General Synthesis of Conformationally Constrained Noncanonical Amino Acids with C(sp3)-Rich Benzene Bioisosteres.

Recent years have seen novel modalities emerge for the treatment of human diseases resulting in an increase in beyond rule of 5 (bRo5) chemical matter. As a result, synthetic innovations aiming to enable rapid access to complex bRo5 molecular entities have become increasingly valuable for medicinal chemists' toolkits. Herein, we report the general synthesis of a new class of noncanonical amino acids (ncAA) with a cyclopropyl backbone to achieve conformational constraint and bearing C(sp3)-rich benzene bioisosteres. We also demonstrate preliminary studies toward utilities of these ncAA as building blocks for medicinal chemistry research.

Effect of elevating luteinizing hormone action using low doses of human chorionic gonadotropin on double ovulation, follicle dynamics, and circulating follicle-stimulating hormone in lactating dairy cows.

Double ovulation and twin pregnancy are undesirable traits in dairy cattle. Based on previous physiological observations, we tested the hypothesis that increased LH action [low-dose human chorionic gonadotropin (hCG)] before the expected time of diameter deviation would change circulating FSH concentrations, maximum size of the second largest (F2) and third largest (F3) follicles, and frequency of multiple ovulations in lactating dairy cows with minimal progesterone (P4) concentrations. In replicate 1, multiparous, nonbred lactating Holstein dairy cows (n = 18) had ovulation synchronized. On d 5 after ovulation, all cows had their corpus luteum regressed and were submitted to follicle (≥3 mm) aspiration 24 h later to induce emergence of a new follicular wave. Cows were then randomized to NoP4 (untreated) and NoP4+hCG (100 IU of hCG every 24 h for 4 d after follicle aspiration). Ultrasound evaluations and blood sample collections were performed every 12 h for 7 d after follicle aspiration. All cows were then treated with 200 µg of GnRH to induce ovulation. In replicate 2, cows (n = 16) were resubmitted to similar procedures (i.e., corpus luteum regression, follicle aspiration, randomization, ultrasound evaluations every 12 h, GnRH 7 d after aspiration). However, cows in replicate 2 received an intravaginal P4 device that had been previously used (∼18 d). Only cows with single (n = 15) and double (n = 16) ovulations were used in the analysis. No significant differences were detected for frequency of double ovulation, follicle sizes, and FSH concentrations across replicates (NoP4 vs. LowP4 and NoP4+hCG vs. LowP4+hCG), so data were combined. Double ovulation was 40% for control cows with no hCG (CONT) and 62.5% with hCG (hCG). Double ovulation increased as the maximum size of F2 increased: <9.5 mm and 9.5-11.5 mm (7.7%) and ≥11.5 mm (94.1%). The hCG group had more cows with F2 > 11.5 (69%) than with 9.5 ≥ F2 ≤ 11.5 (25%) and F2 < 9.5 (6%). In agreement, F2 and F3 maximum size were larger in the hCG group, but FSH concentrations were lower after F1 > 8.5 mm compared with CONT. In contrast, FSH concentrations were greater before deviation (F1 closest value to 8.5 mm) in cows with double ovulations than in those with single ovulations, regardless of hCG treatment. In addition, time from aspiration to deviation was shorter in cows with double rather than single ovulation and in cows treated with hCG as a result of faster F1, F2, and F3 growth rates before diameter deviation. In conclusion, greater FSH and follicle growth before deviation seems to be a primary driver of greater frequency of double ovulation in lactating cows with low circulating P4. Moreover, the increase in follicle growth before deviation and in the maximum size of F2 during hCG treatment suggests that increased LH may also have a role in stimulating double ovulation.

Wales Anaerobic Test: Reliability and Fitness Profiles of International Rugby Union Players.

ABSTRACT: Beard, A, Ashby, J, Chambers, R, Millet, GP, and Brocherie, F. Wales Anaerobic Test (WAT): Reliability and fitness profiles of international rugby union players. J Strength Cond Res 36(9): 2589-2596, 2022-To provide strength and conditioning coaches a practical and evidence-based test for repeated-sprint ability (RSA) in rugby union players, this study assessed the relative and absolute test-retest reliability of the Wales Anaerobic Test (WAT) and its position-specific association with other fitness performance indices. Thirty-four players (forwards: n = 19; backs: n = 15) of the Welsh rugby union male senior national team performed the WAT (10 × 50-m distance, 25-30 seconds of passive recovery) twice within 4 days. Time for each repetition was recorded, with the best (WAT Best ) and total time (WAT TT ) retained for analysis. Relative (intraclass correlation coefficient [ICC]) and absolute ( SEM ) reliability of the WAT indices were quantified. Furthermore, association (Pearson's product-moment correlations and stepwise backward elimination procedure) with other fitness performance indices (10- and 40-m sprinting times, 30-15 intermittent fitness test [30-15 IFT ] and the Yo-Yo intermittent recovery test level 2 [YYIR2]) was investigated. Pooled values revealed "moderate" to "high" ICCs for WAT Best (ICC = 0.89, p = 0.626) and WAT TT (ICC = 0.95, p = 0.342). Good test sensitivity was reported for forwards and backs' WAT TT ( p > 0.101). Both WAT Best and WAT TT correlated with 10-m and 40-m sprinting times ( r > 0.69, p < 0.001) as well as with 30-15 IFT ( r < -0.77, p < 0.001) and YYIR2 ( r < -0.68, p < 0.001) for pooled values. The WAT proved to be a reliable and sensitive test to assess the rugby union specific RSA-related fitness of international players.

Comparison of Game Movement Positional Profiles Between Professional Club and Senior International Rugby Union Players.

The purpose of this study was to compare the game movement demands between professional club and senior international rugby union players. Data were obtained from 188 players from 4 professional club teams (Rabo Direct Pro12) and the affiliated international team during the 2014-15 season. Players were tracked by global positioning system (GPS) sampled at 10 Hz and were categorized into 6 different positional groups (front row forwards, FRF; second row forwards, SRF; back row forwards, BRF; half backs, HB; centres, C; outside backs, OB) and separated into playing standard (club vs. international level). Data on distance, distance per minute, high speed running, maximum velocity, sprint distance and efforts as well as repeated high-intensity locomotion efforts (RHILE) were collected. Significant effects (P<0 .05) between club and international were found for RHILE in all 6 positional groupings with a higher number of RHILE in international vs. club games. Significantly (P<0.05) greater total distance and meterage were also shown in international compared to club for OB position. The RHILE differences between club and international games whatever the positions appear of practical relevance for coaches and performance staff to concentrate on training protocols to enhance this quality as well as evaluation methods.

Research on timed AI in beef cattle: Past, present and future, a 27-year perspective.

This review aimed to (1) summarize the results from fixed-timed artificial insemination (TAI) fertility studies performed during the last 27 years; (2) compile and evaluate, as examples from the literature base, the direct comparisons made of specific manipulations to synchronization protocols; (3) evaluate the impact of the TAI programs on the reproductive performance during the breeding season, and (4) provide perspective on the future of TAI programs in beef cattle. A search of the literature published from 1995 to 2021 was conducted to identify experiments in which synchronization of ovulation and TAI in beef cattle was performed. The primary outcome of interest was fertility expressed as pregnancies per TAI. The literature included two search engines, the SIS Web of Science and the US National Library of Medicine Institutes of Health through PubMed. After the initial search and screening, a total of 228 manuscripts were selected containing a total of 272,668 TAI. A dramatic increase in the number of publications and TAIs occurred throughout the years. Most of them were from Brazil and United States, followed by Canada, Argentina, Uruguay, and Australia. Two main types of TAI programs were identified: GnRH-based and E2/P4-based protocols. In terms of GnRH-based programs, two variations were evaluated in the present manuscript. First, we evaluated the effect of the progesterone implant during the protocol. The progesterone implant increased pregnancy/TAI (P/TAI) from 44.3 to 54.3%. Second, the use of a second prostaglandin F2α treatment in 5-d CO-synch program increased the P/TAI from 53.2 to 60.9%. In E2/P4-based programs, use of GnRH at TAI increased P/TAI from 54.7 to 59.2% in cows. However, no increase was detected in heifers. Other research showed that use of TAI can increase the overall proportion of the cows pregnant at end of the breeding season and produce earlier calvings compared with bulls. In conclusion, there have been a large number of excellent research studies that have been performed during the last 27 years on TAI in beef cattle. This technology is being utilized successfully in the beef cattle industry. This success is largely because of the valid research that underlies the application of the technology and the economic value of the technology.

Serotonin alters the response to a glucose challenge in lactating cows.

Energy partitioning in lactating cows affects milk production, feed efficiency, and body reserves, with the latter having health implications for the transition into the following lactation. One molecule likely involved in the regulation of energy partitioning is serotonin. The objective of this experiment was to explore how increasing circulating serotonin, by intravenous infusion of the serotonin precursor 5-hydroxytryptophan (5-HTP), affects metabolic responses to a glucose challenge in midlactation cows as a means to manipulate energy partitioning. We intravenously infused Holstein cows with 5-HTP (1 mg/kg bodyweight dissolved in saline, n = 11) or saline alone as control (n = 9) over 1 h/day for 3 days. Cows were fasted overnight on day 2. On day 3, fasted cows were given an intravenous bolus of glucose (0.092 g/kg bodyweight). Blood samples were collected for the following 120 min for metabolic and hormonal analysis. Infusion of 5-HTP elevated circulating concentrations of serotonin and free fatty acids, reduced the concentration of insulin and amino acids, and did not affect the concentration of glucose and glucagon before the glucose challenge. Surrogate insulin sensitivity indices indicated improved insulin sensitivity in 5-HTP cows, but due to the unique metabolism of lactating ruminants, these index changes may instead reflect effects in insulin-independent glucose disposal, like milk synthesis. Challenging 5-HTP-treated cows with a glucose bolus reduced the insulin spike and blunted the decrease in free fatty acids, compared to saline cows, without changing glucose dynamics. Overall, these results suggest that serotonin stimulates insulin-independent glucose disposal, requiring less insulin to maintain normoglycemia.

The antidepressant fluoxetine (Prozac®) modulates serotonin signaling to alter maternal peripartum calcium homeostasis.

Antidepressant use is two-fold greater in women compared to men; however, most studies have been performed in male subjects. We aimed to understand the impact of selective serotonin reuptake inhibitors (SSRI, most used antidepressants) on calcium homeostasis and steroid metabolism during the peripartum period. Pregnant sheep (n = 10/group) were treated with vehicle or fluoxetine (most common SSRI) during the last month of gestation. Fluoxetine treatment decreased circulating calcium prior to parturition (8.7 ± 0.1 mg/dL vs 8.2 ± 0.1 mg/dL; P = 0.07). In the control group, total calcium decreased after parturition corresponding to the onset of lactogenesis followed by increase in calcium by day 2 postpartum. Interestingly, this normal transient decrease in circulating calcium was absent in fluoxetine-treated ewes. The steroids cortisol and progesterone were not altered by fluoxetine treatment whereas estradiol was decreased after the onset of treatment (12.4 ± 1.3 vs 9.1 ± 1.2 pg/mL, P = 0.05) and prior to parturition (38.1 ± 8.1 vs 22.3 ± 4.2 pg/mL, P = 0.03). Our hypothesis was supported that fluoxetine treatment alters circulating concentrations of calcium in the peripartum period; however, we surprisingly observed a decrease in estradiol concentrations contrary to reports in in vitro studies.

Fluoxetine-induced perinatal morbidity in a sheep model.

Selective serotonin reuptake inhibitors (SSRI) are the most common antidepressants used by pregnant women. However, adverse pregnancy outcomes have been described in women taking SSRI during pregnancy-placental lesions, premature birth, poor neonatal adaptation. We aimed to investigate the effects of fluoxetine (Prozac® most commonly used SSRI) treatment during the last month of gestation on pregnancy complications, placental and neonatal health in a non-depressed sheep model. On day 119 ± 1 postbreeding (experimental day 0; E0) of a 151-day expected gestation, Hampshire ewes were randomly assigned to receive fluoxetine (n = 9 ewes, 15 lambs; daily intravenously treatment with 10 mg/kg on E0 and E1 and 5 mg/kg daily thereafter until parturition) or to a control group (n = 10; 14 lambs; vehicle only). Blood samples from ewes were collected throughout the experimental period and postpartum; blood from lambs were collected postpartum. Analysis of variance was used for statistical analysis. Fluoxetine treatment reduced placentome growth during the last month of pregnancy. Gestation length was decreased by 4.5 days in fluoxetine-treated ewes. Birthweight was reduced in lambs exposed to fluoxetine in utero; weights remained decreased until postnatal day 3. Placentome diameter by birthweight ratio was not different between groups suggesting that the decreased placentome diameter was accompanied by decreased lamb birthweight. During the first week postnatal, lambs exposed to fluoxetine in utero had decreased blood pH and decreased total carbon dioxide, bicarbonate, and base excess and increased lactate (days 3-6), collectively indicative of metabolic acidemia. Additionally, ionized calcium was decreased between postnatal days 0 to 4 in lambs exposed to fluoxetine in utero. Using a non-depressed animal model clearly defines a role for SSRI on the occurrence of perinatal complications and neonatal morbidity. The decreased placentome diameter, shortened gestation, decreased birthweight, decreased calcium levels, and neonatal acidemia suggest the occurrence of intrauterine growth restriction. The persistence of neonatal acidemia for several days postpartum suggests poor neonatal adaptation to extrauterine environment.

Bartonella spp. in feral pigs, southeastern United States.

In conjunction with efforts to assess pathogen exposure in feral pigs from the southeastern United States, we amplified Bartonella henselae, B. koehlerae, and B. vinsonii subsp. berkhoffii from blood samples. Feral pigs may represent a zoonotic risk for hunters or butchers and pose a potential threat to domesticated livestock.

Effects of Combined Foot/Ankle Electromyostimulation and Resistance Training on the In-Shoe Plantar Pressure Patterns during Sprint in Young Athletes.

Several studies have already reported that specific foot/ankle muscle reinforcement strategies induced strength and joint position sense performance enhancement. Nevertheless the effects of such protocols on sprint performance and plantar loading distribution have not been addressed yet. The objective of the study is to investigate the influence of a 5-wk foot/ankle strength training program on plantar loading characteristics during sprinting in adolescent males. Sixteen adolescent male athletes of a national training academy were randomly assigned to either a combined foot/ankle electromyostimulation and resistance training (FAST) or a control (C) group. FAST consisted of foot medial arch and extrinsic ankle muscles reinforcement exercises, whereas C maintained their usual training routine. Before and after training, in-shoe loading patterns were measured during 30-m running sprints using pressure sensitive insoles (right foot) and divided into nine regions for analysis. Although sprint times remained unchanged in both groups from pre- to post- training (3.90 ± 0.32 vs. 3.98 ± 0.46 s in FAST and 3.83 ± 0.42 vs. 3.81 ± 0.44 s in C), changes in force and pressure appeared from heel to forefoot between FAST and C. In FAST, mean pressure and force increased in the lateral heel area from pre- to post- training (67.1 ± 44.1 vs. 82.9 ± 28.6 kPa [p = 0.06]; 25.5 ± 17.8 vs. 34.1 ± 14.3 N [p = 0.05]) and did not change in the medial forefoot (151.0 ± 23.2 vs. 146.1 ± 30.0 kPa; 142.1 ± 29.4 vs. 136.0 ± 33.8; NS). Mean area increased in FAST under the lateral heel from pre- to post- (4.5 ± 1.3 vs. 5.7 ± 1.6 cm(2) [p < 0.05]) and remained unchanged in C (5.5 ± 2.8 vs. 5.0 ± 3.0 cm(2)). FAST program induced significant promising lateral and unwanted posterior transfer of the plantar loads without affecting significantly sprinting performance. Key pointsWe have evaluated the effects of a foot/ankle strength training program on sprint performance and on related plantar loading characteristics in teenage athletes, and this have not been examined previously.Our results showed no significant pre- to post- changes in sprint performance.This study revealed initially a lateral transfer and secondly a posterior transfer of the plantar loads after the foot/ankle strength training program.

Structure-Based Discovery of Proline-Derived Arginase Inhibitors with Improved Oral Bioavailability for Immuno-Oncology.

Recent data suggest that the inhibition of arginase (ARG) has therapeutic potential for the treatment of a number of indications ranging from pulmonary and vascular disease to cancer. Thus, high demand exists for selective small molecule ARG inhibitors with favorable druglike properties and good oral bioavailability. In light of the significant challenges associated with the unique physicochemical properties of previously disclosed ARG inhibitors, we use structure-based drug design combined with a focused optimization strategy to discover a class of boronic acids featuring a privileged proline scaffold with superior potency and oral bioavailability. These compounds, exemplified by inhibitors 4a, 18, and 27, demonstrated a favorable overall profile, and 4a was well tolerated following multiple days of dosing at concentrations that exceed those required for serum arginase inhibition and concomitant arginine elevation in a syngeneic mouse carcinoma model.

Comprehensive Strategies to Bicyclic Prolines: Applications in the Synthesis of Potent Arginase Inhibitors.

Comprehensive synthetic strategies afforded a diverse set of structurally unique bicyclic proline-containing arginase inhibitors with a high degree of three-dimensionality. The analogs that favored the Cγ-exo conformation of the proline improved the arginase potency over the initial lead. The novel synthetic strategies reported here not only enable access to previously unknown stereochemically complex proline derivatives but also provide a foundation for the future synthesis of bicyclic proline analogs, which incorporate inherent three-dimensional character into building blocks, medicine, and catalysts and could have a profound impact on the conformation of proline-containing peptides and macrocycles.

Discovery and Optimization of Rationally Designed Bicyclic Inhibitors of Human Arginase to Enhance Cancer Immunotherapy.

The action of arginase, a metalloenzyme responsible for the hydrolysis of arginine to urea and ornithine, is hypothesized to suppress immune-cell activity within the tumor microenvironment, and thus its inhibition may constitute a means by which to potentiate the efficacy of immunotherapeutics such as anti-PD-1 checkpoint inhibitors. Taking inspiration from reported enzyme-inhibitor cocrystal structures, we designed and synthesized novel inhibitors of human arginase possessing a fused 5,5-bicyclic ring system. The prototypical member of this class, 3, when dosed orally, successfully demonstrated serum arginase inhibition and concomitant arginine elevation in a syngeneic mouse carcinoma model, despite modest oral bioavailability. Structure-based design strategies to improve the bioavailability of this class, including scaffold modification, fluorination, and installation of active-transport recognition motifs were explored.

Factors influencing the interconversion of a new class of dibenzodiazepine sulfonamide atropisomers.

A novel family of atropisomers based on a conformationally constrained seven membered ring system is investigated using a combination of preparative chiral chromatography, circular dichroism, and other analytical techniques. The influence of structure on the rate of atropisomer interconversion was explored with a series of analogs showing a range of interconversion rates ranging from very fast (undetectable on the HPLC timescale) to very slow (half life of many days).

Upper-body repeated-sprint training in hypoxia in international rugby union players.

This study investigated the effects of upper-body repeated-sprint training in hypoxia vs. in normoxia on world-level male rugby union players' repeated-sprint ability (RSA) during an international competition period. Thirty-six players belonging to an international rugby union male national team performed over a 2-week period four sessions of double poling repeated-sprints (consisting of 3 × eight 10-s sprints with 20-s passive recovery) either in normobaric hypoxia (RSH, simulated altitude 3000 m, n = 18) or in normoxia (RSN, 300 m; n = 18). At pre- and post-training intervention, RSA was evaluated using a double-poling repeated-sprint test (6 × 10-s maximal sprint with 20-s passive recovery) performed in normoxia. Significant interaction effects (P < 0.05) between condition and time were found for RSA-related parameters. Compared to Pre-, peak power significantly improved at post- in RSH (423 ± 52 vs. 465 ± 69 W, P = 0.002, η²=0.12) but not in RSN (395 ± 65 vs. 397 ± 57 W). Averaged mean power was also significantly enhanced from pre- to post-intervention in RSH (351 ± 41 vs. 388 ± 53 W, P < 0.001, η²=0.15), while it remained unchanged in RSN (327 ± 49 vs. 327 ± 43 W). No significant change in sprint decrement (P = 0.151, η² = 0.02) was observed in RSH (-17 ± 2% vs. -16 ± 3%) nor RSN (-17 ± 2% vs. -18 ± 4%). This study showed that only four upper-body RSH sessions were beneficial in enhancing repeated power production in international rugby union players. Although the improvement from RSA to game behaviour remains unclear, this finding appears of practical relevance since only a short preparation window is available prior to international games.

Repeated-Sprint Training in Hypoxia in International Rugby Union Players.

Purpose: To investigate the effects of repeated-sprint training in hypoxia vs in normoxia on world-level male rugby union players' repeated-sprint ability (RSA) during an international competition period. Methods: A total of 19 players belonging to an international rugby union senior male national team performed 4 sessions of cycling repeated sprints (consisting of 3 × eight 10-s sprints with 20 s passive recovery) either in normobaric hypoxia (RSH, 3000 m; n = 10) or in normoxia (RSN, 300 m; n = 9) over a 2-wk period. Before and after the training intervention, RSA was evaluated using a cycling repeated-sprint test (6 × 10-s maximal sprint and 20-s passive recovery) performed in normoxia. Results: Significant interaction effects (all P < .05, ηp2>.37 ) between condition and time were found for RSA-related parameters. Compared with Pre, maximal power significantly improved at Post in RSH (12.84 [0.83] vs 13.63 [1.03] W·kg-1, P < .01, ηp2=.15 ) but not in RSN (13.17 [0.89] vs 13.00 [1.01] W·kg-1, P = .45, ηp2=.01 ). Mean power was also significantly enhanced from Pre to Post in RSH (11.15 [0.58] vs 11.86 [0.63] W·kg-1, P < .001, ηp2=.26 ), whereas it remained unchanged in RSN (11.54 [0.61] vs 11.75 [0.65] W·kg-1, P = .23, ηp2=.03 ). Conclusion: As few as 4 dedicated specific RSH sessions were beneficial to enhance repeated power production in world-level rugby union players. Although the improvement from RSA to game behavior remains unclear, this finding appears to be of practical relevance as only a short preparation window is available prior to international rugby union games.

The Use of Wearable Microsensors to Quantify Sport-Specific Movements.

BACKGROUND: Microtechnology has allowed sport scientists to understand the locomotor demands of various sports. While wearable global positioning technology has been used to quantify the locomotor demands of sporting activities, microsensors (i.e. accelerometers, gyroscopes and magnetometers) embedded within the units also have the capability to detect sport-specific movements. OBJECTIVE: The objective of this study was to determine the extent to which microsensors (also referred to as inertial measurement units and microelectromechanical sensors) have been utilised in quantifying sport-specific movements. METHODS: A systematic review of the use of microsensors and associated terms to evaluate sport-specific movements was conducted; permutations of the terms used included alternate names of the various technologies used, their applications and different applied environments. Studies for this review were published between 2008 and 2014 and were identified through a systematic search of six electronic databases: Academic Search Complete, CINAHL, PsycINFO, PubMed, SPORTDiscus, and Web of Science. Articles were required to have used athlete-mounted sensors to detect sport-specific movements (e.g. rugby union tackle) rather than sensors mounted to equipment and monitoring generic movement patterns. RESULTS: A total of 2395 studies were initially retrieved from the six databases and 737 results were removed as they were duplicates, review articles or conference abstracts. After screening titles and abstracts of the remaining papers, the full text of 47 papers was reviewed, resulting in the inclusion of 28 articles that met the set criteria around the application of microsensors for detecting sport-specific movements. Eight articles addressed the use of microsensors within individual sports, team sports provided seven results, water sports provided eight articles, and five articles addressed the use of microsensors in snow sports. All articles provided evidence of the ability of microsensors to detect sport-specific movements. Results demonstrated varying purposes for the use of microsensors, encompassing the detection of movement and movement frequency, the identification of movement errors and the assessment of forces during collisions. CONCLUSION: This systematic review has highlighted the use of microsensors to detect sport-specific movements across a wide range of individual and team sports. The ability of microsensors to capture sport-specific movements emphasises the capability of this technology to provide further detail on athlete demands and performance. However, there was mixed evidence on the ability of microsensors to quantify some movements (e.g. tackling within rugby union, rugby league and Australian rules football). Given these contrasting results, further research is required to validate the ability of wearable microsensors containing accelerometers, gyroscopes and magnetometers to detect tackles in collision sports, as well as other contact events such as the ruck, maul and scrum in rugby union.

Kinetics and mechanism of the oxidation of guanosine derivatives by Pt(IV) complexes.

The kinetics of redox reactions of the PtIV complexes trans-Pt(d,l)(1,2-(NH2)2C6H10)Cl4 ([PtIVCl4(dach)]) and Pt(NH2CH2CH2NH2)Cl4 ([PtIVCl4(en)]) with 5'- and 3'-dGMP (G) have been studied. These redox reactions involve substitution followed by an inner-sphere electron transfer. The substitution is catalyzed by PtII and follows the classic Basolo-Pearson PtII-catalyzed PtIV-substitution mechanism. We found that the substitutution rates depend on the steric hindrance of PtII, G, and PtIV with the least sterically hindered PtII complex catalyzing at the highest rate. 3'-dGMP undergoes substitution faster than 5'-dGMP, and [PtIVCl4(en)] substitutes faster than [PtIVCl4(dach)]. The enthalpies of activation of the substitution, DeltaH double dagger s, of 3'-dGMP is only 70% greater than that of 5'-dGMP (50.4 vs 30.7 kJ mol(-1)), but the entropy of activation of the substitution, DeltaS double dagger s, of 3'-dGMP is much greater than that of 5'-dGMP (-59.4 vs -129.5 J K(-1) mol(-1)), indicating that steric hindrance plays a major role in the substitution. The enthalpy of activation of electron transfer, DeltaH double dagger e, of 3'-dGMP is smaller than that of 5'-dGMP (88.8 vs 137.8 kJ mol(-1)). The entropy of activation of electron transfer, DeltaS double dagger e, of 3'-dGMP is negative, but that of 5'-dGMP is positive (-27.8 vs +128.8 J K-1 mol-1). The results indicate that 5'-hydroxo has less rotational barrier than 5'-phosphate, but it is geometrically unfavorable for internal electron transfer. The electron-transfer rate also depends on the reduction potential of PtIV. Because of its higher reduction potential, [PtIVCl4(dach)] has a faster electron transfer than [PtIVCl4(en)].