An ab initio study of electronic factors in metabolic hydroxylation of aliphatic carbon atoms

Testa, Bernard; Mihailova, D.

doi:10.1021/jm00205a017

Cited by 14 publications

(5 citation statements)

References 15 publications

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“…Although the exact position of metabolism in compound 3 was not determined from our metabolism studies with compound 1 , oxidation on either side of the basic piperazine nitrogen was probable, as benzylic C–H bonds and carbons adjacent to a nitrogen atom are particularly prone to oxidation by cytochrome P450 enzymes . In addition, the benzylic position of compound 1 was also predicted to be the most likely site of metabolism using MetaSite prediction software, which was consistent with literature precedent. , Therefore, we examined the effect of methyl (and trifluoromethyl) substitutions on the benzylic position and/or on the piperazine ring in the second phase of our SAR investigations as a potential means of blocking metabolism in this region of the molecule.…”

Section: Resultssupporting

confidence: 65%

Selective Class I Phosphoinositide 3-Kinase Inhibitors: Optimization of a Series of Pyridyltriazines Leading to the Identification of a Clinical Candidate, AMG 511

Norman

Andrews

et al. 2012

J. Med. Chem.

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The phosphoinositide 3-kinase family catalyzes the phosphorylation of phosphatidylinositol-4,5-diphosphate to phosphatidylinositol-3,4,5-triphosphate, a secondary messenger which plays a critical role in important cellular functions such as metabolism, cell growth, and cell survival. Our efforts to identify potent, efficacious, and orally available phosphatidylinositol 3-kinase (PI3K) inhibitors as potential cancer therapeutics have resulted in the discovery of 4-(2-((6-methoxypyridin-3-yl)amino)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (1). In this paper, we describe the optimization of compound 1, which led to the design and synthesis of pyridyltriazine 31, a potent pan inhibitor of class I PI3Ks with a superior pharmacokinetic profile. Compound 31 was shown to potently block the targeted PI3K pathway in a mouse liver pharmacodynamic model and inhibit tumor growth in a U87 malignant glioma glioblastoma xenograft model. On the basis of its excellent in vivo efficacy and pharmacokinetic profile, compound 31 was selected for further evaluation as a clinical candidate and was designated AMG 511.

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Section: Resultssupporting

confidence: 65%

Selective Class I Phosphoinositide 3-Kinase Inhibitors: Optimization of a Series of Pyridyltriazines Leading to the Identification of a Clinical Candidate, AMG 511

Norman

Andrews

et al. 2012

J. Med. Chem.

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“…29 Most recently it has been demonstrated that metabolic hydroxylation of an aliphatic carbon atom showed a marked regioselectivity at the a carbon to heteratoms or systems when quantum-mechanical approaches were used. 43,44 The retention of electronic descriptors (numbers 14 and 15 of Table IV) used in this study implicitly supports this «hydroxylation hypothesis in view of the fact that these two descriptors represent the electronic properties of the N-NO group and the -carbon atom.…”

Section: Discussionsupporting

confidence: 66%

“…nitroso-A-ethylisopropy lamine wc42 A-nitrosodi-n-buty lamine 116 A-nitrosodiethanolamine wc43 A-nitrosodi-n-pentylamine 117 A, A'-dinitroso-A, A'-dimethylphthalamide wc44 A-nitroso-A-methylviny lamine nitroso-A-methyl-n-propy lamine+ c 120 2,2,6,6-tetramethyl-A-nitrosopiperidine -47 A-nitroso-A-methyl-n-but y lamine + c 121 4-terf-butyl-A-nitrosopiperidine -48 ni troso-A-methyl-rc-penty lamine + c 122 2-carboxy-A-nitrosopiperidine -49 A-nitroso-A-(2-hydroxypropyl)-n-propylamine 4-C 123 4-carboxy-A-nitrosopiperidine 50 A-nitroso-A-( 2-oxopropy l)-n-propylamine 124 nitrosoguvacoline -51 A-nitroso-A-methylbenzy lamine + c…”

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confidence: 99%

Computer assisted structure-activity studies of chemical carcinogens. An N-nitroso compound data set

Chou¹,

Jurs²

1979

J. Med. Chem.

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N-nitroso compounds, consisting of nitrosamines and nitrosamides, are potentially important in the etiology of human cancer. An attempt to study the molecular structure-carcinogenicity relations of these compounds is reported. A pattern-recognition approach was used to develop predictive ability for carcinogenic potential. A set of 15 calculated molecular structure descriptors that supported a linear discriminant function able to successfully separate 116 carcinogens from 28 noncarcinogens was identified. Predictive ability of an overall of 91%--93% for carcinogens and 85% for noncarcinogens--was obtained in the randomized testing. This relatively high predictability demonstrates that pattern-recognition methods can be useful in analyzing these compounds for carcinogenic activity. The inclusion of two electronic descriptors implicitly supports the alpha-hydroxylation hypothesis. The relations of descriptors used and possible mechanism of action are discussed.

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“…Under this circumstance, the intermolecular CT states may significantly contribute to the excitonic couplings via the superexchange mechanism. [51][52][53][54] Both the shortrange exchange and superexchange interactions make the relationship between the relative molecular orientation and the signs of couplings ambiguous. One thus cannot use conventional H-and J-aggregate to predict the signs of excitonic couplings.…”

Section: The Aggregation Packing Type Versus the Signs Of Excitonic C...mentioning

confidence: 99%

Switching on/off phosphorescent or non‐radiative channels by aggregation‐induced quantum interference

et al. 2023

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Pure organic materials with persistent and efficient room‐temperature phosphorescence have recently aroused great research interest due to their vast potential in applications. One crucial design principle for such materials is to suppress as much as possible the non‐radiative decay of the triplet exciton while maintaining a moderate phosphorescent radiative rate. However, molecular engineering often exhibits similar regulation trends for the two processes. Here, we propose that the quantum interference caused by aggregation can be utilized to control the phosphorescent and non‐radiative decay channels. We systematically analyze various constructive and destructive transition pathways in aggregates with different molecular packing types and establish clear relationships between the luminescence characters and the signs of the singlet and triplet excitonic couplings. It is shown that the decay channels can be flexibly switched on or off by regulating the packing type and excitonic couplings. Most importantly, an enhanced phosphorescent decay and a completely suppressed non‐radiative decay can be simultaneously realized in the aggregate packed with inversion symmetry. This work lays the theoretical foundation for future experimental realization of quantum interference effects in phosphorescence.

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An ab initio study of electronic factors in metabolic hydroxylation of aliphatic carbon atoms

Cited by 14 publications

References 15 publications

Selective Class I Phosphoinositide 3-Kinase Inhibitors: Optimization of a Series of Pyridyltriazines Leading to the Identification of a Clinical Candidate, AMG 511

Selective Class I Phosphoinositide 3-Kinase Inhibitors: Optimization of a Series of Pyridyltriazines Leading to the Identification of a Clinical Candidate, AMG 511

Computer assisted structure-activity studies of chemical carcinogens. An N-nitroso compound data set

Switching on/off phosphorescent or non‐radiative channels by aggregation‐induced quantum interference

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