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Mariana Nacht,
Lixin Qiao,
Michael P Sheets,
Thia St Martin,
Matthew Labenski,
Hormoz Mazdiyasni,
Russell Karp, Zhendong Zhu,
Prasoon Chaturvedi,
Deepa Bhavsar,
Deqiang Niu,
William Westlin,
Russell C Petter,
Aravind Prasad Medikonda,
Juswinder Singh
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ABSTRACT: PI3Kα has been identified as an oncogene in human tumors. Using rational drug design, a targeted covalent inhibitor 3 (CNX-1351) was created that potently and specifically inhibits PI3Kα. We demonstrate, using mass spectrometry and x-ray crystallography, that the selective inhibitor covalently modifies PI3Kα on cysteine 862 (C862), an amino acid unique to the alpha isoform, and that PI3K β, δ, and γ are not covalently modified. 3 is able to potently (EC50 < 100 nM) and specifically inhibit signaling in PI3Kα-dependent cancer cell lines, and this leads to a potent antiproliferative effect (GI50 < 100nM). A covalent probe, 8 (CNX-1220), which selectively bonds to PI3Kα, was used to investigate the duration of occupancy of 3 with PI3Kα in vivo. This is the first report of a PI3Kα-selective inhibitor and these data demonstrate the biological impact of selectively targeting PI3Kα.
Journal of Medicinal Chemistry 01/2013; · 4.80 Impact Factor
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ABSTRACT: CBS-QB3 enthalpies of reaction have been computed for the conjugate additions of MeSH to six α,β-unsaturated ketones. Compared with addition to methyl vinyl ketone, the reaction becomes 1-3 kcal mol(-1) less exothermic when an α-Me, β-Me, or β-Ph substituent is present on the C=C bond. The lower exothermicity for the substituted enones occurs because the substituted reactant is stabilized more by hyperconjugation or conjugation than the product is stabilized by branching. Substituent effects on the activation energies for the rate-determining step of the thiol addition (reaction of the enone with MeS(-)) were also computed. Loss of reactant stabilization, and not steric hindrance, is the main factor responsible for controlling the relative activation energies in the gas phase. The substituent effects are further magnified in solution; in water (simulated by CPCM calculations), the addition of MeS(-) to an enone is disfavored by 2-6 kcal mol(-1) when one or two methyl groups are present on the C=C bond (ΔΔG(‡)). The use of CBS-QB3 gas-phase energies in conjunction with CPCM solvation corrections provides kinetic data in good agreement with experimental substituent effects. When the energetics of the thiol additions were calculated with several popular density functional theory and ab initio methods (B3LYP, MPW1PW91, B1B95, PBE0, B2PLYP, and MP2), some substantial inaccuracies were noted. However, M06-2X (with a large basis set), B2PLYP-D, and SCS-MP2 gave results within 1 kcal mol(-1) of the CBS-QB3 benchmark values.
The Journal of Organic Chemistry 06/2011; 76(12):5074-81. · 4.45 Impact Factor
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Margit Hagel,
Deqiang Niu,
Thia St Martin,
Michael P Sheets,
Lixin Qiao,
Hugues Bernard,
Russell M Karp, Zhendong Zhu,
Matthew T Labenski,
Prasoon Chaturvedi,
Mariana Nacht,
William F Westlin,
Russell C Petter,
Juswinder Singh
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ABSTRACT: Designing selective inhibitors of proteases has proven problematic, in part because pharmacophores that confer potency exploit the conserved catalytic apparatus. We developed a fundamentally different approach by designing irreversible inhibitors that target noncatalytic cysteines that are structurally unique to a target in a protein family. We have successfully applied this approach to the important therapeutic target HCV protease, which has broad implications for the design of other selective protease inhibitors.
Nature Chemical Biology 01/2011; 7(1):22-4. · 14.69 Impact Factor
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ABSTRACT: p-biphenylyl, o-biphenylyl, and 1-naphthyl azides were deposited in argon at low temperature in the presence and absence of HCl. In the absence of HCl, the known electronic and vibrational spectra of the corresponding triplet nitrenes, azirines, and didehydroazepines were observed, whereas in the presence of HCl, photolysis of these azides produces new electronic spectra assigned to the corresponding nitrenium cations. For p-biphenylyl azide the resulting spectrum of the nitrenium ion is very similar to the previously observed solution-phase spectrum of this species. The vibrational spectrum of this cation was recorded for the first time. Spectroscopic evidence for the previously unknown o-biphenylylnitrenium cation and 1-naphthylnitrenium cation are provided. The spectra of p- and o-biphenylylnitrenium cations and 1-naphthylnitrenium cation are well reproduced by CASSCF and CASPT2 calculations. The same nitrenium cations were detected in solution by femtosecond time-resolved laser flash photolysis of the appropriate azides in 88% formic acid. The transient spectra of the nitrenium cations recorded in solution are in good agreement with the spectra obtained in HCl matrices. The rates of formation of these cations equal the rates of decay of the singlet nitrenes in 88% formic acid and are as follows: p-biphenylyl (taugrowth = 11.5 ps), o-biphenylyl (taugrowth = 7.7 ps), and 1-naphthylnitrenium cations (taugrowth = 8.4 ps). The decay lifetimes of p- and o-biphenylylnitrenium cations are 50 and 27 ns, respectively. The decay lifetimes of 1-naphthylnitrenium cation is 860 ps in 88% formic acid.
Journal of the American Chemical Society 08/2007; 129(26):8380-8. · 9.91 Impact Factor
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ABSTRACT: We report the first detection of triplet alkyl nitrenes in fluid solution by laser flash photolysis of alpha-azido acetophenone derivatives, 1. Alphazides 1 contain an intramolecular triplet sensitizer, which ensures formation of the triplet alkyl nitrene by bypassing the singlet nitrene intermediate. At room temperature, azides 1 cleave to form benzoyl and methyl azide radicals in competition with triplet energy transfer to form triplet alkyl nitrene. The major photoproduct 3 arises from interception of the triplet alkyl nitrene with benzoyl radicals. The triplet alkyl nitrene intermediates are also trapped with molecular oxygen to yield the corresponding 2-nitrophenylethanone. Laser flash photolysis of 1 reveals that the triplet alkyl nitrenes have absorption around 300 nm. The triplet alkyl nitrenes were further characterized by obtaining their UV and IR spectra in argon matrices. (13)C and (15)N isotope labeling studies allowed us to characterize the C-N stretch of the nitrene intermediate at 1201 cm(-)(1).
The Journal of Organic Chemistry 11/2003; 68(21):7951-60. · 4.45 Impact Factor
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ABSTRACT: Photolysis of methyl α-diazo-(2-naphthyl)acetate at 450 nm yields primarily the triplet ground state of 2-naphthyl(carbomethoxy)carbene (3NCC), which was characterized by its UV/visible, IR, and ESR spectra as well as by trapping with O2 and CO. Bleaching of the weak visible bands of 3NCC (λ > 515 nm) leads to the disappearance of the triplet ESR spectrum and to a new optical spectrum with broad bands in the near-UV region. The spectra of 3NCC can be almost fully recovered in the dark at 12 K. The same process also occurs upon irradiation at 450 nm, with the exception that the recovery of 3NCC is accompanied by the formation of small amounts of 2-naphthyl(methoxy)ketene and 2-(2-naphthyl)propiolactone. The observed optical and IR spectra of the intermediate that is formed reversibly from 3NCC are in full accord with quantum chemical model calculations for the singlet state of the same carbene 1NCC, but not with the tricyclic cyclopropene derivative observed previously for the parent 2-naphthylcarbene or the 1-(2-naphthyl)-2-methoxyoxirene. Exploration of the potential energy surfaces for singlet and triplet NCC show that a barrier between the two states is created by a pronounced change in conformation of the carbomethoxy group, which may furthermore be hindered in a solid matrix environment.
03/1999;
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ABSTRACT: Upon ionization in argon matrices by X-irradiation, o-vinylbenzaldehyde (VBA) partially undergoes transfer of the formyl hydrogen atom to the vinylic CH2 group, thereby forming a quinoketene radical cation of the type previously described (Bally, T.; Michalak, J. J. Photochem. Photobiol. A: Chem. 1992, 69, 185). This process does not manifest itself clearly in the optical spectra because the transitions of the quinoketene cation coincide with the much more intense ones of VBA•+ and are mostly obscured by those. However, the IR spectra show unambiguously that the rearrangement occurs rather efficiently. Also they show that in the course of the X-irradiation, the tautomerized cations are reneutralized to from the quinoketene tautomer of VBA in good yield. The quinoketene and its radical cation were independently obtained from 2-methylbenzocyclobutenone which undergoes spontaneous ring-opening on photolysis and/or ionization. The optical spectra of the radical cations are assigned on the basis of CASPT2 calculations and the different species involved in this study are characterized at the B3LYP/6-31G* level.
03/1997;
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ABSTRACT: Pentalene (1) is generated for the first time in argon matrices by photocleavage of the corresponding dimer (2). It is found that the cleavage occurs in two distinct steps, the first of which leads presumably to a diradical. 1 is characterized by its electronic and vibrational absorption spectra which are assigned and interpreted with reference to different quantum chemical calculations. These show that the first two excited states of pentalene involve a doubly excited configuration which had been ignored in previous discussion of the electronic structure. Due to the antiaromatic nature of pentalene, the distortive force of the π-electrons which favor a C2h structure with localized single and double bonds predominates over the effect of the σ-electrons which drive the molecule to a D2h structure.
02/1997;
