"Several birds with one stone": exploring the potential of AI methods for multi-target drug design.

Drug discovery is a time-consuming and expensive process. Artificial intelligence (AI) methodologies have been adopted to cut costs and speed up the drug development process, serving as promising in silico approaches to efficiently design novel drug candidates targeting various health conditions. Most existing AI-driven drug discovery studies follow a single-target approach which focuses on identifying compounds that bind a target (i.

Experimental Evidence for Zerovalent Pd(NHC) as a Competent Catalyst in C-N Cross-Coupling (NHC = DiMeIHept).

Use of the branched N-heterocyclic carbene (NHC) ligand 1,3-bis(2,6-bis(3-methyl-1-(2-methylpropyl)butyl)phenyl)-4,5-dichloro-1,3-dihydro-2-imidazole-2-ylidene (DiMeIHept) facilitated the stabilization of several relevant intermediates for Pd(NHC)-catalyzed C-N cross-coupling reactions. Complexes [Pd(DiMeIHept)](μ-N), [Pd(DiMeIHept)](μ-η-1,2-η-4,5-CH), and Pd(DiMeIHept)(pyridine), representing zerovalent Pd(NHC) bearing labile ligands, were isolated and structurally characterized, along with divalent PdCl(Ph)(DiMeIHept) and PdCl(Ph)(DiMeIHept)(-propylamine). The former is a 14-electron Pd complex, which is stable under air and chromatography on silica gel or neutral alumina.

Design and synthesis of novel main protease inhibitors of COVID-19: quinoxalino[2,1-]quinazolin-12-ones.

The COVID-19 pandemic represents a substantial global challenge, being a significant cause of mortality in numerous countries. Thus, it is imperative to conduct research to develop effective therapies to combat COVID-19. The primary aim of this study is to employ a two-step tandem reaction involving 2,3-dichloroquinoxaline and 2-amino--substituted benzamides in alkaline media/DMF at an elevated temperature to design and synthesize a series of polycyclic derivatives endowed with quinoxalino[2,1-]quinazolin-12-one framework.

Restricted access and advanced disease in post-pandemic testicular cancer.

Introduction: Urologists observed reduced cancer consultations and surgeries during the SARS-CoV-2 pandemic, raising concern about treatment delays. Testicular cancer serves as a particularly sensitive marker of this phenomenon, as the clinical stage of testicular cancer at presentation is predictive of cancer-specific survival. We aimed to investigate whether COVID-related restrictions to primary care access resulted in increased incidence of metastatic germ cell testis cancer.

Impact of the COVID-19 pandemic on diagnosis of renal cell carcinoma and disease stage at presentation.

Introduction: Renal cell carcinoma (RCC) is often associated with significant morbidity and mortality, with overall survival contingent on multiple factors - most importantly, disease stage at diagnosis. Disruptions in healthcare delivery during the COVID-19 pandemic have resulted in various reported diagnostic and treatment delays, which have had detrimental impacts on malignancies such as RCC.

Methods: Surgically managed cases of RCC at our center were identified using a retrospective chart review of all nephrectomies conducted from March 1, 2018, to February 28, 2023.

A General Approach to Optically Pure, α-Methyl Non-Natural Amino Acids: Enabling Unique Peptides as Drug Candidates.

An α-methyl, non-natural amino acid (NNAA) building block equipped with an alkyl halide tail that could be readily transformed into an organozinc was prepared. This single organometallic was cross-coupled to an array of heterocyclic electrophiles using the Pd-PEPPSI-IHept catalyst to produce a wide selection of optically pure α-methyl NNAAs. With these in hand, non-natural peptides are being produced for evaluation in a variety of therapeutic areas in drug discovery.

The Utility of Salvage Radiotherapy for an Inoperable Inguinal Recurrence of Squamous Cell Carcinoma of the Penis.

Penile cancer is a rare genitourinary malignancy for which limited treatment options exist beyond primary surgical resection. Metastatic lymphadenopathy represents a particularly poor prognosis with a lack of literature to suggest the effectiveness of radiation or systemic therapies. Our case documents an inguinal recurrence of penile squamous cell carcinoma not amenable to surgical intervention demonstrating complete response to salvage radiotherapy in the palliative setting.

A quality assurance review of penile cancer diagnostic delays and stage at presentation during the COVID-19 pandemic.

Introduction: Penile carcinomas represent a rare malignancy associated with significant psychosocial impacts that deter afflicted individuals from seeking medical attention, thus, worsening prognosis. Following the dramatic shift in healthcare delivery to virtual platforms, it is suspected that prevalent psychosocial impacts have been further compounded by the COVID-19 pandemic, resulting in several late-stage presentations and engendering poorer outcomes.

Methods: A retrospective chart review of surgically managed cases of penile cancer was conducted from January 2020 to June 2022 to identify patients that may have been unduly impacted by the COVID-19 pandemic.

Impact of N-Aryl- and NHC Core-Substituents on the Coupling of Alkylzinc Nucleophiles: Is Bigger always Better?

Bulky Pd-N-heterocyclic carbene (NHC) catalysts (e. g., N-(di-2,6-(3-pentyl)phenyl), IPent) have been shown to have significantly higher reactivity in a wide variety of cross-coupling applications (i.

Structural Insights into the Inhibition of Undecaprenyl Pyrophosphate Synthase from Gram-Positive Bacteria.

The polyprenyl lipid undecaprenyl phosphate (CP) is the universal carrier lipid for the biosynthesis of bacterial cell wall polymers. CP is synthesized in its pyrophosphate form by undecaprenyl pyrophosphate synthase (UppS), an essential -prenyltransferase that is an attractive target for antibiotic development. We previously identified a compound (MAC-0547630) that showed promise as a novel class of inhibitor and an ability to potentiate β-lactam antibiotics.

(DiMeIHept)Pd: A Low-Load Catalyst for Solvent-Free (Melt) Amination.

, a hyper-branched N-aryl Pd NHC catalyst, has been shown to be efficient at performing amine arylation reactions in solvent-free ("melt") conditions. The highly lipophilic environment of the alkyl chains flanking the Pd center serves as lubricant to allow the complex to navigate through the paste-like environment of these mixtures. The protocol can be used on a multi-gram scale to make a variety of aniline derivatives, including substrates containing alcohol moieties.

Sodium Butylated Hydroxytoluene: A Functional Group Tolerant, Eco-Friendly Base for Solvent-Free, Pd-Catalysed Amination.

NaBHT (sodium 2,6-di-tert-butyl-4-methylphenolate), a strong, but hindered and lipophilic base, has been effectively paired with similarly lipophilic, high-reactivity Pd-NHC (N-heterocyclic carbene) catalysts to produce an ideal combination for performing solvent-free (melt) cross-coupling amination. The mild nucleophilicity of NaBHT, coupled with the anti-oxidant properties of its conjugate acid byproduct, BHT means the process seems to have no functional group incompatibilities. Highly effective coupling of base-sensitive and redox-active functional groups was observed in all cases with only 0.

Functional Adrenocortical Carcinoma: A Rare Case With Thrombus Extension Into the Inferior Vena Cava and a Presentation of Cushing Syndrome.

Adrenocortical carcinoma (ACC) is a rare, highly malignant endocrine tumor, often associated with a poor prognosis. Most patients who develop ACC are either children of ages 1-6, or adults in their fourth to fifth decade of life. Individuals with a functional cortisol-secreting ACC frequently present with Cushing syndrome.

Sampling and Analysis in Flow: The Keys to Smarter, More Controllable, and Sustainable Fine-Chemical Manufacturing.

Process analytical technology (PAT) is a system designed to help chemists better understand and control manufacturing processes. PAT systems operate through the combination of analytical devices, reactor control elements, and mathematical models to ensure the quality of the final product through a quality by design (QbD) approach. The expansion of continuous manufacturing in the pharmaceutical and fine-chemical industry requires the development of PAT tools suitable for continuous operation in the environment of flow reactors.

Experimental and Computational Study on the Anti-Markovnikov Hydrofunctionalization of Olefins Using Glycine-Extended AQ-Auxiliaries.

Two similar tridentate directing groups derived from glycine and 8-aminoquinoline were shown to enable the palladium-catalyzed anti-Markovnikov hydrofunctionalization of 4-pentenylamine with drastically different efficiencies. A computational investigation into the origin of the reactivity difference between these isomeric, carbonyl-transposed auxiliaries suggests that protonation state, thus charge of the substrate-metal complex prior to nucleopalladation is key. These investigations have culminated in a directing group design that can undergo Pd-catalyzed hydrofunctionalization under relatively mild conditions, as low as room temperature.

Intelligent Multidimensional Purity Analysis and Confirmation Tool for Multiple Attribute Analysis.

Chiral active pharmaceutical ingredients (APIs) are known to bind to chiral biological targets with better on-target specificity than achiral ones. However, the methods of synthesizing such APIs stereoselectively require the exhaustive optimization of multiple quality attributes of an asymmetric synthesis, wherein all critical quality attributes (for example, chemical and stereochemical purity of the API) are to be optimized in parallel and ideally from the beginning of the drug development program. A multidimensional liquid chromatographic tool capable of simultaneously measuring multiple quality attributes from a single analytical injection is reported.

The Synthesis of Warfarin Using a Reconfigurable-Reactor Platform Integrated to a Multiple-Variable Optimization Tool.

Optimization of the asymmetric synthesis of warfarin, an important anticoagulant, has been evaluated using a reconfigurable reaction platform capable of performing batch, continuous flow, and plug-flow synthesis. Further, this platform has been integrated with a novel, multidimensional, multiple variable analysis tool that can evaluate multiple critical quality attributes (CQA), percent conversion and enantiomeric excess in this case, from a single injection that is repeatedly recycled in a closed loop of chromatography columns, a detector and a heart-cut valve. Further, the new, integrated analysis system also facilitates validation of each QA, providing a high-level of confidence in analytical measurements, which are obtained without operator intervention.

Development of a 3D-printed testicular cancer model for testicular examination education.

Introduction: Testicular cancer is the most commonly diagnosed malignancy in young males. Testicular examination is a non-invasive and inexpensive means of detecting testicular cancer at an early stage. In this project, a set of 3D-printed models was developed to facilitate teaching testicular examination and improving understanding of testicular malignancies among patients and medical learners.

Salt to Taste: The Critical Roles Played by Inorganic Salts in Organozinc Formation and in the Negishi Reaction.

The first cross-coupling of organozinc nucleophiles with aryl halides was reported in 1977 by Negishi. Unknown to all at the time was the importance of salt additives that were often present as a byproduct from the organozinc preparation. For decades, these salt additives were overlooked until 2006 when it was discovered that two different, yet effective methods for preparing organozinc solutions (i.

Anatomical 3D-Printed Silicone Prostate Gland Models and Rectal Examination Task Trainer for the Training of Medical Residents and Undergraduate Medical Students.

The current generation of graduating medical students is entering into practice with minimal exposure to the digital rectal examination (DRE), a necessary component of a complete physical examination. Simulation-based medical education (SBME) using anatomical silicone models and task trainers can provide hands-on training opportunities for medical students to rehearse DREs. However, there is a scarcity of affordable, validated, and anatomically correct silicone prostate models and task trainers for rehearsing DREs.

Nephroureterectomy of Right-to-Left Crossed Fused Renal Ectopia with Urothelial Carcinoma.

Urothelial carcinoma in a crossed fused renal ectopia (CFRE) is an exceedingly rare clinical finding. We describe the surgical management used to treat upper tract urothelial carcinoma in a 64-year-old man with a right-to-left CFRE. Nephroureterectomy with bladder cuff excision was the treatment of choice.

A Path to More Sustainable Catalysis: The Critical Role of LiBr in Avoiding Catalyst Death and its Impact on Cross-Coupling.

The role that LiBr plays in the lifetime of Pd-NHC complexes has been investigated. A bromide ion is proposed to coordinate to Pd thereby preventing beta hydride elimination (BHE) (to form NHC-H ) of the reductive elimination (RE) intermediate that normally completes with the desired cross-coupling catalytic cycle. Coordinating groups, such as anilines, are able to bind suitably well to Pd to prevent this pathway from occurring, thus reducing the need for the added salt.

Identification of tumor size as the only factor associated with nondiagnostic biopsies in patients with small renal masses.

Introduction: As greater numbers of small renal masses (SRMs) are discovered incidentally, renal tumor biopsy (RTB) is an increasingly recognized step for the management of these lesions, ideally for the prevention of surgical overtreatment for benign disease. While the diagnosis can often be obtained preoperatively by RTB, indeterminate results create greater difficulty for patients and clinicians. This study examines a series of RTBs, identifying the portion of these that were able to yield a diagnosis, and correlates patient factors, including RENAL and PADUA scoring, with the outcome of a non-diagnostic result.

Discovery of an antivirulence compound that reverses β-lactam resistance in MRSA.

Staphylococcus aureus is the leading cause of infections worldwide, and methicillin-resistant strains (MRSA) are emerging. New strategies are urgently needed to overcome this threat. Using a cell-based screen of ~45,000 diverse synthetic compounds, we discovered a potent bioactive, MAC-545496, that reverses β-lactam resistance in the community-acquired MRSA USA300 strain.