Discovery of 9-(6-aminopyridin-3-yl)-1-(3-(trifluoromethyl)phenyl)benzo[ h ][1,6]naphthyridin-2(1 H)-one (torin2) as a potent, selective, and orally available mammalian target of rapamycin (mTOR) inhibitor for treatment of cancer
Liu Q.,Dana-Farber Cancer Institute |
Liu Q.,Harvard University |
Wang J.,Dana-Farber Cancer Institute |
Wang J.,Harvard University |
And 11 more authors.
Journal of Medicinal Chemistry | Year: 2011
The mTOR mediated PI3K/AKT/mTOR signal transduction pathway has been demonstrated to play a key role in a broad spectrum of cancers. Starting from the mTOR selective inhibitor 1 (Torin1), a focused medicinal chemistry effort led to the discovery of an improved mTOR inhibitor 3 (Torin2), which possesses an EC50 of 0.25 nM for inhibiting cellular mTOR activity. Compound 3 exhibited 800-fold selectivity over PI3K (EC50: 200 nM) and over 100-fold binding selectivity relative to 440 other protein kinases. Compound 3 has significantly improved bioavailability (54%), metabolic stability, and plasma exposure relative to compound 1. © 2011 American Chemical Society.
Mahajan V.,RWTH Aachen |
Mahajan V.,Sai Advantium Pharma Ltd. |
Gais H.-J.,RWTH Aachen
Chemistry - A European Journal | Year: 2011
A synthesis of sulfoximine-substituted medium-ring nitrogen heterocycles (MRNHs) having a high degree of substitution has been developed. Its key steps are the modular asymmetric synthesis of sulfoximine-substituted N-tethered trienes and their Ru-catalyzed ring-closing metathesis (RCM) reaction. The highly substituted N-tethered trienes were obtained enantio- and diastereopure through 1) the diastereoselective aminoalkylation of sulfoximine-substituted allyltitanium complexes with N-tert-butylsulfonyliminoester, 2) N-allylation of homoallylic N-sulfonyl amines, 3) allylation, hydroxylalkylation, and formylation of α-lithioalkenylsulfoximines, and 4) allylation of α-formylalkenylsulfoximines. The Ru-catalyzed RCM reaction of the sulfoximine-substituted 1,7,10- and 1,7,12-trienes stereoselectively afforded the corresponding nine-, ten-, and eleven-membered MRNHs in good yields. An interesting difference in reactivity was noted in the case of a sulfoximine-substituted 1,7,10-triene and its corresponding 1,10-diene. While the triene readily underwent a RCM reaction, the diene reacted only in the presence of Ti(OiPr)4 under formation of the corresponding MRNH. The feasibility of a removal of the sulfoximine auxiliary and the N-sulfonyl protecting group from the MRNHs were demonstrated through reduction and cleavage, respectively, of a nine-membered heterocycle, both of which proceeded readily and gave the corresponding cyclic alkene and amine, respectively. © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Dasari B.,University of Hyderabad |
Jogula S.,University of Hyderabad |
Borhade R.,Karolinska Institutet |
Balasubramanian S.,Indian Institute of Chemical Technology |
And 5 more authors.
Organic Letters | Year: 2013
A practical and modular approach to obtain a diverse set of 14-membered macrocyclic compounds from carbohydrates is developed that utilizes functional groups at C-1 and C-5. The evaluation of this toolbox in various zebrafish assays led to the identification of 2.7f as an antiangiogenesis agent. © 2013 American Chemical Society.
Sulfoximine-directed single and double ortho-lithiation: Stereoselective rearrangements of o,oa'-Dilithiophenylsulfoximines to o,N- dilithiosulfinylanilines through anionic fries rearrangements of o,oa'-dilithiophenylsulfinamides
Wessels M.,RWTH Aachen |
Wessels M.,Novartis |
Mahajan V.,RWTH Aachen |
Mahajan V.,Sai Advantium Pharma Ltd. |
And 4 more authors.
European Journal of Organic Chemistry | Year: 2011
Treatment of various phenylsulfoximines with nBuLi (1 equiv.) at -78 °C in THF resulted in single ortho-lithiations and gave the corresponding o-lithiosulfoximines. According to NMR spectroscopy, the o-lithiosulfoximines are generally stable at 0 °C. The o-lithiosulfoximines were efficiently trapped through deuteration, alkylation, silylation, and phosphanylation. Treatment of cyclic phenylsulfoximines also containing H atoms at their α-positions with nBuLi (1 equiv.) at -78 °C furnished the o-lithiosulfoximines with high selectivity, whereas similar treatment at -50 °C to room temperature yielded the corresponding α-lithiosulfoximines. At elevated temperatures, o-lithiosulfoximines also possessing α-H atoms underwent quantitative o,α-transmetalation to afford the corresponding α-lithiosulfoximines. Treatment of α,α-disubstituted cyclic and α,α,α-trisubstituted acyclic phenylsulfoximines with nBuLi (2 equiv.) at low temperatures led to double ortho-lithiation and furnished the corresponding o,oa'-dilithiosulfoximines. At elevated temperatures, cyclic o,oa'-dilithiophenylsulfoximines underwent multi-step rearrangements with formation of o,N-dilithiated benzothiazepine and benzothiazocine S-oxide derivatives in high yields. Theacyclic o,oa'-dilithiophenylsulfoximine underwent a similar rearrangement and gave the corresponding o,N-dilithio-sulfinylaniline derivative. The rearrangements involve 1) elimination of the lithium sulfinamide from the o,oa'-dilithiosulfoximine, 2) a Li-N addition of the lithium sulfinamide to the o-lithiobenzyne, and 3) an anionic Fries rearrangement of the o,oa'-dilithiophenylsulfinamide. The rearrangements of the o,oa'-dilithiophenylsulfoximines proceeded with overall retention of configuration at sulfur. Phenylsulfoximines undergo directed single and double ortho-lithiation with nBuLi. The o,oa'-dilithiosulfoximines undergostereoselective rearrangements to o,N-dilithiosulfinyl-anilines. The rearrangements, which proceed with retention of configuration, involve 1) elimination of the lithium sulfinamide, 2) addition of the lithium sulfinamide to o-lithiobenzyne, and 3) anionic Fries rearrangement. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Tele S.S.,Shivaji University |
Tele S.S.,Sai Advantium Pharma Ltd. |
Gadkari T.V.,Sai Advantium Pharma Ltd. |
Patil S.R.,Shivaji University |
Kolekar G.B.,Shivaji University
Journal of Chromatographic Science | Year: 2011
A simple, sensitive, and selective stability indicating highperformance liquid chromatographic method has been developed and validated for quantitative analysis of carprofen (CPF) in presence of its degradation products. All degradation products in acid hydrolysis and photolysis were separated, identified by mass spectroscopic method and probable structures were elucidated. The forced degradation studies were performed on a bulk sample of CPF by using various methods like 0.1 M hydrochloric acid, 0.1 M sodium hydroxide, 0.33% hydrogen peroxide (H2O2), heating at 60°C and exposure to UV light at 254 nm. A 5 μm particle octa desyl silane (ODS) column (150 mm x 4.6 mm) was used with acetonitrile-ammonium acetate (100 mM, pH-6.7) 40:60 (v/v) as a mobile phase at flow rate of 1.2 mL/min. Column oven temperature was maintained at 30°C and quantitation was achieved at 239 nm on the basis of peak area. The linear range and correlation coefficient (r2) was found 0.5-60 μg/mL and 0.9999 respectively. The limit of detection (LOD) and limit of quantitation (LOQ) were obtained 0.066 μg/mL and 0.20 μg/mL respectively. The proposed method was found to be suitable and accurate for quantitative analysis, stability study and characterisation of degradation product of CPF.