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•The rate of cancer-related mortality is at alarming level globally.•Coumarin as a privileged scaffold is endowed with outstanding anticancer profile.•Different classes of coumarins ...have been comprehensively investigated as anticancer agents.•This review provides an overview of different coumarin-based anticancer classes.
Heading the list of the critical health-related issues worldwide, cancer continues to be a one of the most serious life-threatening diseases. The rate of cancer-related mortality is at alarming level globally because of poor ability of prevention, diagnosis and efficient treatment of cancers. Pertaining to its wide prevalence in many naturally occurring compounds, coumarin as a privileged scaffold is endowed with outstanding anticancer profile. Different classes of coumarin-based anticancer agents that act through diverse mechanisms of action have been comprehensively investigated by many researchers, such as alkylating agents, topoisomerase inhibitors, hormone antagonists, angiogenesis inhibitors, antimitotic agents, apoptosis inducers, human carbonic anhydrase inhibitors, telomerase inhibitors and other mechanisms. Accordingly, medicinal chemists and drug design scientists embarked on exploring diverse coumarin-based derivatives comprehending their potential to develop new efficient anticancer agents. The present review provides an overview of different anticancer classes based on the coumarin scaffold that have been reported since 2015 with particular emphasis on their cellular and enzymatic mechanism of actions.
We report herein, the design and synthesis of thiazolidine-2,4-diones derivatives as new inhibitors for VEGFR-2. The designed members were assessed for their in vitro anticancer activity against four ...cancer cell lines; A549, Caco-2, HepG-2 and MDA-MB-231. Compound 14a showed the most potent effects against Caco-2, and HepG-2 cell lines (IC.sub.50 = of 1.5 and 31.5 muM, respectively). Next, the in vitro VEGFR-2 inhibitory activity, safety profiles and selectivity indices were examined for all the synthesized members against the normal Vero cell line. Compound 14a (the safest member against Caco-2 cell line) was further investigated for its ability to inhibit Caco-2 cells migration and healing. Moreover, the apoptotic induction of compound 14a against Caco-2 cell line was investigated by assessing against four apoptotic genes (Bcl2, Bcl-xl, TGF, and Survivin). The results revealed that compound 14a can exert apoptosis through significant reduction of Bcl2, Survivin, and TGF gene expression levels. Finally, deep computational studies including molecular docking, ADMET, toxicity studies, and MD simulation were carried out. Also, the DFT calculations were performed and discussed, and the results confirmed the inhibitory reactivity of 14a against VEGFR-2. Compound 14a is expected to be used as a potential lead in the development of new VEGFR-2 inhibitors with increased potency.
Three series of 6-aryl-2-methylnicotinohydrazides 4a-i, N'-arylidene-6-(4-bromophenyl)-2-methylnicotino hydrazides 7a-f, and N'-(un/substituted ...2-oxoindolin-3-ylidene)-6-(4-fluorophenyl)-2-methylnicotinohydrazides 8a-c were synthesized and evaluated for their potential in vitro antimycobacterial activity against M. tuberculosis. The results showed that isatin hydrazides 8a-c are remarkably more active than the parent hydrazide 4c. Hydrazides 8b and 8c exhibited the highest activity among all the tested compounds (MIC = 12.5 and 6.25 µg/mL, respectively). Compounds 8b and 8c were also devoid of apparent cytotoxicity to HT-29, PC-3, A549, HepG2 and MCF-7 cancer cell lines. Besides, 8b and 8c showed good drug-likeness scores of 0.62 and 0.41, respectively. Those two isatin hydrazides could offer an excellent framework for future development to obtain more potent antitubercular agents. The SAR study suggested that lipophilicity of the synthesized derivatives is a crucial element that accounts for their antimycobacterial activity. Finally, a theoretical kinetic study was established to predict the ADME of the active derivatives.
In the current work, we designed and synthesized three families of non-fused and fused compounds based on cyanopyridone: derivatives of 6-amino-1,2-dihydropyridine-3,5-dicarbonitrile (5a-f) and ...3,4,7,8-tetrahydro pyrimidine-6-carbonitrile (6a-b and 7a-e). The newly synthesized compounds’ structure were determined using a variety of techniques, including 1H NMR, 13C NMR, mass spectrum, infrared spectroscopy, and elemental analysis. The developed compounds were tested for the ability to inhibit the growth of breast adenocarcinoma (MCF-7) and hepatic adenocarcinoma (HepG2) cell lines using MTT assay. Some of the synthesized compounds were more effective towards the cancer cell lines than the standard treatment taxol. The best antiproliferative activities were demonstrated by non-fused cyanopyridones 5a and 5e against the MCF-7 cell line (IC50 = 1.77 and 1.39 μM, respectively) and by compounds 6b and 5a against the HepG2 cell line (IC50 = 2.68 and 2.71 μM, respectively). We further explored 5a and 5e, the two most potent compounds against the MCF-7 cell line, for their ability to inhibit VEGFR-2 and HER-2. Finally, docking and molecular dynamics simulations were performed as part of the molecular modeling investigation to elucidate the molecular binding modes of the tested compounds, allowing for a more thorough comprehension of the activity of compounds 5a and 5e.
A thiazolidine-2,4-dione nucleus was molecularly hybridised with the effective antitumor moieties; 2-oxo-1,2-dihydroquinoline and 2-oxoindoline to obtain new hybrids with potential activity against ...VEGFR-2. The cytotoxic effects of the synthesised derivatives against Caco-2, HepG-2, and MDA-MB-231 cell lines were investigated. Compound 12a was found to be the most potent candidate against the investigated cell lines with IC
50
values of 2, 10, and 40 µM, respectively. Furthermore, the synthesised derivatives were tested in vitro for their VEGFR-2 inhibitory activity showing strong inhibition. Moreover, an in vitro viability study against Vero non-cancerous cell line was investigated and the results reflected a high safety profile of all tested compounds. Compound 12a was further investigated for its apoptotic behaviour by assessing the gene expression of four genes (Bcl2, Bcl-xl, TGF, and Survivin). Molecular dynamic simulations authenticated the high affinity, accurate binding, and perfect dynamics of compound 12a against VEGFR-2.
In our endeavor towards the development of effective anticancer agents, a novel series of pyridine-ureas
⁻
were synthesized. All the newly prepared derivatives were evaluated in vitro for their ...growth inhibitory activity towards the proliferation of breast cancer MCF-7 cell line. Compounds
and
were found to be the most active congeners against MCF-7 cells (IC
= 0.22 and 1.88 µM after 48 h treatment; 0.11 and 0.80 µM after 72 h treatment, respectively) with increased activity compared to the reference drug doxorubicin (IC
= 1.93 µM). Moreover, eight selected pyridines
,
,
,
,
and
⁻
were evaluated for their in vitro anticancer activity according to the US-NCI protocol. Pyridines
and
proved to be the most effective anticancer agents in the NCI assay with mean inhibition = 43 and 49%, respectively. Both
and
exhibited anti-proliferative activity against all tested cancer cell lines from all subpanels growth inhibition (GI for
; 12⁻78%, GI for
; 15⁻91%). Pyridines
and
were screened in vitro for their inhibitory activity against VEGFR-2. Both compounds inhibited VEGFR-2 at micromolar IC
values 5.0 ± 1.91 and 3.93 ± 0.73 µM, respectively. The most active pyridines were filtered according to the Lipinski and Veber rules and all of them passed these filters. Finally, several ADME descriptors were predicted for the active pyridines through a theoretical kinetic study.
We describe the design and synthesis of two isatin-tethered quinolines series (
-
and
-
), in connection with our research interest in developing novel isatin-bearing anti-tubercular candidates. In a ...previous study, a series of small molecules bearing a quinoline-3-carbohydrazone moiety was developed as anti-tubercular agents, and compound
disclosed the highest potency with MIC value equal to 6.24 µg/mL. In the current work, we adopted the bioisosteric replacement approach to replace the 3,4,5-trimethoxy-benzylidene moiety in the lead compound
with the isatin motif, a privileged scaffold in the TB drug discovery, to furnish the first series of target molecules
-
. Thereafter, the isatin motif was
-substituted with either a methyl or benzyl group to furnish the second series
-
. All of the designed quinoilne-isatin conjugates
-
and
-
were synthesized and then biologically assessed for anti-tubercular actions towards drug-susceptible, MDR, and XDR strains. Superiorly, the
-benzyl-bearing compound
possessed the best activities against the examined
strains with MICs equal 0.06, 0.24, and 1.95 µg/mL, respectively.
The tumor microenvironment is crucial for the growth of cancer cells, triggering particular biochemical and physiological changes, which frequently influence the outcome of anticancer therapies. The ...biochemical rationale behind many of these phenomena resides in the activation of transcription factors such as hypoxia-inducible factor 1 and 2 (HIF-1/2). In turn, the HIF pathway activates a number of genes including those involved in glucose metabolism, angiogenesis, and pH regulation. Several carbonic anhydrase (CA, EC 4.2.1.1) isoforms, such as CA IX and XII, actively participate in these processes and were validated as antitumor/antimetastatic drug targets. Here, we review the field of CA inhibitors (CAIs), which selectively inhibit the cancer-associated CA isoforms. Particular focus was on the identification of lead compounds and various inhibitor classes, and the measurement of CA inhibitory on-/off-target effects. In addition, the preclinical data that resulted in the identification of SLC-0111, a sulfonamide in Phase Ib/II clinical trials for the treatment of hypoxic, advanced solid tumors, are detailed.
A hybrid pharmacophore approach was adopted to design and synthesize new series of isatin–pyridine hybrids. All the newly prepared hybrids (5a–o, 8 and 11a–d) were in vitro evaluated for their ...anti-proliferative activity against three human cancer cell lines, namely HepG2 hepatocellular carcinoma, A549 lung cancer and MCF-7 breast cancer. Compound 8 emerged as the most active member against HepG2 cell line (IC50 = 2.5 ± 0.39 μM), with 2.7-fold increased activity than the reference drug, doxorubicin (IC50 = 6.9 ± 2.05 μM). Whilst, compound 11c was found to be the most potent counterpart against A549 and MCF-7 cell lines with IC50 values of 10.8 ± 1.15 and 6.3 ± 0.79, respectively. The weightiness of the utilization of non-cleavable linker, as the chalcone linker, and simplification of the first group, was explored via the SAR study. Furthermore, a QSAR model was built to explore the structural requirements controlling the cytotoxic activities. Notably, the predicted activities by the QSAR model were very close to those experimentally observed, hinting that this model could be safely applied for prediction of more efficacious hits comprising the same skeletal framework. Finally, a theoretical kinetic study was established to predict the ADME of the active hybrids.
Three different sets of isatin-pyridine hybrids were designed and synthesized to evaluate their anti-proliferative activity against HepG2, A549 and MCF-7 cancer cell lines. Two structural modifications for the first series were utilized to improve the activity. Display omitted
•Isatin-pyridine hybrids 5a–o, 8 and 11a–d were designed and synthesized.•Anti-proliferative activity was assessed against HepG2, HT-29 and MCF-7 cell lines.•QSAR analysis was performed by means of the Discovery Studio 2.5 software.•Compound 8 was the most active hybrid against HepG2 (IC50 = 2.5 μM).•Compound 11c (IC50 = 6.3) was equipotent as doxorubicin (IC50 = 6.1) in MCF-7.
In this research, two novel series of dibenzob,fazepines (14 candidates) were designed and synthesised based on the rigidification principle and following the reported doxorubicin's pharmacophoric ...features. The anti-proliferative activity was evaluated at the NCI against a panel of 60 cancer cell lines. Further, the promising candidates (5a-g) were evaluated for their ability to inhibit topoisomerase II, where 5e was noticed to be the most active congener. Moreover, its cytotoxicity was evaluated against leukaemia SR cells. Also, 5e arrested the cell cycle at the G1 phase and increased the apoptosis ratio by 37.34%. Furthermore, in vivo studies of 5e showed the inhibition of tumour proliferation and the decrease in its volume. Histopathology and liver enzymes were examined as well. Besides, molecular docking, physicochemical, and pharmacokinetic properties were carried out. Finally, a SAR study was discussed to open the gate for further optimisation of the most promising candidate (5e).
Highlights
Two novel series of dibenzob,fazepines were designed and synthesised based on the rigidification principle in drug design.
The anti-proliferative activity was evaluated at the NCI against a panel of 60 cancer cell lines.
5e was the most active anti-topo II congener (IC
50
= 6.36 ± 0.36 µM).
5e was evaluated against leukaemia SR cells and its cytotoxic effect was confirmed (IC
50
= 13.05 ± 0.62 µM).
In vivo studies of 5e significantly inhibited tumour proliferation by 62.7% and decreased tumour volume to 30.1 mm
3
compared to doxorubicin treatment.
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