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Twelve new thienylbenzamidines and their analogues 4 a–i, 7, and 12 a, b were synthesized and their anti‐proliferative activity was evaluated against 60 cancer cell lines. The tested compounds showed potent anticancer activity against most cancer cell lines with median growth inhibition (GI50)<2 μM. Leukemia and renal cancer cell lines were the most responsive. Compound 12 a was the most active exhibiting GI50, total growth inhibition (TGI), and median lethal concentration (LC50) at 1.65, 3.71, and 9.3 μM, respectively. The benzamidine derivatives exerted their anti‐proliferative activity without causing any toxicity in normal human lung fibroblast (WI‐38) cells. The selectivity index (SI) ranged from 5.6 to 59.0 fold. Compound 4 h was the most selective compound (SI=59), and it was the least cytotoxic to WI‐38 cells. The cationic compounds 4 c, 4 h, 4 i, 7, and 12 b with high SI were selected for further mechanistic studies. Compounds 4 c, 4 h, and 4 i exerted their antiproliferative activity by inducing the cell cycle arrest (elevated p53 and downregulated cyclin‐dependent kinase 1 (cdk1)) and inducing apoptosis (elevated caspase 3). Compounds 7 and 12 b exerted their activity by inhibiting the growth and proliferation of cancer cells through inhibiting both topoisomerase II (topoII) and thioredoxin reductase1 (txnrd1). Finally, in silico predictions of the physicochemical, pharmacokinetic and drug‐likeness profiles of these new derivatives proved the oral availability and the inability to cross the blood‐brain barrier. [ABSTRACT FROM AUTHOR]

Abstract A series of thirteen new aryl/hetarylbichalcophene-5-carboxamidines was prepared and screened for an in vitro anti-proliferative activity against sixty cancer cell lines. The tested monocationic bichalcophenes displayed promising potent anticancer activity against most cancer cell lines with GI 50 values of 1.34–3.09 μM. The most potent compound was derivative 8 (median GI 50 and TGI values of 1.34 and 3.23 μM, respectively), being also the least cytotoxic in this bichalcophene series with an LC 50 of 77.6 μM. The most responsive cancer cell lines were leukemia (SR and K-562) and colon (HCT-15 and HT29) with GI 50 in the sub-micromolar range. The effect of the tested bichalcophenes on normal human lung fibroblast (WI-38) cell line showed that they exerted their antiproliferative activity outside the realms of causing any toxicity in normal cells. To study apoptotic profiles of representatives of this class, compounds 4h , 4i , and 8 were found to cause significant reductions in cdk1 expression in HCT-116 colon cells by 46, 79, and 84%, respectively versus 52% reduction by 5- Flourouracil (5-FU). These three compounds were also unique being the only derivatives that significantly elevated the expression of p53 by ∼2, 4, and 5 folds, respectively. The tested bichalcophenes exhibited moderate to potent antioxidant activity in DPPH and ABTS as well as hydroxyl radical scavenging assays. Moreover, compounds IIIb , IIIc , 4c , and 4i , showed the highest pro-oxidant activity. Finally, to aid future endeavors for optimization of this series, a 5 descriptor 2D-QSAR model was derived from the common physicochemical parameters of these bichalcophenes and the external validation proved the model's good predictive efficiency. Graphical abstract Image 1 Highlights • A new series of aryl/hetarylbichalcophene-5-carboxamidines was prepared. • The new monoamidines displayed potent anti-proliferative activity. • The most potent and least cytotoxic compound was isoquinoline derivative 8. • The most responsive cancer cell lines were leukemia SR and K-562. • Most of the tested monoamidines exhibited significant selectivity index. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract Two new series of furochromone and benzofuran derivatives were designed, synthesized and evaluated for their in vitro anticancer activity against MCF-7 and MDA231 breast cancer cell lines. Compounds 5, 6, 7, 9, 15a, 16 , 17a and 18 exhibited the best antiproliferative activities with IC 50 values ranging from 1.19 to 2.78 µM against MCF-7 superior to lapatinib as reference standard (IC 50 ; 4.69 µM). Compounds 15a and 18 revealed significant cytotoxic activity against MCF-7 and MDA231, therefore their inhibitory potencies against p38α MAP kinase were evaluated. Remarkably they exhibited significant IC 50 of 0.04 µM comparable to SB203580 (IC 50 ; 0.50 µM) as a reference standard. These promising results of cytotoxic activity and significant inhibition of p38α MAP kinase, were confirmed by exploring the effect of benzofuran derivative (18) on the apoptotic induction and cell cycle progression of MCF-7 cell line. Compound 18 induced preG1 apoptosis and cell growth arrest at G2/M phase preventing the mitotic cycle. Moreover it activated the caspase-7 which executes apoptosis. Molecular docking study was carried out using GOLD program to predict the mode of binding interaction of the synthesized compounds into the target p38α MAPK. Additionally, the physicochemical properties and ADME parameters of compound 18 were examined in silico to investigate its drug-likeness. [ABSTRACT FROM AUTHOR]

PIM-1 kinases play an established role in prostate cancer development and progression. This research work tackles the design and synthesis of new PIM-1 kinase targeting 2,5-disubstituted-1,3,4-oxadiazoles 10a-g&11a-f , and investigation thereof as potential anti-cancer agents through in vitro cytotoxicity assay followed by in vivo studies along with exploration of this chemotype's plausible mechanism of action. In vitro cytotoxicity experiments have disclosed 10f as the most potent derivative against PC-3 cells (IC 50 = 16 nM) compared to the reference drug Staurosporine (IC 50 = 0.36 μM), also eliciting good cytotoxicity against HepG2 and MCF-7 cells (IC 50 = 0.13 and 5.37 μM, respectively). Investigating PIM-1 kinase inhibitory activity of compound 10f revealed an IC 50 of 17 nM paralleled to that of Staurosporine (IC 50 = 16.7 nM). Furthermore, compound 10f displayed an antioxidant activity eliciting a DPPH inhibition ratio of 94% as compared to Trolox (96%). Further investigation demonstrated that 10f induced apoptosis in treated PC-3 cells by 43.2-fold (19.44%) compared to 0.45% in control. 10f also disrupted the PC-3 cell cycle by increasing the cell population at the PreG1-phase by 19.29-fold while decreasing the G2/M-phase by 0.56-fold compared to control. Moreover, 10f affected a downregulation of JAK2, STAT3 and Bcl-2 and upregulation of caspases 3, 8 and 9 levels that activated the caspase-dependent apoptosis. Finally, in vivo 10f -treatment caused a significant increase in tumor inhibition by 64.2% compared to 44.5% in Staurosporine treatment of the PC-3 xenograft mouse model. Additionally, it improved the hematological, biochemical parameters, and histopathological examinations compared to control untreated animals. Finally, docking of 10f with the ATP-binding site of PIM-1 kinase demonstrated good recognition of and effective binding to the active site. In conclusion, compound 10f represents a promising lead compound that merits further future optimization for controlling prostate cancer. [Display omitted] • Discovering new PIM-1 inhibitors based on a 2,5-disubstituted-1,3,4-oxadiazole scaffold. • 10f shows potent cytotoxicity against PC-3 (IC 50 = 16 nM) compared to Staurosporine (IC 50 = 0.36 μM). • 10f is also cytotoxic against HepG2 and MCF-7 (IC 50 = 0.13 and 5.37 μM, respectively). • 10f induces apoptosis in PC-3 cells by 43.2-fold compared to untreated cells. • In vivo, 10f causes 64.2% growth tumor inhibition compared to 44.5% by Staurosporine. [ABSTRACT FROM AUTHOR]

New semi-synthetic effective and safe anticancer agents isoeugenol derivatives were synthesized, characterized, and screened for their cytotoxic activity against MCF-7. Moreover, their selective cytotoxicity was assessed against MCF-10A. Three derivatives, 2, 8 and 10 were significantly more active than the reference drug 5-FU with IC 50 values of 6.59, 8.07 and 9.63 and 30.93 μM, respectively. Also interestingly, these derivatives demonstrated some degree of selectivity to cancer cells over normal cells. Furthermore, derivative 2 was subjected to other in vitro experiments against MCF-7 where it inhibited colony formation by 87.5% and lowered ERα concentration to 395.7 pg/mL compared to 1129 pg/mL in untreated control cells. In continuation of the investigation, the apoptotic activity of compound 2 , was assessed where it significantly enhanced total apoptotic cell death by 9.16-fold (18.70% compared to 1.64% for the untreated MCF-7 control cells) and arrested the cell cycle at the G2/M phase. Furthermore, the molecular mechanism of apoptotic activity was investigated at both the gene (RT-PCR) and protein (western plotting) levels where upregulation of pro-apoptotic and down regulation of anti-apoptotic genes was detected. Additionally, compound 2 treatment enhanced the antioxidant (GSH, CAT, SOD) activities. Finally, in vivo experiments verified the effective anticancer activity of compound 2 through inhibition of tumor proliferation by 47.6% compared to 22.9% for 5-FU and amelioration of the hematological, biochemical, and histopathological examinations near normal. In effect, compound 2 can be viewed as a promising semi-synthetic derivative of isoeugenol with some degree of selectivity for management of breast cancer through apoptotic induction and ERα downregulation. [Display omitted] • Synthesis of new semisynthetic isoeugenols as cytotoxic agents. • The new isoeugenol derivatives induce apoptosis on MCF-7 ER + breast cancer cells. • Derivative 2 causes cell cycle accumulation at the G2/M phase upon treatment. • Derivative 2 reduces ERα expression levels in MCF-7 treated cells. • Effective in vivo anticancer effect on SEC mouse model compared to 5-FU standard. [ABSTRACT FROM AUTHOR]

• Design and synthesis of new 3-cyano-6-naphthylpyridine scaffold-based selective VEGFR-2 cytotoxic agents. • Sub-micromolar IC 50 values against VEGFR-2. • Nanomolar in vitro cytotoxicity against PC3, DU145, MCF-7, MDA-MB435 and BT549. • Potent anticancer effect in in vivo xenograft animal models. • Apoptosis and G1 phase cell cycle arrest of 11b treated breast cancer cells. • Promising ADME and drug-like profiles. VEGFR-2 is a key regulator in cancer angiogenesis. This research displays the design and synthesis of novel 3-cyano-6-naphthylpyridine scaffold-based derivatives as selective VEGFR-2 inhibitors and cytotoxic agents. In vitro percent kinase activity inhibition screening against a panel of 23 kinases at a single high dose (30 nM) affirmed that VEGFR-2 was selectively the most responsive to inhibition by the investigated chemotypes. IC 50 values determination demonstrated kinase inhibitory activities of the test compounds at the sub-nanomolar level. In vitro testing of the new compounds against two prostate cancer cell lines namely PC3 and DU145 and two breast cancer cell lines namely MCF-7 and MDA-MB435 confirmed their potent cytotoxic activity with IC 50 s at the nanomolar level. The most active compound against MCF-7 viz. 11d was subjected to an in vivo examination against a xenograft mouse model and was found effective. Studying the tissue mRNA expression levels of various cell cycle controlling biomolecules in 11d -treated MCF-7 cells demonstrated (i) upregulation of p53, p21 and p27, (ii) cleavage of PARP protein, (iii) activation of caspase-3, −8 and −9, (iv) downregulation of the anti-apoptotic protein Bcl, (v) upregulation of the pro-apoptotic protein Bax, and (vi) decreased expression of Cdks 2, 4, 6 and cyclin D1. Additionally, 11d affected a cell cycle arrest at the G1 phase in treated MCF-7 cells and an S phase arrest in MCF-7 p53 knockdown cells. Additionally, molecular docking was performed to predict how 11d might bind to its biological target VEGFR-2. Finally, in-silico ADME and drug-likeness profiling of these derivatives demonstrated favorable properties thereof. [ABSTRACT FROM AUTHOR]

Despite advances in cancer treatment modalities, DNA still stands as one of the targets for anticancer agents. DNA minor groove binders (MGBs) represent an important investigational chemotherapeutic class with promising cytotoxic capacity. Herein this study reports the potent cytotoxic effect of a series of repurposed flexible bis-imidamides 1 – 4 , triaryl bis-guanidine 5 and bis- N -substituted guanidines 6,7 having a 1,4-diphenoxybenzene scaffold backbone on MCF-7 and MDA-MB-231 breast cancer cell lines. Of these compounds, imidamide 4 was chosen for further in-vitro , in-vivo and molecular dynamics (MD) studies owing to its promising anti-tumor activity, with IC 50 values on MCF-7 and MDA-MB-231 breast cancer cell lines of 1.9 and 2.08 μM, respectively. Annexin V/propidium iodide apoptosis assay revealed apoptosis induction on imidamide 4 treated MCF-7 cells. RT-PCR assay results demonstrated the proapoptotic effect of compound 4 through increase of mRNA levels of the pro-apoptotic genes; p53, PUMA, and Bax, and inhibiting the anti-apoptotic Bcl-2 gene expression in MCF-7 cells. Moreover, compound 4 induced a G 0 /G 1 cell-cycle arrest in MCF-7 in a dose-dependent manner. Corroborating in-vivo experiments on Ehrlich ascites carcinoma (EAC)-bearing mice, reflected the anticancer strength of derivative 4. For further target validation, molecular dynamics (MD) studies demonstrated an energetically favorable binding of imidamide 4 with the DNA minor groove AT rich site. In effect, imidamide 4 can be viewed as a promising hit dicationic compound with good cytotoxic and apoptotic inducing activity against breast cancer that can be adopted for future optimization. Image 1 • In vitro cytotoxicity of flexible triaryl guanidines and imidamides against breast cancer. • Flow cytometric cell cycle and apoptosis analysis of MCF-7 cells treated with imidamide 4. • Imidamide 4 induces significant increase of p53, PUMA and Bax gene expression and reduction of Bcl-2. • In vivo anticancer effect on treated EAC-bearing mice. • Reduction in oxidative stress and elevation of antioxidant parameters. [ABSTRACT FROM AUTHOR]

• New thiazolidinone, thiazinone and dithiazepinone-benzenesulfonamides as cytotoxic agents. • Effect of 5a-d on MCF-7 and HepG2 cell cycle phase distribution. • Caspase 8 and 9 levels determination in MCF-7 and HepG2 after test agents' treatment. • In vivo biodistribution study of radioiodinated-5c. A new series of thiazolidinone (5a-g), thiazinone (9a-g) and dithiazepinone (9a-g) heterocycles bearing a benzenesulfonamide scaffold was synthesized. Cytotoxicity of these derivatives was assessed against MCF-7, HepG2, HCT-116 and A549 cancer cell lines and activity was compared to the known cytotoxic agents doxorubicin and 5-FU where the most active compounds displayed better to nearly similar IC 50 values to the reference compounds. For assessing selectivity, the most active derivatives against MCF-7, 5b , 5c and 5e , were also assessed against the normal breast cell line MCF-10 A where they demonstrated high selective cytotoxicity to cancerous cells over that to normal cells. Further, the effect of the most active compounds 5b-e on MCF-7 and HepG2 cell cycle phase distribution was assessed and the tested sulfonamide derivatives were found to induce accumulation of cells in the <2n phase. To further confirm apoptosis induction, caspase 8 and 9 levels in MCF-7 and HepG2 were evaluated before and after treatment with compounds 5b-e and were found to be significantly higher after exposure to the test agents. Since 5c was the most active, its effect on the cell cycle regulation was confirmed where it showed inhibition of the CDK2/cyclin E1. Finally, in vivo biodistribution study using radioiodinated-5c revealed a significant uptake and targeting ability into solid tumor in a xenograft mouse model. [ABSTRACT FROM AUTHOR]