Design, synthesis and antiproliferative screening of newly synthesized coumarin-acrylamide hybrids as potential cytotoxic and apoptosis inducing agents.

On the basis of the observed biological activity of coumarin and acrylamide derivatives, a new set of coumarin-acrylamide-CA-4 hybrids was designed and synthesized. These compounds were investigated for their cytotoxic activity against cancerous human liver cell line HepG2 cells using 5-fluorouracil (5-FU) as a reference drug. Compound 6e had promising antiproliferative activity with an IC50 value of 1.88 µM against HepG2 cells compared to 5-FU (IC50 = 7.18 µM). The results of ß-tubulin polymerization inhibition indicated that coumarin-acrylamide derivative 6e was the most active, with a percentage inhibition value of 84.34% compared to podophyllotoxin (88.19% ß-tubulin inhibition). Moreover, the active coumarin-acrylamide molecule 6e exerted cell cycle cession at the G2/M phase stage of HepG2 cells. In addition, this compound produced a 15.24-fold increase in apoptotic cell induction compared to no-treatment control. These observations were supported by histopathological studies of liver sections. The conducted docking studies illustrated that 6e is perfectly positioned within the tubulin colchicine binding site, indicating a significant interaction that may underlie its potent tubulin inhibitory activity. The main objective of the study was to develop new potent anticancer compounds that might be further optimized to prevent the progression of cancer disease.

"Employment of PEGylated ultra-deformable transferosomes for transdermal delivery of tapentadol with boosted bioavailability and analgesic activity in post-surgical pain".

The utilization of the proper and safe analgesics was considered a major concern in pain alleviation especially that associated with surgical procedures. Novel analgesics as Tapentadol hydrochloride (TAP) was involved efficiently instead of the common opioids to overcome the subsequent severe and common adverse effects associated with opioids utilization. Unfortunately, the extensive first pass metabolism limits the oral bioavailability of TAP and predisposes to a diminished duration of action, hence larger frequent doses of TAP will be required. Therefore, the target of this study was to lodge TAP into PEGylated transferosomes to boost its transdermal delivery. The PEGylation contemplated to boost both TAP permeability and bioavailability besides offering extra resilience to the vesicles. The impact of diverse variables on the characteristics of the vesicles and distinguishing the optimal formula were implemented adopting 23 factorial experiment via Design Expert® software. The resulted eight formulae were fabricated by thin film hydration technique, additionally they were evaluated based on the findings of entrapment efficiency percent (EE%), particle size (PS), polydispersity index (PDI), zeta potential (ZP) and the optimal one was involved in further assessments. The optimal formula (F8) exhibited spherical vesicles with EE% of 77.9 ± 3.4 %, PS of 150.5 ± 5.33 nm, PDI of 0.47 ± 0.05, ZP of -40.7 ± 4.6 mV and it also revealed greater deformability index (30.9 ± 6.1 g) relative to traditional transferosomes (12.15 ± 2.49 g). In addition, confocal laser scanning microscopy examination affirmed the superior penetration of Rhodamine B (RhB) dye thorough the rat's skin from F8 relative to the dye solution. The safety of F8 was confirmed by histopathological study. Moreover, dermato-kinetic study disclosed that TAP exhibited higher retention within the rat's skin form F8 relative to TAP dispersion. Furthermore, the in vivo pharmacodynamics activities conducted on male rats confirmed the superiority of F8 over the drug dispersion in alleviation the induced pain by IP injection of acetic acid and by formation of paw incisions. Collectively, the credibility of F8 as panel for transdermal delivery of TAP with boosted bioavailability and analgesic activity could be ensured on the basis of the obtained findings.

Design and synthesis of new trimethoxylphenyl-linked combretastatin analogues loaded on diamond nanoparticles as a panel for ameliorated solubility and antiproliferative activity.

A new series of vinyl amide-, imidazolone-, and triazinone-linked combretastatin A-4 analogues have been designed and synthesised. These compounds have been evaluated for their cytotoxic activity against MDA-MB-231 breast cancer cells. The triazinone-linked combretastatin analogues (6 and 12) exhibited the most potent cytotoxic activity, in sub-micromolar concentration compared with combretastatin A-4 as a reference standard. The results of ß-tubulin polymerisation inhibition assay appear to correlate well with the ability to inhibit ß-tubulin polymerisation. Additionally, these compounds were subjected to biological assays relating to cell cycle aspects and apoptosis induction. In addition, the most potent compound 6 was loaded on PEG-PCL modified diamond nanoparticles (PEG-PCL-NDs) and F4 was picked as the optimum formula. F4 exhibited enhanced solubility and release over the drug suspension. In the comparative cytotoxic activity, PEG-PCL modified F4 was capable of diminishing the IC50 by around 2.89 times for nude F4, while by 3.48 times relative to non-formulated compound 6.

Design and Synthesis of Some New Furan-Based Derivatives and Evaluation of In Vitro Cytotoxic Activity.

New furan-based derivatives have been, designed, synthesized, and evaluated for their cytotoxic and tubulin polymerization inhibitory activities. DNA flow cytometric study of pyridine carbohydrazide 4 and N-phenyl triazinone 7 demonstrated G2/M phase cell cycle disruptions. Accumulation of cells in the pre-G1 phase and positive annexin V/PI staining, which may be caused by degeneration or fragmentation of the genetic components, suggested that cell death occurs via an apoptotic cascade. Furthermore, compounds 4 and 7 had a strong pro-apoptotic impact through inducing the intrinsic mitochondrial mechanism of apoptosis. This mechanistic route was verified by an ELISA experiment that indicated a considerable rise in the levels of p53 and Bax and a drop in the level of Bcl-2 when compared with the control.

Protective potential of curcumin in L-NAME-induced hypertensive rat model: AT1R, mitochondrial DNA synergy.

BACKGROUND & OBJECTIVES: Hypertension can be induced by inhibiting nitric oxide synthesis with L-NAME, which also has a role in oxidative stress. Curcumin has strong antioxidant property. Our aim was to examine the possible preventive role of curcumin on renal dysfunction secondary to hypertension. MATERIAL & METHODS: Twenty-four adult male Albino rats were divided in four groups: normal (N); curcumin (C; received curcumin 100 mg/kg/day by oral gavage for 10 weeks); hypertensive (H; received L-NAME 40 mg/kg/day in their drinking water for 4 weeks); and hypertensive-curcumin (HC; received L-NAME and curcumin). Arterial blood pressure was evaluated non-invasively for 4 weeks. Rats were then sacrificed for assessment of oxidative stress (catalase, lipid peroxidase, reduced glutathione and superoxide dismutase), renal function and structure, and biomarkers of apoptosis (Bcl-2 and caspase-3). AT1R expression and renal mtDNA integrity were also assessed. RESULTS: Curcumin attenuated the effects of L-NAME on blood pressure and renal function. The renal histopathological changes observed in the L-NAME group were improved by curcumin administration. The expression of Bcl2 and caspase-3 was improved associated with downregulation of AT1R in curcumin treated groups. The antioxidant markers and mtDNA fragmentation show marked increase in hypertensive group which significantly decreased after curcumin treatment. CONCLUSION: Curcumin improved blood pressure elevation renal dysfunction. These improvements mediated through anti-oxidant capabilities and downregulation of AT1R favoring reduced apoptosis and preserved mitochondrial DNA.