A practical and asymmetric synthesis of potent anti-HIV nucleoside MK-8527 is described. The key discoveries are a novel stereoselective dynamic kinetic resolution (DKR) Mitsunobu glycosylation and selective amination of the resulting 2,6-dichloro nucleoside. The new route was successfully demonstrated on the kilogram scale and provided isolated MK-8527 with more than 99% HPLC purity through crystallization.

3099 Background: Prognosis in mUM is poor with limited efficacy of currently available therapies. The melanocortin-1 receptor (MC1R) is an attractive target for radiopharmaceutical therapy given high expression in UM. 225 Ac-MTI-201 is a novel alpha particle emitting MC1R bound radiopharmaceutical with high biostability, affinity, and MC1R-specific cytotoxicity with defined dosimetry and pharmacokinetics in pre-clinical studies. Methods: In this first-in-human study (NCT05496686) of a single IV dose of 225 Ac-MTI-201, we enrolled mUM patients (pts) who had disease progression on at least 1 prior therapy. Pts had adequate organ and functional status; prior radiotherapy to >25% of bone marrow was exclusionary. The primary objective was safety and toxicity of 225 Ac-MTI-201 with secondary endpoints of pharmacokinetics (PK) and clearance of 225 Ac-MTI-201, response rate, progression-free survival (PFS), and overall survival (OS). Up to 12 dose levels [from 4.7 microcurie (µCi) to 1327 µCi] for 225 Ac-MTI-201 were planned per a modified continual re-assessment method (CRM) with a cohort size of one based on dose limiting toxicity (DLT) assessment within 28 days of drug administration using CTCAE v5.0. Response was assessed by RECIST 1.1. Results: Sixteen pts (8 male, 8 female), median age 63 years (43, 84) have been treated. Median number of prior systemic regimens was 2 (0,4), 8 pts had prior liver directed treatment. Dose of 225 Ac-MTI-201 was escalated to level 6 (152 µCi) when one DLT (G4 thrombocytopenia and G4 neutropenia) was observed requiring de-escalation per CRM. A second DLT (G4 neutropenia) at level 5 (76 µCi) required expansions at levels 4 (38 µCi; n=5) and 5 (n=6) where all remaining pts were treated without further DLT with 1 pt currently pending final DLT assessment. Adverse events (AEs) were mostly G1-2 including leucopenia, lymphopenia, neutropenia, thrombocytopenia, anemia, nausea, fatigue and ↑ AST. Reversible myelosuppression [lymphopenia (7), neutropenia (5), thrombocytopenia (2)] was the most common > G3 AE. No non-hematological DLT was seen. Best response was stable disease (4/15; 27%); seen at dose levels 4 and 5. The median PFS was 2.30 months (95% CI: 1.84, 3.65); 6-month PFS was 0.07 (95% CI: 0.0, 0.26) and 12-month OS was 0.39 (95% CI: 0.13, 0.64). Median distribution phase half-life (n=15) was 6.19 minutes followed by a slower median elimination phase half-life of 74.06 minutes with significant positive correlation between fast and slow half-lives (Spearman = 0.696, p= 0.0039), independent of dose level. Conclusions: Single dose administration of 225 Ac-MTI-201 with dose escalation to 76 µCi appears safe and feasible in mUM. Disease stability in this difficult to treat population is encouraging and a multi-dose study of 225 Ac-MTI-201 in mUM is planned pending final pt DLT assessment. 225 Ac-MTI-201 has Orphan Drug designation for mUM. Clinical trial information: NCT05496686 .

Herein is reported a new PtCl2/XPhos/Et3SiH-catalyzed hydroboration method for unactivated terminal alkynes. Significantly, the reaction proceeds in hindered alkyne systems, and works well on acetylenes that contain multiple heteroatom-groups to provide the desired (E)-1,2-vinyl boronates in reasonable to high yields with excellent levels of stereo- and regio-control.

We report an operationally simple calcium catalysed Strecker type reaction for the synthesis of α-aminonitriles from readily available N,O-acetals. The reaction is tolerant to a wide range of useful functional groups, including heterocycles, and provides the product in good to excellent yields. Additionally, the reaction does not require the need for anhydrous or air-free conditions, making it a suitable candidate for high throughput experimentation.

The Peterson olefination describes the regioselective transformation of carbonyl compounds to olefins mediated by α-silyl carbanions and has been extensively studied since its discovery. This review provides an insight into the mechanism behind the Peterson olefination, and summarizes work conducted in this area over the last 20 years, including new methodologies and applications in total syntheses.

We present the first study on the application of platinum complexes in the hydrostannylation of terminal alkynes. A range of platinum complexes were screened, with PtCl2/XPhos proving to provide the best selectivity for the beta-(E)-vinyl stannane. The catalyst system is able to provide the corresponding vinyl stannane in selectivities which surpasses that which is typically afforded under palladium catalysis. Additionally, a telescoped hydrometallation/cross-coupling sequence has been developed, allowing for application of the vinyl stannanes without excessive manipulation or purification of the intermediate stannane.

Organostannanes have represented one of the most widely applied reagents in modern cross-coupling chemistry and represent a key reagent in the synthesis of a range of pharmaceutically relevant scaffolds. This Concept article reviews recent advances in approaches to the synthesis of these building blocks in a stereocontrolled and regiocontrolled manner. Particular focus is paid to methods which allow for divergent synthesis of alkenylstannanes and developments in methods which present opportunities for sustainable synthesis. This Concept article summarises recent advances in approaches to the synthesis of important vinyl stannane building blocks in a stereocontrolled and regiocontrolled manner. Particular emphasis is put on those routes in which judicious choice of ligand affords a switchable reaction, providing routes to stereodefined olefins from a single starting material.image

The α-functionalization of amines and related scaffolds plays a key role in both target synthesis and medicinal chemistry. As such, elegant solutions employing transition metal catalysis, photoredox catalysis, and electrosynthetic methods have been described. The methods often rely on harsh activation conditions or difficult-to-access catalysts and experimental setups. Here, we report a calcium-catalyzed addition of aniline derivatives into N-acyliminium ions under mild conditions to access a diverse range of Mannich-type products. The reaction is unified and can be applied to N,O-acetal derivatives to access di-substituted amides and also isoindolinones as a method to functionalize medicinally relevant scaffolds. The reaction displays a high level of functional group tolerance and provides access to a diverse range of scaffolds.

We present a rapid (0.25-1 h), method to produce functionalised allylsilanes from readily available vinylsilanes. Employing a Bronsted acid catalysed dehydration as the key step, allylsilanes are produced in good yields (22-98%) and, in most cases, as a single geometric isomer. Furthermore, a possible allylation-Cope pathway was discovered for certain substrates and attempts to optimise this are described. image

This article focusses on the characteristics and synthesis of a range of bicyclic 5-5 systems bearing four heteroatoms in a 2:2 fashion. Theoretical and structural characteristics of these interesting scaffolds are discussed, before detailing the many methods of synthesis. Most bicycles contain nitrogen, oxygen and sulfur atoms, and the most novel or well-characterized methods are described in terms of the mechanistic rationale, where appropriate. The article is divided into conjugated and nonconjugated rings systems to aid the reader, with subdivisions focusing on specific reaction types. Finally, we highlight how these heterocycles were used in materials science and medicinal chemistry.

Herein, we report the development of a novel route to tricyclic lactam products via a facile aza-[4 + 2] cycloaddition of catalytically generated acyliminium ions. Employing a Ca(NTf2)2/nBu4NPF6 catalyst system in low loadings, a range of diverse fused ring systems can be synthesised in predominantly good yields.

Organosilicon reagents are highly versatile and privileged scaffolds in modern synthetic chemistry, largely due to the range of transformations the groups are amenable to. The β‐Silicon effect is one of the fundamental phenomena underpinning the inherent reactivity of organosilicon reagents, allowing unsaturated organosilanes to undergo a range of electrophilic substitutions with a variety of nucleophiles. The application of the β‐Silicon effect in a range of organic transformations is reviewed with the discussion divided up based on the class of silane. The reactivity of these compounds towards carbon, heteroatom and metallic electrophiles is discussed from classical applications such as the Sakurai allylation to contemporary applications such as cross‐coupling chemistry. In addition, examples of these transformations in the context of methodology development and natural product synthesis are provided.

BACKGROUND:Inferior vena cava tumor thrombus (IVC-TT) is a rare yet deadly sequel of renal cell carcinoma (RCC) with limited treatment options. The standard treatment is extirpative surgery, which has high rates of morbidity and mortality. As a result, many patients are unfit or unwilling to undergo surgery and face poor prognosis. This stresses the need for alternative options for local disease control. Our study aims to assess the feasibility and oncological outcomes of stereotactic ablative radiation (SAbR) for IVC-TT. METHODS:A retrospective study reviewing six leading international institutions' experience in treating RCC with IVC-TT with SAbR. Primary end point was overall survival using Kaplan-Meier. RESULTS:Fifteen patients were included in the cohort. Over 50% of patients had high level IVC-TT (level III or IV), 66.7% had metastatic disease. Most eschewed surgery due to high surgical risk (7/15) or recurrent thrombus (3/15). All patients received SAbR to the IVC-TT with a median biologically equivalent dose (BED10) of 72 Gy (range: 37.5-100.8) delivered in a median of 5 fractions (range 1-5). Median overall survival was 34 months. Radiographic response was observed in 58% of patients. Symptom palliation was recorded in all patients receiving SAbR for this indication. Only grade 1 to 2 adverse events were noted. CONCLUSIONS:SAbR for IVC-TT appears feasible and safe. In patients who are not candidates for surgery, SAbR may palliate symptoms and improve outcomes. SAbR may be considered as part of a multimodal treatment approach for patients with RCC IVC-TT.

Organosilicon reagents are highly versatile and privileged scaffolds in modern synthetic chemistry, largely due to the range of transformations the groups are amenable to. The beta-Silicon effect is one of the fundamental phenomena underpinning the inherent reactivity of organosilicon reagents, allowing unsaturated organosilanes to undergo a range of electrophilic substitutions with a variety of nucleophiles. The application of the beta-Silicon effect in a range of organic transformations is reviewed with the discussion divided up based on the class of silane. The reactivity of these compounds towards carbon, heteroatom and metallic electrophiles is discussed from classical applications such as the Sakurai allylation to contemporary applications such as cross-coupling chemistry. In addition, examples of these transformations in the context of methodology development and natural product synthesis are provided.

In the past two decades, extensive efforts have been made to develop agents targeting prostate-specific membrane antigen (PSMA) for prostate cancer imaging and therapy. To date, represented by two recent approvals of [68Ga]Ga-PSMA-11 and [18F]F-DCFPyL by the United States Food and Drug Administration (US-FDA) for positron emission tomography (PET) imaging to identify suspected metastases or recurrence in patients with prostate cancer, PSMA-targeting imaging and theranostic agents derived from small molecule PSMA inhibitors have advanced to clinical practice and trials of prostate cancer. The focus of current development of new PSMA-targeting agents has thus shifted to the improvement of in vivo pharmacokinetics and higher specific binding affinity with the aims to further increase the detection sensitivity and specificity and minimize the toxicity to non-target tissues, particularly the kidneys. The main strategies involve systematic chemical modifications of the linkage between the targeting moiety and imaging/therapy payloads. In addition to a summary of the development history of PSMA-targeting agents, this review provides an overview of current advances and future promise of PSMA-targeted imaging and theranostics with focuses on the structural determinants of the chemical modification towards the next generation of PSMA-targeting agents.

The regio and stereoselective hydrosilylation of a variety of homopropargylic alcohols and their derivatives is described. The reaction is tolerant to a variety of sterically and electronically varied substrates, affording only the E-vinyl silane as a sole regioisomer. The application of the resultant vinyl silanes towards the diastereoselective synthesis of tetrasubstituted oxetanes is demonstrated.

Purpose/Objective(s) Patients with renal cell carcinoma (RCC) not suitable for surgery have few curative treatment options, particularly as thermal ablation has diminishing efficacy in RCC > 3 cm or adjacent to collecting system. Stereotactic ablative body radiotherapy (SABR) is a novel option limited by lack of long-term outcome data. We hypothesize that SABR represents an effective and safe, nephron-sparing alternative for RCC in the long-term. Materials/Methods Individual patient data from 12 institutions from IROCK were pooled. Patients with M1 disease and/or upper tract urothelial carcinoma were excluded. Minimum eligible follow-up was ≥ 2 years. Demographics, treatment, oncologic and renal function outcomes were assessed using descriptive statistics. Kaplan-Meier estimates and univariable and multivariable Cox proportional hazards regression were generated for oncologic outcomes. Local failure was investigator defined using RECIST 1.1. Patterns of failure were described using a cumulative incidence function with death as competing event. Toxicity was described using CTCAE v4.0. Results In 190 patients, the median follow-up was 5.0 years (range?). The mean ± SD tumor diameter was 4.2 ± 2.2 cm and 95 patients (50%) had ≥ T1b (≥ 4 cm) primaries. Median age was 74 years (interquartile range [IQR]: 66-82), 73.2% were male and 87.6% had good performance status (ECOG 0-1 or KPS ≥ 70%). In patients for whom operability details were reported, 75.0% were defined as inoperable by the referring urologist, mostly for cardiovascular comorbidities (46.9%). Baseline tumor complexity was moderate (median RENAL [1] score of 7 [IQR: 5-9]), and 56 patients (29.5%) had a solitary kidney. Mean ± SD BED10 delivered was 88.3 ± 24.7 Gy. Mean ± SD baseline estimated glomerular filtration rate (eGFR) was 58.9 ± 22.6 mL/min (mild-to-moderate dysfunction) with 53 patients (28.0%) of the cohort having moderate-to-severe dysfunction (eGFR < 45 mL/min). At 3- and 5-years following SABR, mean ± SD eGFR decreased by -10.8 ± 16.6 mL/min and -13.5 ± 14.9 mL/min, respectively. Nine patients (4.7%) required dialysis. Seventy patients (36.8%) had a grade 1-2 toxicity, and one patient (0.5%) had a grade 4 toxicity (gastrointestinal). Cancer-specific survival (CSS) and progression-free survival (PFS) at 3 years were 95.5% and 72.1%, and at 5 years were 92.0% and 63.6%, respectively. Local, distant and any failure at 5 years were 5.5%, 10.8% and 13.0%. On multivariable analysis, increasing tumor size was associated with inferior CSS (HR per 1 cm increase: 1.41; 95% CI: 1.15-1.71; p < 0.001), PFS (HR: 1.10; 95% CI: 1.01-1.19; p=0.030), and any failure (HR: 1.20; 95% CI: 1.10-1.32; p < 0.001). Conclusion At 5-years post-therapy, SABR for primary RCC was associated with excellent local efficacy and good oncological outcomes, with only modest impact on renal function. [1] A. Kutikov & R.G. Uzzo "The RENAL nephrometry score: a comprehensive standardized system for quantitating renal tumor size, location and depth." J. Urol (2009)182(3):844

A range of highly functionalized polycyclic fragments have been synthesized, employing a catalytic dehydrative cyclization. A range of nucleophiles are shown to be successful, with the reaction producing numerous high value motifs.

Cucurbitacins are dietary compounds that have been shown to elicit a range of anti-tumour, anti-inflammatory and anti-atherosclerotic activities. Originally identified as signal transducer and activator of transcription, STAT, inhibitors, a variety of mechanisms of action have since been described, including dysregulation of the actin cytoskeleton and disruption of integrin function. Integrin outside-in signalling and cytoskeletal rearrangements are critical for the propagation of stable thrombus formation and clot retraction following platelet adhesion at the site of vessel damage. The effects of cucurbitacins on platelet function and thrombus formation are unknown. We report for the first time anti-platelet and anti-thrombotic effects of cucurbitacins B, E and I in human platelets. Treatment of platelets with cucurbitacins resulted in attenuation of platelet aggregation, secretion and fibrinogen binding following stimulation by platelet agonists. Cucurbitacins were also found to potently inhibit other integrin- and cytoskeleton-mediated events, including adhesion, spreading and clot retraction. Further investigation of cytoskeletal dynamics found treatment with cucurbitacins altered cofilin phosphorylation, enhanced activation and increased F actin polymerisation and microtubule assembly. Disruption to cytoskeletal dynamics has been previously shown to impair integrin activation, platelet spreading and clot retraction. Anti-platelet properties of cucurbitacins were found to extend to a disruption of stable thrombus formation, with an increase in thrombi instability and de-aggregation under flow. Our research identifies novel, anti-platelet and anti-thrombotic actions of cucurbitacins that appear to be linked to dysregulation of cytoskeletal dynamics and integrin function.

N-acyliminium ions are highly electrophilic reactive intermediates which allow functionalization α to an amide or carbamate. Traditionally accessed using stoichiometric quantities, catalytic generation continually offers greater control and selectivity. This review provides an overview of the most recent advancements in catalytic access to N-acyliminium ions using Brønsted acid, Lewis acid, photoredox and redox mediated pathways.