Design, synthesis and evaluation of novel thienopyrimidine-based agents bearing diaryl urea functionality as potential inhibitors of angiogenesis

Design, synthesis and evaluation of novel tetrahydropyridothienopyrimidin-ureas as cytotoxic and anti-angiogenic agents

“…We decided to use the number and the length of capillary blood vessels as the index of anti-angiogenic activity. Consequently, the prepared images were analyzed by the advantageous software, Image J 22 , 23 .…”

“…The presence of a hydrogen bond acceptor meaning urea or amide along with heterocyclic aromatic core are among the most important structural features of these inhibitors. According to our previous findings on thienopyrimidines 22 , 23 , scaffold hopping and redesign approaches were applied to investigate new series of novel thienopyrimidine derivatives considering the structure of sorafenib and synthesized compounds by Yang in which the hydrophobic tail (occupied the allosteric binding region) is substituted phenyl ring 24 . The bioisoesteric replacement of phenyl in quinazoline core by thiophene ring resulted in our designed compounds (Fig.…”

In Vitro Anticancer Activity Screening of Novel Fused Thiophene Derivatives as VEGFR-2/AKT Dual Inhibitors and Apoptosis Inducers

“…This system has also attracted great attention due to its versatile synthetic approaches and the reported broad biological activities [5][6][7][8] that range from antihypertensive through alpha-1 adrenergic receptor antagonism [9], antiplatelet aggregation [10], antidepressant activity [11], treatment of erectile dysfunction, phosphodiesterase-5 inhibition [12], anti-inflammatory through COX-II inhibition [13], antimicrobial activity [14,15], and many other pledging activities [8], Noteworthy is the antiproliferative activity in which thienopyrimidine derivatives display potent activity with several mechanisms of action such as PI3K pathway inhibition [8,16,17], focal adhesion kinase (FAK) inhibition [18], kinases inhibitory activity against Tie-2 [19], cell cycle arrest and apoptosis induction [20][21][22]. Last but not least, they have promising anticancer activity by inhibiting the pathways under investigation,VEGFR-2 [23,24] and AKT-1 [25], that end in cancer cell proliferation, growth, and survival inhibition. Exemplified structures are presented in Figure 1.…”

“…Exemplified structures are presented in Figure 1. Thienopyrimidine derivatives with potential activities as anticancer agents; structures adopted from (I) [8,16], (II) [16,18], (III) [21], (IV) [8], (V) [23], and (VI) [25].…”

“…Thus, inhibiting the VEGF binding to its receptor either by neutralizing the ligand or the receptor by antibodies or direct inhibition of intracellular kinase domain through competing with the ATPbinding site is considered a very successful therapeutic strategy to halt tumor progress [27,[29][30][31]. Additionally, VEGF binding to VEGFR-2 causes the activation of a central enzyme in cell survival, which is AKT (a serine/threonine kinase that belongs to the AGC kinase family) that is crucially involved in cell proliferation, evading apoptosis, protein Thienopyrimidine derivatives with potential activities as anticancer agents; structures adopted from (I) [8,16], (II) [16,18], (III) [21], (IV) [8], (V) [23], and (VI) [25].…”