- Optimizing Pyrazolopyrimidine Inhibitors of Calcium Dependent Protein Kinase 1 for Treatment of Acute and Chronic Toxoplasmosis
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Calcium dependent protein kinase 1 (CDPK1) is an essential Ser/Thr kinase that controls invasion and egress by the protozoan parasite Toxoplasma gondii. The Gly gatekeeper of CDPK1 makes it exquisitely sensitive to inhibition by small molecule 1H-pyrazolo
- Janetka, James W.,Hopper, Allen T.,Yang, Ziping,Barks, Jennifer,Dhason, Mary Savari,Wang, Qiuling,Sibley, L. David
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supporting information
p. 6144 - 6163
(2020/07/10)
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- COMPOUNDS AND COMPOSITIONS USEFUL FOR TREATING DISORDERS RELATED TO NTRK
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This invention relates to inhibitors of NTRK that are active against wild-type NTRK and its resistant mutants.
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Page/Page column 85; 90
(2017/03/14)
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- Selective aliphatic carbon-hydrogen bond activation of protected alcohol substrates by cytochrome P450 enzymes
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Protected cyclohexanol and cyclohex-2-enol substrates, containing benzyl ether and benzoate ester moieties, were designed to fit into the active site of the Tyr96Ala mutant of cytochrome P450cam. The protected cyclohexanol substrates were efficiently and selectively hydroxylated by the mutant enzyme at the trans C-H bond of C-4 on the cyclohexyl ring. The selectivity of oxidation of the benzoate ester protected cyclohexanol could be altered by making alternative amino acid substitutions in the P450cam active site. The addition of the double bond in the cyclohexyl ring of the benzoate ester protected cyclohex-2-enol has a debilitative effect on the activity of the Tyr96Ala mutant with this substrate. However, the Phe87Ala/Tyr96Phe double mutant, which introduces space at a different location in the active site than the Tyr96Ala mutant, was able to efficiently hydroxylate the C-H bonds of 1-cyclohex-2-enyl benzoate at the allylic C-4 position. Mutations at Phe87 improved the selectivity of the oxidation of 1-phenyl-1-cyclohexylethylene to trans-4-phenyl-ethenylcyclohexanol (92%) when compared to single mutants at Tyr96 of P450cam. the Partner Organisations 2014.
- Bell, Stephen G.,Spence, Justin T. J.,Liu, Shenglan,George, Jonathan H.,Wong, Luet-Lok
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p. 2479 - 2488
(2014/04/03)
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- Trifluoromethyl-substituted indenyl rhodium and iridium complexes are highly selective catalysts for directed hydroboration reactions
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(equation presented) Rhodium and iridium catalysts containing trifluoromethyl-substituted indenyl ligands (Ind′MCod, Ind′ = C9H7, (1-CF3)C9H6, (2-CF3)C9H6, (1,3-CFsub
- Brinkman, John A.,Nguyen, Tam T.,Sowa Jr., John R.
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p. 981 - 983
(2007/10/03)
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- Biohydroxylation reactions catalyzed by enzymes and whole-cell systems
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The biohydroxylation of a number of cyclic substrates (3-24) containing aromatic side chains was used to compare substrate specificity and selectivity of hydroxylation using microbial enzymes and whole-cell biocatalysts. In general, the regioselectivity of reaction was remarkably similar between the different catalysts in that little aromatic or benzylic, but significant aliphatic hydroxylation was observed. However, a more detailed investigation of isolated products showed complementary substrate specificity, functional group compatibility, and regioselectivity of hydroxylation. Substrate specificity and regioselectivity could be further modulated by small changes to the nature of the aromatic side chain, which appears to play an important role in substrate recognition.
- Flitsch, Sabine L.,Aitken, Suzanne J.,Chow, Cathy S.-Y.,Grogan, Gideon,Staines, Adam
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- Inhibition of human erythrocyte membrane phosphatidylinositol 4-kinase by phospholipid analogues
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Analogues of phosphatidylinositol (PtdIns, 1) have been synthesized to investigate the structural requirements for inhibition of a PtdIns 4-kinase obtained from human erythrocyte membranes. While the presence of either D-1 or D-3 stereochemistry in the inositol moiety greatly influences the degree of inhibition produced by PtdIns analogues, the stereochemistry of the glycerol moiety is of little consequence. Neither structural feature however, makes a significant contribution to binding affinity. Competitive inhibitory activity was found to be retained (or even enhanced) in substantially simpler analogues consisting of 1 or 2 hydrocarbon chains attached to a charged phosphate head group, such as in the phosphatidic acids, 24 and 26. The observation that the phosphatidylinositol 4-phosphate (PtdIns 4P) and phosphatidic acid analogues (eg, 16 or 17, and 26 respectively) inhibit PtdIns 4-kinase may suggest that such species have a regulatory role in PtdIns turnover.
- Young,Downes,Jones,Milliner,Rana,Ward
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p. 537 - 549
(2007/10/02)
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- Regiochemical Control of the Ring-Opening of 1,2-Epoxides by Means of Chelating Processes. Synthesis and Reactions of the cis- and trans-Oxides Derived from 4-(Benzyloxy)cyclohexene
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The synthesis and reactions of diastereomeric epoxides cis-1 and trans-2 with heteronucleophiles were carried out in order to probe the effect of remote polar functionality on the regioselectivity of nucleophilic addition to the epoxide ring.The reaction
- Chini, Marco,Crotti, Paolo,Flippin, Lee A.,Macchia, Franco
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p. 4265 - 4272
(2007/10/02)
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- Generalization, Alteration, and Enhancement of the Stereoselectivity in the Cieplak-Mode Reductions of 4-Alkoxy(or Silyloxy)cyclohexanones
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Reductions of 4-alkoxy(or silyloxy)cyclohexanones with LiAlH4, AlH(i-Bu)2, and Li(s-Bu)3BH afforded the correponding cis alcohols in 73-80percent selectivities.Similar reduction of 4-benzyloxy- and 4-t-butyldiphenylsilyloxy-cyclohexanones with AlH(i-Bu)2
- Nagao, Yoshimitsu,Goto, Michimasa,Ochiai, Masahito
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p. 1507 - 1510
(2007/10/02)
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