Identification of GNE-477, a potent and efficacious dual PI3K/mTOR inhibitor

Synthesis of thiophene and N-substituted thieno[3,2-d] pyrimidine derivatives as potent antitumor and antibacterial agents

“…-A mixture of compound 9 (2.78 g, 10 mmol), and 4-benzylidene-2-phenyl-4H-oxazol-5-one (2.49 g, 10 mmol) in glacial acetic acid (20 mL) containing fused sodium acetate (2 g) was refl uxed for 5 h. The reaction mixture was cooled and then poured onto cold water, the solid obtained was crystallized from DMF as a white powder. [2,3-e] [1,2,4]triazolo [1,5-c]pyrimidine-2(3H)-thione (11). -A mixture of compound 9 (2.78 g, 10 mmol) and thiourea (0.76 g, 10 mmol) was fused over an oil bath at 220 °C for 30 min.…”

“…The solid thus obtained was crystallized from ethanol as a yellow powder. [2,3-e]pyrimido [3,4-c] [1,2,4,5]tetrazine (12) (24). -A mixture of compound 9 (2.78 g, 10 mmol) and phosphorous pentasulfi de (2.66 g, 12 mmol) in pyridine (20 mL) was refl uxed for 12 h, the reaction mixture was concentrated and allowed to cool.…”

“…The synthetic route of target compounds 2-13 is illustrated in Schemes Thionation of compound 9 by treatment with P 2 S 5 in pyridine gave unexpectedly new bis-6,6'-(4-dichlorophenyl)-thieno [2,3-e]pyrimido [3,4-c] [1,2,4,5]tetrazine (12) rather than the expected monothione derivative (13). IR spectrum of compound 12 showed the absence of NH 2 , while the IR spectrum of compound 13 showed that the NH 2 group was still present, in addition to the presence of C=S at 1265 cm -1 (Scheme 2).…”

“…They have been widely employed due to their activities as antitumor (3,4), antimetabolite (5), antiviral, anti-HIV-1 (6), antiproliferative (7), antimicrobial (10,11), analgesic and anti-infl ammatory (12,13) agents, as well as kinase (8) and phospho-diesterase IV inhibitors (9). Among these active compounds, thieno [3,2-d]pyrimidines have generated wide-spread interest due to their remarkable antitumor activities (3,4,14). Thus, substituted thieno [3,2-d]pyrimidines exert pronounced activity as PI3K inhibitors (GDC-0941) and EGFR and VEGFR dual inhibitors, which are used in the treatment of cancers (15)(16)(17).…”

“…IR spectra (KBr) were recorded on a Perkin Elmer 1650 spectrometer (USA) while 1 H NMR and 13 C NMR spectra were recorded on JEOL EX-300 and JEOL ECA-500 (Shimadzu) instruments, resp. Chemical shift s were expressed in ppm relative to SiMe 4 as internal standard in DMSO-d 6 as solvent. For mass spectra recording, a 70 eV Finnigan SSQ 7000 spectrometer (Thermo-Instrument System Incorporation, USA) was used.…”