Synthesis, anticancer activity and molecular docking studies on a series of heterocyclic trans-cyanocombretastatin analogues as antitubulin agents

Abstract

A series of heterocyclic combretastatin analogues have been synthesized and evaluated for their anticancer activity against a panel of 60 human cancer cell lines. The most potent compounds were two 3,4,5-trimethoxy phenyl analogues containing either an (Z)-indol-2-yl (8) or (Z)-benzo[b]furan-2-yl (12) moiety; these compounds exhibited GI50 values of <10 nM against 74% and 70%, respectively, of the human cancer cell lines in the 60-cell panel. Compounds 8, and 12 and two previously reported compounds in the same structural class, i.e. 29 and 31, also showed potent anti-leukemic activity against leukemia MV4-11 cell lines with LD50 values = 44 nM, 47 nM, 18 nM, and 180 nM, respectively. From the NCI anti-cancer screening results and the data from the in vitro toxicity screening on cultured AML cells, seven compounds: 8, 12, 21, 23, 25, 29 and 31 were screened for their in vitro inhibitory activity on tubulin polymerization in MV4-11 AML cells; at 50 nM, 8 and 29 inhibited polymerization of tubulin by >50%. The binding modes of the three most active compounds (8, 12 and 29) to tubulin were also investigated utilizing molecular docking studies. All three molecules were observed to bind in the same hydrophobic pocket at the interface of α- and β-tubulin that is occupied by colchicine, and were stablized by van der Waals’ interactions with surrounding tubulin residues. The results from the tubulin polymerization and molecular docking studies indicate that compounds 8 and 29 are the most potent anti-leukemic compounds in this structural class, and are considered lead compounds for further development as anti-leukemic drugs.

Biobanked Glioblastoma Patient-Derived Organoids as a Precision Medicine Model to Study Inhibition of Invasion

“…U-251 MG is an established GBM cell line [ 15 ], part of the NCI-60 human cancer cell lines [ 25 ], with the ability to form spheroids with invasive properties [ 26 ]; it has been used in the screening of pharmaceutical agents to identify, characterize, and select novel compounds with growth inhibition and/or killing of tumor cells. A series of 22 different compounds called BS, BSK, JVM PNR, and ST [ 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 ] whose the chemical structures, details, and activity are explained in Table 1 and Figure S1 , were incubated with the spheroids for 48 h to define the toxicity the effects on their invasiveness. These compounds have anti-invasive properties, as they interfere with pathways of cell invasion ( Figure 2 ).…”

Antitumor activities of new iso(thio)cyanates and their nitrogen and sulphur heterocyclic phosphorus derivatives

“…BITC was the most potent growth inhibitor with half-maximum IC50 values on HeLa, Fem-x and LS 174 cells. Penthala et al (2015) reported that trans-cyanostilbene analogues which contained the 3,4,5-trimethoxyphenyl and dimethoxyphenyl moieties exhibited low micromolar growth inhibition against human cancer in the panel. Luo et al (2017) suggested that acetyl chloride-mediated creation of PEITC derivatives proves to be convenient and provides the expected excellent products yields.…”

Synthesis and biological evaluation of novel 4,5-disubstituted 2H-1,2,3-triazoles as cis-constrained analogues of combretastatin A-4

“…Docking was performed using SwissDock (http://www.swissdock.ch/), based on the docking algorithm EADock DSS [27]. Docking was performed using protocols established in our previous studies [16]. Use of the most exhaustive and unbiased option in SwissDock ensured the sampling of the maximum number of binding modes for each molecule.…”

“…The reaction mixture was stirred at room temperature for 2–3 hours for the reaction to complete and the final product to crash out of the solution. The precipitate is filtered, washed with water and dried to yield the final compounds with yields ranging from 70–95 % (Scheme 1) [16]. …”