92-81-9Relevant articles and documents
Structure-based design of selective inhibitors of dihydrofolate reductase: Synthesis and antiparasitic activity of 2,4-diaminopteridine analogues with a bridged diarylamine side chain
Rosowsky, Andre,Cody, Vivian,Galitsky, Nikolai,Fu, Hongning,Papoulis, Andrew T.,Queener, Sherry F.
, p. 4853 - 4860 (1999)
As part of a larger search for potent as well as selective inhibitors of dihydrofolate reductase (DHFR) enzymes from opportunistic pathogens found in patients with AIDS and other immune disorders, N-[(2,4-diaminopteridin-6- yl)methyl]dibenz[b,f]azepine (4a) and the corresponding dihydrodibenz[b,f]azepine, dihydroacridine, phenoxazine, phenothiazine, carbazole, and diphenylamine analogues were synthesized from 2,4-diamino-6- (bromomethyl)pteridine in 50-75% yield by reaction with the sodium salts of the amines in dry tetrahydrofuran at room temperature. The products were tested for the ability to inhibit DHFR from Pneumocystis carinii (pcDHFR), Toxoplasma gondii (tgDHFR), Mycobacterium avium (maDHFR), and rat liver (rlDHFR). The member of the series with the best combination of potency and species selectivity was 4a, with IC50 values against the four enzymes of 0.21, 0.043, 0.012, and 4.4μM, respectively. The dihydroacridine, phenothiazine, and carbazole analogues were also potent, but nonselective. Of the compounds tested, 4a was the only one to successfully combine the potency of trimetrexate with the selectivity of trimethoprim. Molecular docking simulations using published 3D structural coordinates for the crystalline ternary complexes of pcDHFR and hDHFR suggested a possible structural interpretation for the binding selectivity of 4a and the lack of selectivity of the other compounds. According to this model, 4a is selective because of a unique propensity of the seven-membered ring in the dibenz[b,f]azepine moiety to adopt a puckered orientation that allows it to fit more comfortably into the active site of the P. carinii enzyme than into the active site of the human enzyme. Compound 4a was also evaluated for the ability to be taken up into, and retard the growth of, P. carinii and T. gondii in culture. The IC50 of 4a against P. carinii trophozoites after 7 days of continuous drug treatment was 1.9μM as compared with previously observed IC50 values of >340μM for trimethoprim and 0.27 μM for trimetrexate. In an assay involving [3H]uracil incorporation into the nuclear DNA of T. gondii tachyzoites as the surrogate endpoint for growth, the IC50 of 4a after 5 h of drug exposure was 0.077 μM. The favorable combination of potency and enzyme selectivity shown by 4a suggests that this novel structure may be an interesting lead for structure-activity optimization.
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Sargent,Small
, p. 447,451 (1948)
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Cliff,Jones
, p. 1705 (1970)
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Birch Reduction of Arenes Using Sodium Dispersion and DMI under Mild Conditions
Asako, Sobi,Ilies, Laurean,Kurogi, Takashi,Murakami, Yoshiaki,Takahashi, Ikko,Takai, Kazuhiko
supporting information, p. 38 - 40 (2022/01/12)
An easy-to-handle sodium dispersion in paraffin oil (SD), in combination with inexpensive and environmentally benign 1,3- dimethyl-2-imidazolidinone (DMI) as an additive enables the Birch-type reduction of a variety of arenes with high yields, selectivity, and tolerance of functionality such as ether, alcohol, amine, amide, and carboxylic acid.
Acid-catalyzed oxidative cross-coupling of acridans with silyl diazoenolates and a Rh-catalyzed rearrangement: two-step synthesis of γ-(9-acridanylidene)-β-keto esters
Li, Weiyu,Xu, Hao,Zhou, Lei
, p. 5649 - 5657 (2021/07/02)
A MsOH-catalyzed oxidative cross-coupling of acridans and silyl diazoenolates and a Rh2(OAc)4-catalyzed rearrangement of the resultant diazo products are described. The reactions provide various γ-(9-acridanylidene)-β-keto esters in good yields, which bear an active α-methylene unit for further functionalization.
Visible-Light-Enhanced Cobalt-Catalyzed Hydrogenation: Switchable Catalysis Enabled by Divergence between Thermal and Photochemical Pathways
Mendelsohn, Lauren N.,MacNeil, Connor S.,Tian, Lei,Park, Yoonsu,Scholes, Gregory D.,Chirik, Paul J.
, p. 1351 - 1360 (2021/02/01)
The catalytic hydrogenation activity of the readily prepared, coordinatively saturated cobalt(I) precatalyst, (R,R)-(iPrDuPhos)Co(CO)2H ((R,R)-iPrDuPhos = (+)-1,2-bis[(2R,5R)-2,5-diisopropylphospholano]benzene), is described. While efficient turnover was observed with a range of alkenes upon heating to 100 °C, the catalytic performance of the cobalt catalyst was markedly enhanced upon irradiation with blue light at 35 °C. This improved reactivity enabled hydrogenation of terminal, di-, and trisubstituted alkenes, alkynes, and carbonyl compounds. A combination of deuterium labeling studies, hydrogenation of alkenes containing radical clocks, and experiments probing relative rates supports a hydrogen atom transfer pathway under thermal conditions that is enabled by a relatively weak cobalt-hydrogen bond of 54 kcal/mol. In contrast, data for the photocatalytic reactions support light-induced dissociation of a carbonyl ligand followed by a coordination-insertion sequence where the product is released by combination of a cobalt alkyl intermediate with the starting hydride, (R,R)-(iPrDuPhos)Co(CO)2H. These results demonstrate the versatility of catalysis with Earth-abundant metals as pathways involving open-versus closed-shell intermediates can be switched by the energy source.
