Доміно-реакції 3-метил-5-амінопіразолу з 1-феніл-3-(4-алкоксифеніл)піразол-4-карбальдегідами та 2,2-диметил-1,3-діоксан-4,6-діоном

Aim. To synthesize 1-phenyl-3-(4-alkoxyphenyl)pyrazole-4-carbaldehydes and determine the direction of their interaction in the three-component condensation with 3-methyl-5-aminopyrazole and 2,2-dimethyl-1,3-dioxane-4,6-dione.Results and discussion. A series of 1-phenyl-3-(4-alkoxyphenyl)pyrazole-4-carbaldehydes was synthesized from arylhydrazone by the Vilsmeier–Haak reaction. The domino-reactions of these aldehydes with 3-methyl-5-aminopyrazole and 2,2-dimethyl-1,3-dioxane-4,6-dione lead to pyrazolo[3,4-b]pyridone systems.Experimental part. The synthesis of 1-phenyl-3-(4-alkoxyphenyl)pyrazole-4-carbaldehyde was carried out by formylation of arylhydrazones under the conditions of the Vilsmeier–Haack reaction with the yield of 55 – 88 %. Refluxing in 2-propanol equimolar amounts of these aldehydes, 3-methyl-5-aminopyrazole and 2,2-dimethyl-1,3-dioxane-4,6-dione gave 3-methyl-4-(1',3'-diarylpyrazol-4'-yl)tetrahydropyrazolo[3,4-b]pyridin-6-ones with the yield of 48 – 75 %. The structure and composition of all substances synthesized were proven by 1H NMR, IR-spectra and elemental analysis.Conclusions. It has been found that the reactions of 1,3-diaryl substituted pyrazole-4-carbaldehydes with 3-methyl-5-aminopyrazole and 2,2-dimethyl-1,3-dioxane-4,6-dione are regioselective and lead to the formation of pyrazolo[3,4-b]pyridone systems. This orientation of the process corresponds to the interaction of the β-carbon atom of the probable intermediate, which is formed at the first stage of the reaction from dioxandione and aldehyde, with the carbon nucleophilic center in the aminoazole molecule, and then the exocyclic amino group in the heterylamine attacks the C=O group in the dioxane-4,6-dione fragment.Цель. Синтезировать 1-фенил-3-(4-алкоксифенил)пиразол-4-карбальдегиды и установить направленность их взаимодействия в трехкомпонентной конденсации с 3-метил-5-аминопиразолом и 2,2-диметил-1,3-диоксан-4,6-дионом.Результаты и их обсуждение. Формилированием арилгидразонов по Вильсмейеру–Хааку синтезирован ряд 1-фенил-3-(4-алкоксифенил)пиразол-4-карбальдегидов. Домино-реакции этих альдегидов с 3-метил-5-амино­пиразолом и 2,2-диметил-1,3-диоксан-4,6-дионом завершаются образованием пиразоло[3,4-b]-пиридоновых систем.Экспериментальная часть. Синтез 1-фенил-3-(4-алкоксифенил)­пира­зол-4-карбальдегидов осуществлен  формилированием арилгидразонов в условиях реакции Вильсмейера–Хаака с выходом 55 – 88 %. Кипячением в 2-пропаноле эквимолярных количеств этих альдегидов, 3-метил-5-аминопиразола и 2,2-диметил-1,3-диоксан-4,6-диона получены 3-метил-4-(1′,3′-диарилпиразол-4′-ил)тетрагидропиразоло[3,4-b]пиридин-6-оны. Выход целевых соединений – 48 – 75 %. Строение и состав всех синтезированных веществ доказаны данными 1Н ЯМР-, ИК-спектров и элементным анализом.Выводы. Установлено, что реакции 1,3-диарилзамещенных пиразол-4-карбальдегидов с 3-метил- 5-аминопиразолом и 2,2‑диметил-1,3-диоксан-4,6-дионом региоселективны и завершаются образованием 3,4-пиразоло[3,4-b]пиридоновых систем. Такая направленность процесса отвечает взаимодействию β-углеродного атома возможного интермедиата, образующегося на первой стадии из диоксандиона и альдегида, с углеродным нуклеофильным центром в молекуле аминоазола, а атома углерода С=О группы диоксан-4,6-диона – с экзоциклической аминогруппой гетериламина. Received: 13.01.2019Revised: 31.01.2020Accepted: 27.02.2020Мета. Синтезувати 1-феніл-3-(4-алкоксифеніл)піразол-4-карбальдегіди і встановити направленість їх взаємодії у трикомпонентній конденсації з 3-метил-5-амінопіразолом та 2,2-диметил-1,3-діоксан-4,6-діоном.Результати та їх обговорення. Синтезовано ряд 1-феніл-3-(4-алкоксифеніл)піразол-4-карбальдегідів формілюванням арилгідразонів за Вільсмейером–Хааком. Доміно-реакції цих альдегідів з 3-метил-5-амінопіразолом та 2,2-диметил-1,3-діоксан-4,6-діоном завершуються утворенням піразоло[3,4-b]піридонових систем.Експериментальна частина. Синтез 1-феніл-3-(4-алкоксифеніл)піразол-4-карбальдегідів здійснено формілюванням арилгідразонів в умовах реакції Вільсмейера–Хаака з виходом 55 – 88 %. Кип’ятінням у 2-пропанолі суміші еквімольних кількостей цих альдегідів, 3-метил-5-амінопіразолу та 2,2-диметил-1,3-діоксан-4,6-діону одержано 3-метил-4-(1',3'-діарилпіразол-4'-іл)тетрагідропіразоло[3,4-b]піридин-6-они. Вихід цільових сполук – 48 – 75 %. Структуру і склад усіх синтезованих речовин доведено даними 1Н ЯМР-, ІЧ-спектрів та елементним аналізом.Висновки. Встановлено, що реакції 1,3-діарилзаміщених піразол-4-карбальдегідів з 3-метил-5-амінопіразолом та 2,2‑диметил-1,3-діоксан-4,6-діоном є регіоселективними і завершуються утворенням виключно 3,4-піразоло[3,4-b]-піридин-6-онових систем. Така направленість процесу відповідає взаємодії β-вуглецевого атома ймовірного інтермедіату, який утворюється на першій стадії з діоксандіону та альдегіду, з вуглецевим нуклеофільним центром у молекулі аміноазолу, а атома вуглецю С=О групи діоксан-4,6-діону – з екзоциклічною аміногрупою гетериламіну. Received: 13.01.2019Revised: 31.01.2020Accepted: 27.02.202

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

The regioselective synthesis of spirooxindolo pyrrolidines and pyrrolizidines via three-component reactions of acrylamides and aroylacrylic acids with isatins and α-amino acids

The regioselective three-component condensation of azomethine ylides derived from isatins and α-amino acids with acrylamides or aroylacrylic acids as dipolarophiles has been realized through a one-pot 1,3-dipolar cycloaddition protocol. Decarboxylation of 2'-aroyl-2-oxo-1,1',2,2',5',6',7',7a'-octahydrospiro[indole-3,3'-pyrrolizine]-1'-carboxylic acids is accompanied by cyclative rearrangement with formation of dihydropyrrolizinyl indolones

Novel (2-amino-4-arylimidazolyl)propanoic acids and pyrrolo[1,2-c]imidazoles via the domino reactions of 2-amino-4-arylimidazoles with carbonyl and methylene active compounds

The unexpectedly uncatalyzed reaction between 2-amino-4-arylimidazoles, aromatic aldehydes and Meldrum’s acid has selectively led to the corresponding Knoevenagel–Michael adducts containing a free amino group in the imidazole fragment. The adducts derived from Meldrum’s acid have been smoothly converted into 1,7-diaryl-3-amino-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-ones and 3-(2-amino-4-aryl-1H-imidazol-5-yl)-3-arylpropanoic acids. The interaction of 2-amino-4-arylimidazoles with aromatic aldehydes or isatins and acyclic methylene active compounds has led to the formation of pyrrolo[1,2-c]imidazole-6-carbonitriles, pyrrolo[1,2-с]imidazole-6-carboxylates and spiro[indoline-3,7'-pyrrolo[1,2-c]imidazoles], which can be considered as the analogues of both 3,3’-spirooxindole and 2-aminoimidazole marine sponge alkaloids

Novel (2-amino-4-arylimidazolyl)propanoic acids and pyrrolo[1,2-c]imidazoles via the domino reactions of 2-amino-4-arylimidazoles with carbonyl and methylene active compounds

The unexpectedly uncatalyzed reaction between 2-amino-4-arylimidazoles, aromatic aldehydes and Meldrum's acid has selectively led to the corresponding Knoevenagel-Michael adducts containing a free amino group in the imidazole fragment. The adducts derived from Meldrum's acid have been smoothly converted into 1,7-diaryl-3-amino-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-ones and 3-(2-amino-4-aryl-1H-imidazol-5-yl)-3-arylpropanoic acids. The interaction of 2-amino-4-arylimidazoles with aromatic aldehydes or isatins and acyclic methylene active compounds has led to the formation of pyrrolo[1,2-c]imidazole-6-carbonitriles, pyrrolo[1,2-с]imidazole-6-carboxylates and spiro[indoline-3,7'-pyrrolo[1,2-c]imidazoles], which can be considered as the analogues of both 3,3'-spirooxindole and 2-aminoimidazole marine sponge alkaloids.status: publishe