOM fiber bags with or without 2.19 mg of isoflavones in the form of a control, powder, or pulverized tablet, resulting in a 2 × 3 factorial arrangements of treatments. Measurements of pH, VFA, bacterial taxa, as well as the disappearance of neutral detergent fiber (aNDF), acid detergent fiber (ADF), and crude protein (CP) were taken after 48 h of incubation. aNDF disappearance values were significantly altered by seed type (P = 0.003) and isoflavone treatment (P = 0.005), and ADF disappearance values were significantly different in a seed × isoflavone treatment interaction (P ≤ 0.05). A seed × isoflavone treatment interaction was also observed with respect to CP disappearance (P ≤ 0.05). Eighteen bacterial taxa were significantly altered by seed × isoflavone treatment interaction groups (P ≤ 0.05), eight bacterial taxa were increased by isoflavones (P ≤ 0.05), and ten bacterial taxa were altered by seed type (P ≤ 0.05). Due to the beneficial effect of isoflavones on tall fescue seed fiber degradation, these compounds may be viable options for mitigating fescue toxicosis. Further research should be conducted to determine physiological implications as well as microbiological changes in vivo.

Lolium arundinaceum [(Darbyshire) tall fescue] toxicosis is responsible for substantial beef production losses in the United States, due to its negative effects on reproduction, growth, and feed efficiency. These effects are consequences of toxic alkaloids within tall fescue. Interseeding legumes, such as Trifolium pratense (red clover), into pastures has been shown to mitigate a portion of these effects. Clovers contain isoflavones, which may play a role in tall fescue toxicosis mitigation. The present study utilized 36 Angus steers to determine the effects of daily supplementation with a red clover-isolated isoflavone feed additive on physiological symptoms of tall fescue toxicosis and the rumen microbial environment over a 21-d period. Angus steers were initially stratified based upon their single nucleotide polymorphism genotype at the DRD2 receptor. Treatments were then randomly assigned in a 2 × 2 factorial arrangement within a completely randomized design, where treatment factors consisted of tall fescue seed type (endophyte-infected tall fescue seed vs. endophyte-free tall fescue seed) supplemented with and without the isoflavone additive. Steers that consumed endophyte-infected tall fescue seed had lower serum prolactin concentrations (P = 0.0007), average daily gain (ADG; P = 0.003), final body weight (BW; P = 0.004), and feed efficiency (P = 0.018) when compared with steers that consumed endophyte-free tall fescue seed. Serum insulin-like growth factor-1 (IGF-1) tended to be reduced with supplementation of isoflavones (P = 0.06) but was unaffected by seed type (P ≥ 0.10) and seed by treatment interaction (P ≥ 0.10). Isoflavones reduced serum glucose levels (P = 0.023), but neither seed type, isoflavones, or their interaction affected serum urea nitrogen (SUN), nonesterified fatty acids (NEFA), or insulin (P ≥ 0.10). Volatile fatty acid concentrations, dry matter intake (DMI), ruminal pH, and overall feeding behaviors were also unaffected by seed type or isoflavone treatments (P ≥ 0.10). Twenty-eight ruminal bacteria taxa shifted as a result of seed type or isoflavone treatment (P < 0.05). In this experiment, feeding isoflavones to Angus cattle did not completely mitigate all symptoms of fescue toxicosis. However, dose–response trials may aid future research to determine if dietary supplementation with isoflavones alleviates fescue toxicosis symptoms and promotes livestock growth and performance.

The objective of this experiment was to evaluate the impact of complexed trace mineral supplementation on ovum pick-up (OPU) and in vitro embryo production in lactating beef cows. Thirty days prior to fixed-time artificial insemination (FTAI; day −30), 68 postpartum cows were stratified by BW, BCS, and parity before being randomly assigned to 10 pens of either a treatment (TRT; n = 5) or a control (CNT; n = 5) group. Each group received a weekly mineral supplement allotment of 1.16 kg × week −1 × cow–calf pair −1 for 14 wk. Cows assigned to the TRT group received a mineral supplement that contained amino acid complexes of zinc, copper, and manganese, as well as cobalt glucoheptonate (Availa Plus; Zinpro Corp., Eden Prairie, MN, USA), while cows assigned to the CNT group received a mineral supplement that was formulated to contain similar concentrations of these trace minerals from inorganic sources. All cows were submitted to a 7 d CO-Synch + CIDR protocol on day −10 and bred using FTAI on day 0. Pregnancy diagnosis was performed on day 28 and nonpregnant cows were removed. All pregnant cows were subjected to ovum pick-up (OPU) on day 52 and 67 of gestation. Cumulus-oocyte complexes (COCs) were evaluated and graded prior to in vitro fertilization (IVF). Analysis of variance was conducted to determine effects of treatment on response variables, and pen was considered the experimental unit. Supplement consumption did not differ ( P = 0.48) between treatments (1.16 ± 0.12 vs. 1.07 ± 0.15 kg of DM × week −1 × cow–calf pair −1 for TRT and CNT, respectively). Total COC recovery was greater ( P = 0.03) from TRT when compared with CNT cows (22.4 ± 2.0 vs. 16.4 ± 1.4 COCs × pen −1 , respectively) and the number of COCs meeting maturation criteria was increased in TRT cows ( P = 0.05) when compared with CNT cows (15.9 ± 1.6 vs. 11.8 ± 1.0 COCs × pen −1 , respectively). Production of transferable embryos tended to be greater ( P = 0.06) for TRT than CNT cows (4.7 ± 0.6 vs. 2.7 ± 0.7 embryos × pen −1 , respectively). Furthermore, when expressed as a ratio, the number of recovered COCs meeting maturation criteria that were required to produce a transferable embryo tended to be lower for TRT than CNT cows (3.10 ± 0.93 vs. 7.02 ± 1.60; P = 0.06). In summary, complete replacement with complexed trace mineral improved COC recovery and in vitro embryo production when compared with inorganic forms of these trace minerals in beef cows.

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