C-5 Aryl Substituted Azaspirooxindolinones Derivatives: Synthesis and Biological Evaluation as Potential Inhibitors of Tec Family Kinases

<p>The interleukin-2-inducible kinase (ITK) and Bruton tyrosine kinase (BTK) are two crucial Tec family kinase members with important roles in the development of hematopoietic malignancies, autoimmune disorders and other diseases in human. Thus, ITK and BTK are key targets for drug development. Spirooxindoles are important scaffolds for the synthesis of small molecules with broad and potent biological activities. In this study, we performed a structure-activity relationship study of a new series of 5'-(benzo[d][1,3]dioxol-5-yl)spiro[piperidine-4,3'-pyrrolo[2,3-b]pyridin]-2'(1'H)-one linked with N-acyl and C-5 aryl-substituted scaffolds in a panel of ITK and BTK cancer cell lines. Four compounds <b>11</b>, <b>12</b>, <b>14</b> and <b>15</b> showed high antiproliferative activity against ITK and BTK cell lines. Compounds <b>11</b> and <b>12</b> with a C-5 benzodioxole group and gem-dialkyl group attached to carbonyl on piperidine were highly effective in ITK-high Jurkat and CEM cell lines, and compound <b>14, </b>a<strong> </strong>biotin analogue, was identified as a good inhibitor of BTK-high RAMOS cells. Compound <b>15 </b>with cyclopropyl group attached to carbonyl on piperidine also showed good activity in ITK and BTK cell lines.<b> </b></p>

C-5 Aryl Substituted Azaspirooxindolinones Derivatives: Synthesis and Biological Evaluation as Potential Inhibitors of Tec Family Kinases

<p>The interleukin-2-inducible kinase (ITK) and Bruton tyrosine kinase (BTK) are two crucial Tec family kinase members with important roles in the development of hematopoietic malignancies, autoimmune disorders and other diseases in human. Thus, ITK and BTK are key targets for drug development. Spirooxindoles are important scaffolds for the synthesis of small molecules with broad and potent biological activities. In this study, we performed a structure-activity relationship study of a new series of 5'-(benzo[d][1,3]dioxol-5-yl)spiro[piperidine-4,3'-pyrrolo[2,3-b]pyridin]-2'(1'H)-one linked with N-acyl and C-5 aryl-substituted scaffolds in a panel of ITK and BTK cancer cell lines. Four compounds <b>11</b>, <b>12</b>, <b>14</b> and <b>15</b> showed high antiproliferative activity against ITK and BTK cell lines. Compounds <b>11</b> and <b>12</b> with a C-5 benzodioxole group and gem-dialkyl group attached to carbonyl on piperidine were highly effective in ITK-high Jurkat and CEM cell lines, and compound <b>14, </b>a<strong> </strong>biotin analogue, was identified as a good inhibitor of BTK-high RAMOS cells. Compound <b>15 </b>with cyclopropyl group attached to carbonyl on piperidine also showed good activity in ITK and BTK cell lines.<b> </b></p>

C-5 Aryl Substituted Azaspirooxindolinones Derivatives: Synthesis and Biological Evaluation as Potential Inhibitors of Tec Family Kinases

<p>The interleukin-2-inducible kinase (ITK) and Bruton tyrosine kinase (BTK) are two crucial Tec family kinase members with important roles in the development of hematopoietic malignancies, autoimmune disorders and other diseases in human. Thus, ITK and BTK are key targets for drug development. Spirooxindoles are important scaffolds for the synthesis of small molecules with broad and potent biological activities. In this study, we performed a structure-activity relationship study of a new series of 5'-(benzo[d][1,3]dioxol-5-yl)spiro[piperidine-4,3'-pyrrolo[2,3-b]pyridin]-2'(1'H)-one linked with N-acyl and C-5 aryl-substituted scaffolds in a panel of ITK and BTK cancer cell lines. Four compounds <b>11</b>, <b>12</b>, <b>14</b> and <b>15</b> showed high antiproliferative activity against ITK and BTK cell lines. Compounds <b>11</b> and <b>12</b> with a C-5 benzodioxole group and gem-dialkyl group attached to carbonyl on piperidine were highly effective in ITK-high Jurkat and CEM cell lines, and compound <b>14, </b>a<strong> </strong>biotin analogue, was identified as a good inhibitor of BTK-high RAMOS cells. Compound <b>15 </b>with cyclopropyl group attached to carbonyl on piperidine also showed good activity in ITK and BTK cell lines.<b> </b></p>

Intramolecular Friedel–Crafts alkylation with a silylium-ion-activated cyclopropyl group: formation of tricyclic ring systems from benzyl-substituted vinylcyclopropanes and hydrosilanes

Downstream to alkene hydrosilylation, the opening of the cyclopropane ring in benzyl-substituted VCPs is interlinked with an SEAr of the aryl group.

An umpolung reaction of α-iminothioesters possessing a cyclopropyl group

Tandem N-alkylation/oxidation/second addition reaction to α-cyclopropyl α-imino(thio)esters gave N-alkylated ring-opened products in good yields.

Revealing Solvent-Dependent Folding Behavior of Mycolic Acids from Mycobacterium Tuberculosis by Advanced Simulation Analysis

<p>Mycobacterium tuberculosis remains a persistent pathogen, partly due to its lipid rich cell wall, of which mycolic acids (MAs) are a major component. The fluidity and conformational flexibilities of different MAs in the bacterial cell wall significantly influence its properties, function, and observed pathogenicity, thus a proper conformational description of different MAs in different environments (e.g. in vacuum, in solution, in monolayers) can inform about their potential role in the complex setup of the bacterial cell wall. Previously, we have shown that molecular-dynamics (MD) simulations of MA folding <i>in vacuo</i>can be used to characterise MA conformers in seven groupings relating to bending at the functional groups (W, U and Z-conformations). Providing a new OPLS-based forcefield parameterisation for the critical cyclopropyl group of MAs and extensive simulations in explicit solvents (TIP4P water, hexane) we now present a more complete picture of MA folding properties together with improved simulation analysis techniques. We show that the ‘WUZ’ distance-based analysis can be used pinpoint conformers with hairpin bends at the functional groups, with these conformers constituting only a fraction of accessible conformations. Applying principle component analysis (PCA) and refinement using free energy landscapes (FELs), we are able to discriminate a complete and unique set of conformational preferences for representative alpha-, methoxy-, and keto-MAs, with overall preference for folded conformations. A control backbone-MA without any mero-chain functional groups showed significantly less folding in the mero-chain, confirming the role of functionalisation in directing folding. Keto-MA showed the highest percentage of WUZ-type conformations and, in particular, a tendency to fold at its alpha-methyl trans-cyclopropane group, in agreement with results from Villeneuve <i>et al.</i>MAs demonstrate similar folding in vacuum and water, with a majority of folded conformations around the W-conformation, although the molecules are more flexible in vacuum than in water. Exchange between conformations, with a disperse distribution that includes unfolded conformers, is common in hexane for all MAs, although with more organisation for Keto-MA. Globular, folded conformations are newly defined and may be specifically relevant in biofilms.</p>

Revealing Solvent-Dependent Folding Behavior of Mycolic Acids from Mycobacterium Tuberculosis by Advanced Simulation Analysis

<p>Mycobacterium tuberculosis remains a persistent pathogen, partly due to its lipid rich cell wall, of which mycolic acids (MAs) are a major component. The fluidity and conformational flexibilities of different MAs in the bacterial cell wall significantly influence its properties, function, and observed pathogenicity, thus a proper conformational description of different MAs in different environments (e.g. in vacuum, in solution, in monolayers) can inform about their potential role in the complex setup of the bacterial cell wall. Previously, we have shown that molecular-dynamics (MD) simulations of MA folding <i>in vacuo</i>can be used to characterise MA conformers in seven groupings relating to bending at the functional groups (W, U and Z-conformations). Providing a new OPLS-based forcefield parameterisation for the critical cyclopropyl group of MAs and extensive simulations in explicit solvents (TIP4P water, hexane) we now present a more complete picture of MA folding properties together with improved simulation analysis techniques. We show that the ‘WUZ’ distance-based analysis can be used pinpoint conformers with hairpin bends at the functional groups, with these conformers constituting only a fraction of accessible conformations. Applying principle component analysis (PCA) and refinement using free energy landscapes (FELs), we are able to discriminate a complete and unique set of conformational preferences for representative alpha-, methoxy-, and keto-MAs, with overall preference for folded conformations. A control backbone-MA without any mero-chain functional groups showed significantly less folding in the mero-chain, confirming the role of functionalisation in directing folding. Keto-MA showed the highest percentage of WUZ-type conformations and, in particular, a tendency to fold at its alpha-methyl trans-cyclopropane group, in agreement with results from Villeneuve <i>et al.</i>MAs demonstrate similar folding in vacuum and water, with a majority of folded conformations around the W-conformation, although the molecules are more flexible in vacuum than in water. Exchange between conformations, with a disperse distribution that includes unfolded conformers, is common in hexane for all MAs, although with more organisation for Keto-MA. Globular, folded conformations are newly defined and may be specifically relevant in biofilms.</p>