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991.
Protein Engineering of the Progesterone Hydroxylating P450‐Monooxygenase CYP17A1 Alters Its Regioselectivity 下载免费PDF全文
Lisa K. Morlock Sascha Grobe Dr. Kathleen Balke Dr. Stephan Mauersberger Dr. Dominique Böttcher Prof. Dr. Uwe T. Bornscheuer 《Chembiochem : a European journal of chemical biology》2018,19(18):1954-1958
The CYP171 enzyme is known to catalyse a key step in the steroidogenesis of mammals. The substrates progesterone and pregnenolone are first hydroxylated at the C17 position, and this is followed by cleavage of the C17?C20 bond to yield important precursors for glucosteroids and androgens. In this study, we focused on the reaction of the bovine CYP17A1 enzyme with progesterone as a substrate. On the basis of a created homology model, active‐site residues were identified and systematically mutated to alanine. In whole‐cell biotransformations, the importance of the N202, R239, G297 and E305 residues for substrate conversion was confirmed. Additionally, mutation of the L206, V366 and V483 residues enhanced the formation of the 16α‐hydroxyprogesterone side product up to 40 % of the total product formation. Furthermore, residue L105 was found not to be involved in this side activity, which contradicts a previous study with the human enzyme. 相似文献
992.
993.
Cover Feature: Characterisation of the Carboxypeptidase G2 Catalytic Site and Design of New Inhibitors for Cancer Therapy (ChemBioChem 18/2018) 下载免费PDF全文
994.
Identification and Optimization of 4‐Anilinoquinolines as Inhibitors of Cyclin G Associated Kinase 下载免费PDF全文
Dr. Christopher R. M. Asquith Prof. Dr. Tuomo Laitinen James M. Bennett Dr. Paulo H. Godoi Dr. Michael P. East Dr. Graham J. Tizzard Prof. Dr. Lee M. Graves Prof. Dr. Gary L. Johnson Ronna E. Dornsife Carrow I. Wells Dr. Jonathan M. Elkins Prof. Dr. Timothy M. Willson Prof. Dr. William J. Zuercher 《ChemMedChem》2018,13(1):48-66
4‐Anilinoquinolines were identified as potent and narrow‐spectrum inhibitors of the cyclin G associated kinase (GAK), an important regulator of viral and bacterial entry into host cells. Optimization of the 4‐anilino group and the 6,7‐quinoline substituents produced GAK inhibitors with nanomolar activity, over 50 000‐fold selectivity relative to other members of the numb‐associated kinase (NAK) subfamily, and a compound (6,7‐dimethoxy‐N‐(3,4,5‐trimethoxyphenyl)quinolin‐4‐amine; 49 ) with a narrow‐spectrum kinome profile. These compounds may be useful tools to explore the therapeutic potential of GAK in prevention of a broad range of infectious and systemic diseases. 相似文献
995.
Cytotoxic Activity and Structure–Activity Relationship of Triazole‐Containing Bis(Aryl Ether) Macrocycles 下载免费PDF全文
Dr. Eduardo Hernández‐Vázquez Dr. Alejandra Chávez‐Riveros Dr. Adriana Romo‐Pérez María Teresa Ramírez‐Apán Dr. Alma D. Chávez‐Blanco Dr. Rocío Morales‐Bárcenas Dr. Alfonso Dueñas‐González Dr. Luis D. Miranda 《ChemMedChem》2018,13(12):1193-1209
Cancer continues to be a worldwide health problem. Certain macrocyclic molecules have become attractive therapeutic alternatives for this disease because of their efficacy and, frequently, their novel mechanisms of action. Herein, we report the synthesis of a series of 20‐, 21‐, and 22‐membered macrocycles containing triazole and bis(aryl ether) moieties. The compounds were prepared by a multicomponent approach from readily available commercial substrates. Notably, some of the compounds displayed interesting cytotoxicity against cancer (PC‐3) and breast (MCF‐7) cell lines, especially those bearing an aliphatic or a trifluoromethyl substituent on the N‐phenyl moiety (IC50<13 μm ). Additionally, some of the compounds were able to induce apoptosis relative to the solvent control; in particular, (Z)‐N‐cyclohexyl‐7‐oxo‐6‐[4‐(trifluoromethyl)phenyl]‐11H‐3,10‐dioxa‐6‐aza‐1(4,1)‐triazola‐4(1,3),9(1,4)‐dibenzenacyclotridecaphane‐5‐carboxamide ( 12 f ) was the most potent in this regard (22.7 % of apoptosis). 相似文献
996.
Synthesis and Evaluation of the Anticancer and Trypanocidal Activities of Boronic Tyrphostins 下载免费PDF全文
Noemi de J. Hiller Nayane A. A. e Silva Dr. Robson X. Faria Dr. André Luís A. Souza Dr. Jackson A. L. C. Resende André Borges Farias Dr. Nelilma Correia Romeiro Dr. Daniela de Luna Martins 《ChemMedChem》2018,13(14):1395-1404
Molecules containing an (cyanovinyl)arene moiety are known as tyrphostins because of their ability to inhibit proteins from the tyrosine kinase family, an interesting target for the development of anticancer and trypanocidal drugs. In the present work, (E)‐(cyanovinyl)benzeneboronic acids were synthesized by Knoevenagel condensations without the use of any catalysts in water through a simple protocol that completely avoided the use of organic solvents in the synthesis and workup process. The in vitro anticancer and trypanocidal activities of the synthesized boronic acids were also evaluated, and it was discovered that the introduction of the boronic acid functionality improved the activity of the boronic tyrphostins. In silico target fishing with the use of a chemogenomic approach suggested that tyrosine‐phosphorylation‐regulated kinase 1a (DYRK1A) was a potential target for some of the designed compounds. 相似文献
997.
998.
Cover Feature: Discovery of Benzimidazole–Quinolone Hybrids as New Cleaving Agents toward Drug‐Resistant Pseudomonas aeruginosa DNA (ChemMedChem 10/2018) 下载免费PDF全文
999.
Synthesis and Evaluation of a Series of Bis(pentylpyridinium) Compounds as Antifungal Agents 下载免费PDF全文
Dr. Daniel Obando Dr. Yasuko Koda Namfon Pantarat Dr. Sophie Lev Dr. Xiaoming Zuo Johanes Bijosono Oei Dr. Fred Widmer Prof. Julianne T. Djordjevic Prof. Tania C. Sorrell Prof. Katrina A. Jolliffe 《ChemMedChem》2018,13(14):1421-1436
A series of bis(4‐pentylpyridinium) compounds with a variety of spacers between the pyridinium headgroups was synthesised, and the antifungal activity of these compounds was investigated. Lengthening the alkyl spacer between the pentylpyridinium headgroups from 12 to 16 methylene units resulted in increased antifungal activity against C. neoformans and C. albicans, but also resulted in increased hemolytic activity and cytotoxicity against mammalian cells. However, inclusion of an ortho‐substituted benzene ring in the centre of the alkyl spacer resulted in decreased cytotoxicity and hemolytic activity, while maintaining antifungal potency. Replacement of the alkyl and aromatic‐containing spacers by more hydrophilic ethylene glycol groups resulted in a loss of antifungal activity. Some of the compounds inhibited fungal PLB1 activity, but the low correlation of this inhibition with antifungal potency indicates PLB1 inhibition is unlikely to be the predominant mode of antifungal action of this class of compounds, with preliminary studies suggesting they may act via disruption of fungal mitochondrial function. 相似文献
1000.
Brain‐Penetrant Triazolopyrimidine and Phenylpyrimidine Microtubule Stabilizers as Potential Leads to Treat Human African Trypanosomiasis 下载免费PDF全文
Dr. Ludovica Monti Steven C Wang Dr. Killian Oukoloff Dr. Amos B. Smith III Dr. Kurt R. Brunden Dr. Conor R. Caffrey Dr. Carlo Ballatore 《ChemMedChem》2018,13(17):1751-1754
In vitro whole‐organism screens of Trypanosoma brucei with representative examples of brain‐penetrant microtubule (MT)‐stabilizing agents identified lethal triazolopyrimidines and phenylpyrimidines with sub‐micromolar potency. In mammalian cells, these antiproliferative compounds disrupt MT integrity and decrease total tubulin levels. Their parasiticidal potency, combined with their generally favorable pharmacokinetic properties, which include oral bioavailability and brain penetration, suggest that these compounds are potential leads against human African trypanosomiasis. 相似文献