Abstract
Currently, the humanity is in a fierce battle against various health-related challenges especially those associated with human malignancies. This created the urge to develop potent and ...selective inhibitors for tumor cells through targeting specific oncogenic proteins possessing crucial roles in cancer progression and survive. In this respect, new series of pyrazole-thiazol-4-one hybrids (
9a–p
) were synthesized as potential anticancer agents. All the synthesized molecules exhibited potent antiproliferative actions against breast cancer (BC) T-47D and MDA-MB-231 cell lines with IC
50
ranges 3.14–4.92 and 0.62–58.01, respectively. Moreover, the most potent anti-proliferative counterparts
9g
and
9k
were assessed against EGFR. They displayed nanomolar inhibitory activity, IC
50
267 ± 12 and 395 ± 17 nM, respectively. Worth noting, both compounds 9g and 9k induced apoptosis in MDA-MB-231 cells, and resulted in a cell cycle arrest at G2/M phase. Furthermore, an in silico analysis including docking and molecular dynamic simulations was performed.
There is an urgent need to design new anticancer agents that can prevent cancer cell proliferation even with minimal side effects. Accordingly, two new series of 3-methylquinoxalin-2(1H)-one and ...3-methylquinoxaline-2-thiol derivatives were designed to act as VEGFR-2 inhibitors. The designed derivatives were synthesised and evaluated in vitro as cytotoxic agents against two human cancer cell lines namely, HepG-2 and MCF-7. Also, the synthesised derivatives were assessed for their VEGFR-2inhibitory effect. The most promising member 11e were further investigated to reach a valuable insight about its apoptotic effect through cell cycle and apoptosis analyses. Moreover, deep investigations were carried out for compound 11e using western-plot analyses to detect its effect against some apoptotic and apoptotic parameters including caspase-9, caspase-3, BAX, and Bcl-2. Many in silico investigations including docking, ADMET, toxicity studies were performed to predict binding affinity, pharmacokinetic, drug likeness, and toxicity of the synthesised compounds. The results revealed that compounds 11e, 11g, 12e, 12g, and 12k exhibited promising cytotoxic activities (IC
50
range is 2.1 − 9.8 µM), comparing to sorafenib (IC
50
= 3.4 and 2.2 µM against MCF-7 and HepG2, respectively). Moreover, 11b, 11f, 11g, 12e, 12f, 12g, and 12k showed the highest VEGFR-2 inhibitory activities (IC
50
range is 2.9 − 5.4 µM), comparing to sorafenib (IC
50
= 3.07 nM). Additionally, compound 11e had good potential to arrest the HepG2 cell growth at G2/M phase and to induce apoptosis by 49.14% compared to the control cells (9.71%). As well, such compound showed a significant increase in the level of caspase-3 (2.34-fold), caspase-9 (2.34-fold), and BAX (3.14-fold), and a significant decrease in Bcl-2 level (3.13-fold). For in silico studies, the synthesised compounds showed binding mode similar to that of the reference compound (sorafenib).
Quercetin is a naturally existing plant pigment belonging to the flavonoid group; it is contained in a wide range of vegetables and fruits. The accumulated evidence points to the potential uses of ...quercetin in protection of some disease conditions. Lead is one of the highly toxicant heavy metals that are widely spread in the environment and implicated in a wide spectrum of industries. No previous study has been reported to evaluate the effect of quercetin on lead toxicity. Therefore, the present study was conducted to elucidate some aspects of quercetin bioactivities in regard to its ability to combat the oxidative stress induced by lead toxicity. For this purpose, a total of sixty male Wistar rats were randomly and equally divided into three groups of 20 animals each; untreated control animals (group 1), lead-exposed animals (group 2; exposed to lead daily by oral gavage at the dose of 80 mg/Kg b.w.), and group 3 of animals, which were exposed to lead and daily received quercetin (10 h gap time between lead exposure and the receiving of quercetin) by oral gavage at the dose of 350 mg/Kg b.w. The experiment period was 8 weeks. All the assayed hematological and biochemical parameters of animals exposed to lead were significantly altered compared with the untreated control levels. Animals exposed to lead (group 2) exhibited significant decrements of the erythrocytic and total leucocytic counts, hemoglobin concentration, packed cell volume percent, total proteins, albumin and globulin. These animals also disclosed significantly decreased levels of antioxidant markers including total thiols, catalase and glutathione. On the other hand, these animals demonstrated significant increments in the levels of bilirubin, urea, creatinine, BUN, serum enzymes, H
O
and MDA. Animals exposed to lead and given quercetin (group 3) exhibited improvement of these parameters, which were brought back at varying degrees toward the untreated control levels. Basing on the improvements of the assayed hematological and biochemical parameters, it was concluded that quercetin as a dietary supplement can act efficiently as an antioxidant to counteract the oxidative stress induced by lead toxicity and to maintain the oxidant antioxidant balance.
A new series of 1,2,4‐triazolo4,3‐cquinazoline derivatives was designed and synthesized as Topo II inhibitors and DNA intercalators. The cytotoxic effect of the new members was evaluated in vitro ...against a group of cancer cell lines including HCT‐116, HepG‐2, and MCF‐7. Compounds 14c, 14d, 14e, 14e, 15b, 18b, 18c, and 19b exhibited the highest activities with IC50 values ranging from 5.22 to 24.24 µM. Furthermore, Topo II inhibitory activities and DNA intercalating affinities of the most promising candidates were evaluated as a possible mechanism for the antiproliferative effect. The results of the Topo II inhibition and DNA binding tests were coherent with that of in vitro cytotoxicity. Additionally, the most promising compound 18c was analyzed in HepG‐2 cells for its apoptotic effect and cell cycle arrest. It was found that 18c can induce apoptosis and arrest the cell cycle at the G2–M phase. Finally, molecular docking studies were carried out for the designed compounds against the crystal structure of the DNA−Topo II complex as a potential target to explore their binding modes. On the basis of these studies, it was hypothesized that the DNA binding and/or Topo II inhibition would participate in the noted cytotoxicity of the synthesized compounds.
A new series of 1,2,4‐triazolo4,3‐cquinazoline derivatives was designed and synthesized as topoisomerase II (Topo II) inhibitors and DNA intercalators, and their cytotoxic effect was evaluated in vitro. Compounds 14c, 14d, 14e, 14e, 15b, 18b, 18c, and 19b exhibited the highest activities. DNA binding and/or Topo II inhibition may contribute to the cytotoxicity of the synthesized compounds
Guided by the structural optimization principle and the promising anticancer effect of the quinoxaline nucleus, a new series of novel HDAC inhibitors were designed and synthesized. The synthesized ...compounds were designed to bear the reported pharmacophoric features of the HDAC inhibitors in addition to an extra moiety to occupy the non-used vacant deep pocket of the HDAC receptor. The newly prepared compounds were evaluated for their
anti-proliferative activities against HepG-2 and HuH-7 liver cancer cell lines. The tested compounds showed promising anti-proliferative activities against both cell lines. The most active ten candidates (
,
,
,
,
,
,
,
,
, and
) were further evaluated for their effect on the gene expression levels of Bax as an apoptotic marker and Bcl-2 as an anti-apoptotic one. Moreover, they were evaluated for their ability to inhibit histone deacetylase (HDAC1, HDAC4, and HDAC6) activities. Compound
achieved the best cytotoxic activities on both HepG-2 and HuH-7 cell lines with IC
values of 1.53 and 3.06 µM, respectively, and also it showed the most inhibitory activities on HDAC1, HDAC4, and HDAC6 with IC
values of 1.76, 1.39, and 3.46 µM, respectively, compared to suberoylanilide hydroxamic acid (SAHA) as a reference drug (IC
= 0.86, 0.97, and 0.93 µM, respectively). Furthermore, it achieved a more characteristic arrest in the growth of cell population of HepG-2 at both G0/G1 and S phases with 1.23-, and 1.18-fold, respectively, compared to that of the control, as determined by cell cycle analysis. Also, compound
showed a marked elevation in the AnxV-FITC apoptotic HepG-2 cells percentage in both early and late phases increasing the total apoptosis percentage by 9.98-, and 10.81-fold, respectively, compared to the control. Furthermore, docking studies were carried out to identify the proposed binding mode of the synthesized compounds towards the prospective target (HDAC4).
ADMET and toxicity studies revealed that most of the synthesized compounds have accepted profiles of drug-likeness with low toxicity. Finally, an interesting SAR analysis was concluded to help the future design of more potent HDACIs in the future by medicinal chemists.
Ehlers–Danlos syndrome (EDS) describes a group of clinical entities in which the connective tissue, primarily that of the skin, joint and vessels, is abnormal, although the resulting clinical ...manifestations can vary widely between the different historical subtypes. Many cases of hereditary disorders of connective tissue that do not seem to fit these historical subtypes exist. The aim of this study is to describe a large series of patients with inherited connective tissue disorders evaluated by our clinical genetics service and for whom a likely causal variant was identified. In addition to clinical phenotyping, patients underwent various genetic tests including molecular karyotyping, candidate gene analysis, autozygome analysis, and whole-exome and whole-genome sequencing as appropriate. We describe a cohort of 69 individuals representing 40 families, all referred because of suspicion of an inherited connective tissue disorder by their primary physician. Molecular lesions included variants in the previously published disease genes
B3GALT6
,
GORAB
,
ZNF469
,
B3GAT3
,
ALDH18A1
,
FKBP14
,
PYCR1
,
CHST14
and
SPARC
with interesting variations on the published clinical phenotypes. We also describe the first recessive EDS-like condition to be caused by a recessive
COL1A1
variant. In addition, exome capture in a familial case identified a homozygous truncating variant in a novel and compelling candidate gene,
AEBP1
. Finally, we also describe a distinct novel clinical syndrome of cutis laxa and marked facial features and propose
ATP6V1E1
and
ATP6V0D2
(two subunits of vacuolar ATPase) as likely candidate genes based on whole-genome and whole-exome sequencing of the two families with this new clinical entity. Our study expands the clinical spectrum of hereditary disorders of connective tissue and adds three novel candidate genes including two that are associated with a highly distinct syndrome.
The cell-traversal protein for ookinetes and sporozoites (CelTOS), expressed on the surface of ookinetes and sporozoitesin 'Plasmodium species', is a promising malaria vaccine candidate. CelTOS is ...essential for parasite invasion into mosquito midgut and human hepatocytes, thereby contributing to malaria transmission and disease pathogenesis. This study explores the genetic diversity, polymorphisms, haplotypes, natural selection, phylogenetic analysis, and epitope prediction in the full-length 'Plasmodium knowlesi CelTOS' gene in clinical samples from Sarawak, Malaysian Borneo, and long-term laboratory strains from Peninsular Malaysia and the Philippines. Our analysis revealed a high level of genetic variation in the 'PkCelTOS' gene, with a nucleotide diversity of pi ~ 0.021, which was skewed towards the 3' end of the gene. This level of diversity is double that observed in PfCelTOS and 20 times that observed in PvCelTOS from worldwide clinical samples. Tests of natural selection revealed evidence for positive selection within clinical samples. Phylogenetic analysis of the amino acid sequence of 'PkCelTOS' revealed the presence of two distinct groups, although no geographical clustering was observed. Epitope prediction analysis identified two potential epitopes (96AQLKATA102 and 124TIKPPRIKED133) using the IEDB server and one epitope (125IKPPRIKED133) by Bcepred server on the C' terminal region of 'PkCelTOS' protein. Both the servers predicted a common epitope region of nine amino acid length (IKPPRIKED) peptide, which can be studied in the future as a potential candidate for vaccine development. These findings shed light on the genetic diversity, polymorphism, haplotypes, and natural selection within 'PkCelTOS' in clinical samples and provide insights about its future prospects as a potential candidate for 'P. knowlesi' malaria vaccine development.
Primordial dwarfism (PD) is a phenotype characterized by profound growth retardation that is prenatal in onset. Significant strides have been made in the last few years toward improved understanding ...of the molecular underpinning of the limited growth that characterizes the embryonic and postnatal development of PD individuals. These include impaired mitotic mechanics, abnormal IGF2 expression, perturbed DNA-damage response, defective spliceosomal machinery, and abnormal replication licensing. In three families affected by a distinct form of PD, we identified a founder truncating mutation in POC1A. This gene is one of two vertebrate paralogs of POC1, which encodes one of the most abundant proteins in the Chlamydomonas centriole proteome. Cells derived from the index individual have abnormal mitotic mechanics with multipolar spindles, in addition to clearly impaired ciliogenesis. siRNA knockdown of POC1A in fibroblast cells recapitulates this ciliogenesis defect. Our findings highlight a human ciliopathy syndrome caused by deficiency of a major centriolar protein.
The pyrrolidine-2,4-dione derivatives were used to conduct a larvicidal test on Culex quinquefasciatus larvae of the second instar. Mannich base condensation method was used to synthesis the ...pyrrolidine-2,4-dione derivatives by grindstone method. The reaction conditions were mild, resulting in high yields. An analysis of the synthesized compounds was carried out using FTIR, 1H NMR, 13C NMR, mass spectrometry, and elemental analysis. Synthesized compounds (1a-h) were evaluated for larvicidal activities. Compound 1e (LD50: 26.06 µg/mL), and 1f (LD50: 26.89 µg/mL), and were notably more active against Culex quinquefasciatus than permethrin (LD50: 26.14 µg/mL). The docking studies also demonstrated that 1e, and 1f are potent larvicides with higher binding energy (−12.6 kcal/mol) than the control in the mosquito odorant binding protein (PDB ID: 3OGN). The larvicidal properties of lead molecules have made them important for use as insecticides.
Novel thiazolidine-2,4-dione derivatives, 11a-g, were designed, and synthesized targeting the VEGFR-2 protein. The in vitro studies indicated the abilities of the synthesized derivatives to inhibit ...VEGFR-2 and prevent the growth of two different cancer cell types, HepG2 and MCF-7. Compound 11 f exhibited the strongest anti-VEGFR-2 activity (IC50 = 0.053 µM). As well, compound 11 f showed impressive anti-proliferative activity against the mentioned cancer cell lines with IC50 values of 0.64 ± 0.01 and 0.53 ± 0.04 µM, respectively. Additionally, compound 11 f arrested the MCF-7 cell cycle at the S phase and increased the overall apoptosis percentage. Furthermore, cell migration assay revealed that compound 11 f has a significant ability to prevent migration and healing potentialities of MCF-7. Moreover, computational studies were used to conduct the molecular investigation of the VEGFR-2-11 f complex. The kinetic and structural features of the complex were examined using molecular dynamics simulations and molecular docking. Besides, Principal component analysis (PCA) was used to explain the dynamics of the VEGFR-2-11 f complex at various spatial scales. The DFT calculations also provided further clarity regarding compound 11 f's structural and electronic features. To evaluate how closely the developed compounds might look like drugs, ADMET and toxicity experiments were computed. To conclude, the presented study demonstrates the potential of compound 11 f as a viable anti-cancer drug, which can serve as a prototype for future structural modifications and further biological investigations.
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•Novel thiazolidine-2,4-dione derivatives were designed and synthesized as VEGFR-2 inhibitors.•In vitro cytotoxic activities against MCF-7 and HepG2 cell lines and VEGFR-2 inhibitory activities were evaluated.•The most promising member was subjected for further mechanistic studies including apoptosis and cell cycle assay.•In silico studies including molecular docking, MD simulation, DFT, ADMET, and toxicity studies were carried out.
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