3-Hydrazinoisatin-based benzenesulfonamides as novel carbonic anhydrase inhibitors endowed with anticancer activity: Synthesis, in vitro biological evaluation and in silico insights

Abo-Ashour, Mahmoud F.; Eldehna, Wagdy M.; Nocentini, Alessio; Bonardi, Alessandro; Bua, Silvia; Ibrahim, Hany S.; Elaasser, Mahmoud M.; Kryštof, Vladimír; Jorda, Radek; Gratteri, Paola; Abou‐Seri, Sahar M.; Supuran, Claudiu T.

doi:10.1016/j.ejmech.2019.111768

Cited by 70 publications

(46 citation statements)

References 38 publications

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“…In contrast to the aforementioned examples of good correlation between hCA IX/XII inhibition and cytotoxicity against cancer cells in hypoxic conditions, the reverse is true for a strikingly large number of examples 50,[55][56][57][60][61][62][63]67 . In these cases, many potent hCA IX/XII inhibitors, such as 14-19, did not possess a substantial activity against cancer cells.…”

Section: Discussionmentioning

confidence: 85%

“…To our delight, however, there is a large number of mechanistically relevant experiments reported in the literature which address the ability of hCA IX/XII inhibitors to block the growth of hypoxic cancer cells overexpressing the target isozymes [49][50][51][52][53][54][55][56][57][58][59][60][61][62][63][64][65][66][67] . Moreover, a certain cohort of studies revealed compounds possessing both favourable hCA inhibitory profile and significant anticancer activity, as exemplified by structures 5-13 ( Figure 2) [49][50][51][52][53][54][55][56][58][59][60][61][64][65][66][67] .…”

Section: Discussionmentioning

confidence: 99%

“…Understanding the significance of the candidate molecule prioritisation problem in question is essential while ignoring it may lead to many promising compounds being overlooked in want of more potent hCA IX/XII inhibitors. Aiming to draw a more informative picture, we have graphically represented the relationship between the anticancer effect (in this case, irrespective of the specific experimental conditions employed in various studies) and the hCA IX/XII inhibitory activity of the compounds [30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][49][50][51][52][53][54][55][56][57][58][71][72][73][74] . In order to summarise the somewhat heterogeneous literature data, we have visualised the reported antiproliferative agents in the plots with the Y-axis displaying K i 's against hCA IX (Figures S1 and S2) and hCA XII ( Figures S3 and S4).…”

Section: Discussionmentioning

confidence: 99%

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Inhibitory activity against carbonic anhydrase IX and XII as a candidate selection criterion in the development of new anticancer agents

Krasavin

Kalinin

Sharonova

et al. 2020

Journal of Enzyme Inhibition and Medicinal Chemistry

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Analysis of the literature data reveals that while inhibition of cancer-related carbonic anhydrase IX and XII isoforms continues to be an important enrichment factor for designing anticancer agent development libraries, exclusive reliance on the in vitro inhibition of these two recombinant isozymes in nominating candidate compounds for evaluation of their effects on cancer cells may lead not only to identifying numerous compounds devoid of the desired cellular efficacy but also to overlooking many promising candidates which may not display the best potency in biochemical inhibition assay. However, SLC-0111, now in phase Ib/II clinical trials, was developed based on the excellent agreement between the in vitro, in vivo and more recently, in-patient data.

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Section: Discussionmentioning

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Inhibitory activity against carbonic anhydrase IX and XII as a candidate selection criterion in the development of new anticancer agents

Krasavin

Kalinin

Sharonova

et al. 2020

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…[17,18] In addition, benzamide and benzenesulfonamide are also important pharmacophores frequently used in the design of anticancer agents. [19][20][21][22][23] The above findings suggest that the incorporation of benzimidazole, benzamide, and/or benzenesulfonamide moieties into the molecule of DAA might be a promising strategy for the discovery of new anticancer agents. Based on this strategy, two series of new N-(1H-benzo[d]imidazol-2-yl)-benzamide/benzenesulfonamide derivatives were designed and synthesized.…”

Section: Introductionmentioning

confidence: 93%

Synthesis, cytotoxicity and apoptosis‐inducing activity of novel 1H‐benzo[d]imidazole derivatives of dehydroabietic acid

Yang

Wang

et al. 2020

J Chinese Chemical Soc

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With the expectation of finding new and effective antitumor drugs, a series of novel N-(1H-benzo[d]imidazole-2-yl)-benzamide/benzenesulfonamide derivatives of dehydroabietic acid were synthesized and evaluated for cytotoxic activity against three human cancer cell lines (MCF-7, HeLa, and HepG2 cells) and one human normal hepatocyte cell line (LO2). As a result, a number of derivatives showed moderate to good antitumor activities. Among them, compound 8h exhibited the most potent activities against three cancer cell lines with IC 50 values of 0.87 ± 0.18, 9.39 ± 0.72, and 8.31 ± 0.64 μM, respectively, and was less active to normal hepatocyte LO2 cells. Further mechanism studies revealed that compound 8h could arrest the cell cycle of MCF-7 cells at S phase and induce the apoptosis of MCF-7 cells in ROS-mediated mitochondrial pathway.

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“…The used abbreviations are as following: s, singlet; d, doublet; m, multiplet. Compound 3 [41], 8a-f [46,47], 4 [48], and 6a-d [49] were synthesized in accordance with the literature procedures.…”

Section: Molecules 2020 25 X For Peer Reviewmentioning

confidence: 99%

Synthesis, Biological Evaluation and In Silico Studies of Certain Oxindole–Indole Conjugates as Anticancer CDK Inhibitors

Al-Warhi,

El Kerdawy,

Aljaeed

et al. 2020

Molecules

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On account of their overexpression in a wide range of human malignancies, cyclin-dependent kinases (CDKs) are among the most validated cancer targets, and their inhibition has been featured as a valuable strategy for anticancer drug discovery. In this study, a hybrid pharmacophore approach was adopted to develop two series of oxindole–indole conjugates (6a–i and 9a–f) and carbocycle–indole conjugates (11a,b) as efficient antitumor agents with potential inhibitory action toward CDK4. All oxindole–indole conjugates, except 6i, 9b, and 9c efficiently affected the growth of the human breast cancer MCF-7 (IC50: 0.39 ± 0.05–21.40 ± 1.58 μM) and/or MDA-MB-231 (IC50: 1.03 ± 0.04–22.54 ± 1.67 μM) cell lines, whereas bioisosteric replacement of the oxindole nucleus with indane or tetralin rings (compounds 11a,b) diminished the anti-proliferative activity. In addition, hybrids 6e and 6f displayed effective cell cycle disturbance and proapoptotic capabilities in MCF-7 cells. Furthermore, the efficient anti-proliferative agents towards MCF-7 and/or MDA-MB-231 cell lines (6a–h, 9a, and 9e) were investigated for their potential inhibitory action toward CDK4. Hybrids 6a and 6e displayed good CDK4 inhibitory activity with IC50s equal 1.82 and 1.26 µM, respectively. The molecular docking study revealed that oxindole moiety is implicated in two H-bonding interactions via both (NH) and (C=O) groups with the key amino acids Glu94 and Val96, respectively, whereas the indole framework is stably accommodated in a hydrophobic sub-pocket establishing hydrophobic interactions with the amino acid residues of Ile12, Val20, and Gln98 lining this sub-pocket. Collectively, these results highlighted hybrids 6a and 6e as good leads for further optimization as promising antitumor drugs toward breast malignancy and CDK inhibitors.

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3-Hydrazinoisatin-based benzenesulfonamides as novel carbonic anhydrase inhibitors endowed with anticancer activity: Synthesis, in vitro biological evaluation and in silico insights

Cited by 70 publications

References 38 publications

Inhibitory activity against carbonic anhydrase IX and XII as a candidate selection criterion in the development of new anticancer agents

Inhibitory activity against carbonic anhydrase IX and XII as a candidate selection criterion in the development of new anticancer agents

Synthesis, cytotoxicity and apoptosis‐inducing activity of novel 1H‐benzo[d]imidazole derivatives of dehydroabietic acid

Synthesis, Biological Evaluation and In Silico Studies of Certain Oxindole–Indole Conjugates as Anticancer CDK Inhibitors

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