Recent syntheses of PI3K/Akt/mTOR signaling pathway inhibitors

Abstract

This review focuses on the syntheses of PI3K/Akt/mTOR inhibitors that have been reported outside of the patent literature in the last 5 years but is largely centered on synthetic work reported in 2011 and 2012. While focused on syntheses of inhibitors, some information on in vitro and in vivo testing of compounds is also included. Many of these reported compounds are reversible, competitive adenosine triphosphate (ATP) binding inhibitors, so given the structural similarities of many of these compounds to the adenine core, this review presents recent work on inhibitors based on where the synthetic chemistry was started, i.e. inhibitor syntheses which started with purines/pyrimidines are followed by inhibitor syntheses which began with pyridines, pyrazines, azoles, and triazines then moves to inhibitors which bear no structural resemblance to adenine: liphagal, wortmannin and quercetin analogs. The review then finishes with a short section on recent syntheses of phosphotidyl inositol (PI) analogs since competitive PI binding inhibitors represent an alternative to the competitive ATP binding inhibitors which have received the most attention.

A Systematic Review on Antitumor Agents with 1, 3, 5-triazines

“…Compound 13 ( Figure 6) was recorded as mTOR inhibitor selective over PI3K and inhibited downstream substrate Pakt of mTOR kinase up to 83% exhibiting dose-dependent inhibition [37]. This compound inhibited 18 cancer cell-lines' proliferation (IC 50 <1 μM) in tissue culture experiments, HGF-stimulated Akt phosphorylation in liver at 30 mg/kg and S6RP phosphorylation at 100 mg/kg in vivo tests.…”

“…The 4-OMe-6-aza compound 3 ( Figure 2) was displayed dramatic loss of activity against p110α, p110β, and p110δ compared with compound 2 which showed that the electron withdrawing effect being highly unfavorable to moral activity. Synthetic study on PI3K inhibitors with the triazine skeleton structure has proceeded recently [37]. = 228 ng/ml) [39].…”

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

“…-A mixture of thiophene derivative 1 (2.53 g, 10 mmol) and phenacyl bromide (1.99 g, 10 mmol) was refl uxed in ethanol for 3 h. The solid obtained was fi ltered and crystallized from dioxane to give 14 as an orange powder. (15). -A mixture of 14 (3.71 g, 10 mmol) and malononotrile (0.66 g, 10 mmol) in ethanol (30 mL) containing sodium ethoxide (0.5 g) was refl uxed for 5 h, the reaction mixture was cooled and acidifi ed with dil.…”

“…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). As a part of our continuing program on the synthesis of antimicrobial and antitumor compounds, we have earlier reported on a series of heterocyclic moieties that have biological activities (11)(12)(13).…”

Targeting the PI3K/AKT Pathway for the Treatment of Gastric Cancer

“…These include the pan-PI3K inhibitors BKM120 (Novartis), PX-886 (Oncothyreon), XL147 (SAR245408; Sanofi) and the p110a selective inhibitors BYL719, GDC0032, and INK1117 etc. [56].Because the catalytic domains of p110 and mTOR are structurally similar and mTOR activation is the downstream event of the PI3K/AKT pathway, it is expected that the dual inhibition of these targets may be more effective. Some of the dual PI3K/mTOR inhibitors currently being investigated in clinical trials include BEZ235, XL765, GDC-0980, GDC0084, SF1126, and PF-46915 etc.…”