Введення гем-дифлуороциклоалкільних замісників у гетероцикли через стратегію «видалення Нітрогену» Левіна

A series of compounds containing heterocyclic cores and gem-difluorocycloalkyl substituents was obtained under conditions of the parallel synthesis (i.e., simultaneous performance of reaction procedures, treatment of the reaction mixture, and product isolation for a number of similar transformations) using the reductive amination – the “Nitrogen deletion” reaction sequence. The synthesis of the target compounds commenced from heteroaromatic aldehydes and the corresponding gem-difluorocycloalkyl or (gem-difluorocycloalkyl)methyl amines and included the NaBH3CN-mediated reductive amination and “Nitrogen deletion” upon the action of Levin’s anomeric amide. It has been shown that the method can be used to obtain compounds with the aforementioned structural fragments separated by one or two methylene units. The developed protocol allowed for the preparation of a 12-member compound library (67 % synthetic efficiency). Therefore, this novel synthetic methodology is suitable for decorating heterocyclic cores with sp3-enriched substituents that are attractive for medicinal chemistry.В умовах паралельного синтезу (тобто одночасного виконання реакції, оброблення реакційної суміші та виділення продукту для низки споріднених перетворень) із застосуванням послідовності реакції відновного амінування та «видалення Нітрогену» було одержано серію сполук, що містять гетероциклічні фрагменти та гем-дифлуороциклоалкільні замісники. Синтез цільових сполук виходив з гетероароматичних альдегідів і відповідних гем-дифлуороциклоалкіл- або (гем-дифлуороциклоалкіл)метиламінів та передбачав відновне амінування за участі NaBH3CN і «видалення Нітрогену» під дією аномерного аміду Левіна. Доведено, що метод застосовний для одержання сполук із вищезгаданими структурними фрагментами, розділеними однією чи двома метиленовими ланками. Розроблений протокол дозволив одержати бібліотеку сполук із 12 представників (синтетична ефективність 67 %). Отже, ця новітня синтетична методологія є придатною для декорування гетероциклічних систем sp3-збагаченими замісниками, що є привабливими для медичної хімії

Oncologic Outcomes of Radical Prostatectomy and Prognostic Stratification in Patients with Clinically Locally Advanced Prostate Cancer

Oncologic outcomes of radical prostatectomy in 106 patients with clinically locally advanced prostate cancer were demonstrated. The mean follow-up was 50.6 (12-129) months. 5-year recurrence-free survival was 47.7 %, 5-year cancer-specific and overall survival - 85.8 %. Patients were devided into three different risk groups: low risk patients had PSA level <20 ng/ml, biopsy Gleason score ≤6 and absence of the seminal vesicle invasion of cancer; intermediate risk was noted when the patient had only one of poor prognostic factors (PSA ≥20 ng/ml or biopsy Gleason score≥7 or presence of cancer invasion to the seminal vesicle) and high risk patients had 2 or 3 poor prognostic factors. For patients of low, intermediate and high risk the biochemical reccurence rates were 14.3 %, 37.1 % and 70.2 %, respectively (p=0.002). The patients of intermediate and high risk had clinically significant higher risk of biochemical reccurence than those of low risk with odds ratio 3.0 and 8.5, respectively. Such grouping may help in guiding the individualized treatment for these patients

Identification of Readily Available Pseudo-Natural Products

Pseudo-natural products (PNPs) combine fragments derived from NPs in ways that are not found in nature, and may lead to the discovery of novel chemotypes for unexpected targets or the identification of unprecedented bioactivities. PNPs have increasingly been explored in recent drug discovery programs, and are strongly enriched in clinical compounds. We describe how a large number of structurally different PNPs can be accessed readily and without the need to execute labor- and time intensive synthesis programs. We employed an improved version of the previously reported natural product fragment combination (NPFC) tool to analyze the full library of 3.5M synthetic small molecules and screening libraries from Enamine for PNP content, assessed the spatial complexity of Enamine-PNPs using the recently developed normalized Spatial Score (nSPS) and evaluated the bioactivity of a selected subset of Enamine-PNPs in the unbiased morphological cell painting assay. A major fraction (32%; 1.1 million compounds) of the Enamine library are PNPs which contain a significant number of compounds with unexpected and probably new bioactivity

Synthesis and chemical transformations of diazolyl alpha,alpha-difluoroacetates

Optimized protocols for the synthesis of diazolyl alpha,alpha-difluoroacetates via deoxofluorination of the corresponding glyoxylates with Morph-DAST are described. The method allowed the preparation of the title fluoridated building blocks in 73-96 % yield on up to 15 g scale. Utility of the hetaryl alpha,alpha-difluoroacetates was demonstrated by the synthesis of advanced building blocks for medicinal chemistry, i.e. carboxylic acids, amides, nitriles, and alcohols

Beyond the Five and Six: Evaluation of Seven-Membered Cyclic Anhydrides in the Castagnoli–Cushman Reaction

The Castagnoli–Cushman reaction with benzo­[<i>d</i>]­oxepine-2,4­(1<i>H</i>,5<i>H</i>)-dione as an anhydride component allowed for preparation of 2,3-disubstituted 4-oxo-2,3,4,5-tetrahydro-1<i>H</i>-benzo­[<i>d</i>]­azepine-1-carboxylic acids in 21–75% yields and with good <i>trans</i> diastereoselectivity. The method worked with imines generated from aromatic or α-branched aliphatic aldehydes and is amenable for both parallel synthesis and scale-up. The procedure for epimerization of the resulting <i>trans</i>-disubstituted tetrahydrobenzo­[<i>d</i>]­azepines to their <i>cis</i> isomers was also developed

Generation of multimillion chemical space based on the parallel Groebke–Blackburn–Bienaymé reaction

Parallel Groebke–Blackburn–Bienaymé reaction was evaluated as a source of multimillion chemically accessible chemical space. Two most popular classical protocols involving the use of Sc(OTf)3 and TsOH as the catalysts were tested on a broad substrate scope, and prevalence of the first method was clearly demonstrated. Furthermore, the scope and limitations of the procedure were established. A model 790-member library was obtained with 85% synthesis success rate. These results were used to generate a 271-Mln. readily accessible (REAL) heterocyclic chemical space mostly containing unique chemotypes, which was confirmed by comparative analysis with commercially available compound collections. Meanwhile, this chemical space contained 432 compounds that already showed biological activity according to the ChEMBL database

1-Alkyl-5-((di)alkylamino) Tetrazoles: Building Blocks for Peptide Surrogates

An approach to the synthesis of 1-alkyl-5-((di)­alkylamino)­tetrazoles by nucleophilic substitution in 1-alkyl-5-sulfonyltetrazoles with anions generated from the primary or secondary amines was developed. Tolerance of the method to the presence of some functional groups (i.e., protected amine) in both components of the reaction was demonstrated. Obtained tetrazoles are promising building blocks for the design of peptide surrogates, in particular, for replacement approaches of alkyl urea derivatives