El-Naggar Abeer M, Khalil Ali K, Zeidan Hala M, El-Sayed Wael M
University of Ain Shams, Faculty of Science, Department of Chemistry, Abbassia, Cairo, 11566. Egypt.
Department of Research on Children with Special Needs, National Research Centre, 12622, Cairo. Egypt.
Anticancer Agents Med Chem. 2017;17(12):1644-1651. doi: 10.2174/1871521409666170412130040.
One of the promising scaffolds in drug discovery is the fused pyrimidine derivatives.
Efficient synthesis of a novel series of 18 new 1,8-naphthyridine-3-carbonitrile, 2-amino pyrido[2,3-d]pyrimidine derivatives via multi-component reactions of aromatic aldehydes, active methylene, and an aromatic amine under microwave irradiation and evaluation of their anticancer activity and possible mechanisms.
Only compounds 5 (a-c) had a significant antiproliferative activity in hepatic HepG2 cells at submicromolar concentration (7.5-10 µM). Similarly, only compound 11 (a-c) had a significant activity in breast MCF7 cells at (4-7 µM). Derivatives with one methoxyphenyl substitution (5a and 11a) were not different from derivatives having dimethoxyphenyl substitution (5b and 11b). However, thiophene substitution (5c and 11c) enhanced the anticancer activity in both cells lines examined by 25% in HepG2 and by ~45% in MCF7 cells compared to a and b derivatives. All compounds were safe to both normal human lung cells (WI-38) and RBCs at concentrations up to 40 mM. The antiproliferative activity of compounds 5 (a-c) in HepG2 could be attributed to an induction of intrinsic apoptotic pathway as evidenced from the induction of initiator caspase 9 by ~ 4 folds. While, the activity of compounds 11 (a-c) could be attributed to their potential to inhibit tyrosine kinases (TK) by up to 85%. The IC50 of derivative 11c against TK was at 173 nM.
The present study reported that derivatives 5 and 11 have merit for further investigation as anticancer and TK inhibitors.
稠合嘧啶衍生物是药物发现中很有前景的支架之一。
通过芳香醛、活性亚甲基和芳香胺在微波辐射下的多组分反应，高效合成一系列18种新型的1,8 - 萘啶 - 3 - 腈、2 - 氨基吡啶并[2,3 - d]嘧啶衍生物，并评估它们的抗癌活性及可能的作用机制。
仅化合物5（a - c）在亚微摩尔浓度（7.5 - 10 μM）时对肝癌HepG2细胞具有显著的抗增殖活性。同样，仅化合物11（a - c）在（4 - 7 μM）时对乳腺癌MCF7细胞具有显著活性。具有一个甲氧基苯基取代的衍生物（5a和11a）与具有二甲氧基苯基取代的衍生物（5b和11b）没有差异。然而，噻吩取代（5c和11c）在两种检测的细胞系中均增强了抗癌活性，与a和b衍生物相比，在HepG2细胞中增强了25%，在MCF7细胞中增强了约45%。所有化合物在浓度高达40 mM时对正常人肺细胞（WI - 38）和红细胞均安全。化合物5（a - c）在HepG2细胞中的抗增殖活性可能归因于内源性凋亡途径的诱导，这从起始半胱天冬酶9的诱导约4倍得到证明。而化合物11（a - c）的活性可能归因于它们高达85%抑制酪氨酸激酶（TK）的潜力。衍生物11c对TK的IC50为173 nM。
本研究报道衍生物5和11作为抗癌和TK抑制剂具有进一步研究的价值。
