Molecular design, synthesis and in vitro biological evaluation of thienopyrimidine–hydroxamic acids as chimeric kinase HDAC inhibitors: a challenging approach to combat cancer

Abstract

A series of thieno [2,3-d]pyrimidine-based hydroxamic acid hybrids was designed and synthesised as multitarget anti-cancer agents, through incorporating the pharmacophore of EGFR, VEGFR2 into the inhibitory functionality of HDAC6. Three compounds (12c, 15b and 20b) were promising hits, whereas (12c) exhibited potent VEGFR2 inhibition (IC 50 ¼185 nM), potent EGFR inhibition (IC 50 ¼1.14 mM), and mild HDAC6 inhibition (23% inhibition). Moreover, compound (15c) was the most potent dual inhibitor among all the synthesised compounds, as it exhibited potent EGFR and VEGFR2 inhibition (IC 50 ¼19 nM) and (IC 50 ¼5.58 mM), respectively. While compounds (20d) and (7c) displayed nanomolar selective kinase inhibition with EGFR IC 50 ¼ 68 nM and VEGFR2 IC 50 ¼ 191 nM, respectively. All of the synthesised compounds were screened in vitro for their cytotoxic effect on 60 human NCI tumour cell lines. Additionally, molecular docking studies and ADMET studies were carried out to gain further insight into their binding mode and predict the pharmacokinetic properties of all the synthesised inhibitors.

Harnessing pyrimidine as a building block for histone deacetylase inhibitors

“…[47] Biological screening of the synthesized compounds against HDACs 1, 3, and 6 was done. Compound 25 [47] was the most potent one in this series, and it had IC 50 values equal to 1.14 ± 0.03 nM, 3.56 ± 0.08 nM, and 11.43 ± 0.12 nM against HDACs [48] were the most active compounds at 10 µM concentrations where they exhibited inhibition percentages of EGFR equal to 66%, 98%, and 92%, respectively. While their VEGFR inhibition percentages were 100%, 32%, and 25%, respectively.…”

“…Another modification of compound 6 resulted in a series of thieno[2,3‐ d ]pyrimidine‐based hydroxamic acids as EGFR/VEGFR‐2/HDAC 6 inhibitors by M. M. Abdel‐Atty et al The main compounds 26–28 [ 48 ] were the most active compounds at 10 µM concentrations where they exhibited inhibition percentages of EGFR equal to 66%, 98%, and 92%, respectively. While their VEGFR inhibition percentages were 100%, 32%, and 25%, respectively.…”

In Silico Screening and Anticancer-Apoptotic Evaluation of Newly Synthesized Thienopyrimidine/Sulfonamide Hybrids

“…Synthesis pathways adopted for preparing the designed compounds 4a ( i – iii ) and 4b ( i – iii ) are illustrated in Scheme 1 and Scheme 2 , respectively. According to the published procedures, the starting aminothiophene esters 1a [ 21 ] and 1b [ 22 , 23 ] were prepared using sulfur element, ethyl cyanoacetate, morpholine, and cycloketone or ethylacetoactate for 1a and 1b , respectively. Refluxing 1a / 1b with excess formamide as reported [ 21 , 22 , 23 , 24 ] gave the cycloheptathieno[2,3-d]pyrimidin-4(3H)-one derivatives 2a / 2b , respectively, which yielded the corresponding para chlorinated derivatives 3a / 3b , respectively, upon treatment with phosphorus oxychloride as described in the literature [ 21 , 25 ].…”

“…According to the published procedures, the starting aminothiophene esters 1a [21] and 1b [22,23] were prepared using sulfur element, ethyl cyanoacetate, morpholine, and cycloketone or ethylacetoactate for 1a and 1b, respectively. Refluxing 1a/1b with excess formamide as reported [21][22][23][24] gave the cycloheptathieno [2,3-d]pyrimidin-4(3H)-one derivatives 2a/2b, respectively, which yielded the corresponding para chlorinated derivatives 3a/3b, respectively, upon treatment with phosphorus oxychloride as described in the literature [21,25]. Refluxing the appropriate sulfonamide derivative sulfaguanidine with 3a/3b in glacial acetic acid was then performed to afford the N-carbamimidoyl-4-((5,6,7,8-tetrahydrobenzo [4,5]thieno [2,3-d]pyrimidin-4-yl)amino)benzenesulfonamide/ethyl-4-((4-(N-carbamimidoylsulfamoyl) phenyl) amino)-5-methylthieno [2,3-d]pyrimidine-6-carboxylate 4ai/4bi, respectively.…”

Medicinal attributes of thienopyrimidine scaffolds incorporating the aryl urea motif as potential anticancer candidates via VEGFR inhibition

“…Scaffolds with no urea nor amide moiety were devoid of activity at all. In the same year, Abdel‐Atty et al [ 98 ] designed and synthesized scaffolds of TP hydroxamic acid with different hydrocarbon linkers 5j–5p (Figure 7). The synthesized TPs were screened by the National Cancer Institute (NCI) against 60 human cancer cell lines.…”