Novel radioiodinated desvenlafaxine-loaded lipid nanocapsule for brain delivery.

Lipid nanocapsules (LNCs) are lipid nanocarriers developed for drug delivery enhancement. The antidepressant drug desvenlafaxine (DSV) was entrapped in LNC to improve its brain delivery. Different DSV-loaded LNCs formulae using different oils and surfactants were studied to obtain the optimum formula for further studies. In vivo biodistribution studies were done using Swiss albino mice by intravenous injection of DSV-loaded LNCs by radioiodination technique. The optimum DSV-loaded LNC formula was obtained by using Labrafil® M1944CS as the oil and Solutol® HS15 as the surfactant in the ratio of 1:1, with a particle size of 34.28 ± 0.41 nm, a polydispersity index of 0.032 ± 0.05, a zeta potential of -25.77 ± 1.41, and good stability for up to 6 months. The in vivo biodistribution and pharmacokinetics data ensure the bioavailability improvement for DSV brain delivery as Cmax and AUC(1-t) increased more than double for intravenously DSV-loaded LNCs compared with the DSV solution. In conclusion, the results obtained from this study give an insight into the great potential of using DSV-loaded LNC for the enhancement of brain delivery.

Evaluation of radioiodinated ethopabate as a potential tumor targeting agent.

Overexpression of folate synthesis and folate receptor in a wide variety of tumors was reported. As a result, folate derivatives have emerged as a potential candidate for tumor imaging and therapy. Ethopabate is a structural analogue of para-aminobenzoic acid (PABA), a precursor of folic acid. Ethopabate was radiolabeled with radioiodine-131 (131I) via direct electrophilic substitution reaction. Several factors that might affect the radiolabeling yield were studied. Paper chromatography was utilized for testing and evaluation of [131I]iodoethopabate, and HPLC was used as a co-chromatographic tool to confirm the radiochemical yield. The biodistribution of [131I]iodoethopabate in normal and tumor-bearing mice was investigated. The radioiodination of ethopabate resulted in a radiochemical yield of 93.70 ± 0.19%. The biodistribution data revealed that [131I]iodoethopabate was taken up by tumors with promising target/non-target (T/NT) ratios. Where, the tumor to-blood ratios were 3.30 ± 0.40 and 4.06 ± 0.10 at 1 and 4 h post injection, respectively. As a result of these findings, [131I]iodoethopabate appears to have excellent tumor uptake and adequate stability to be used for diagnostic purpose in the future.

New benzenesulfonamide scaffold-based cytotoxic agents: Design, synthesis, cell viability, apoptotic activity and radioactive tracing studies.

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 IC50 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.

Dioximes: Synthesis and biomedical applications.

The selective properties of dioxime compounds were discovered and outlined in the beginning of 20th century by Tschugaeff [L.Z. Tschugaeff, Z. Anorg. Allgem. Chem. 46 (1905) 144]. Dioximes have special properties as analytical reagents for transition metals. Dioximes complexation properties with metals were carried out by many investigations and these complexations showed a wide range of applications such as antimicrobial and theranostic agents. This review will provide general synthetic methods of oximes especially dioximes and brief overview on the applications of dioximes (applications of their metal complexes).

Radioiodination and biodistribution of newly synthesized 3-benzyl-2-([3-methoxybenzyl]thio)benzo[g]quinazolin-4-(3H)-one in tumor bearing mice.

3-Benzyl-2-((3-methoxybenzyl)thio)benzo[g]quinazolin-4(3H)-one was previously synthesized and proved by physicochemical analyses (HRMS, 1H and 13C NMR). The target compound was examined for its radioactivity and the results showed that benzo[g]quinazoline was successfully labeled with radioactive iodine using NBS via an electrophilic substitution reaction. The reaction parameters that affected the labeling yield such as concentration, pH and time were studied to optimize the labeling conditions. The radiochemical yield was 91.2 ±â€¯1.22% and the in vitro studies showed that the target compound was stable for up to 24 h. The thyroid was among the other organs in which the uptake of 125I-benzoquinazoline has increased significantly over the time up to 4.1%. The tumor uptake was 6.95%. Radiochemical and metabolic stability of the benzoquinazoline in vivo/in vitro and biodistribution studies provide some insights about the requirements for developing more potent radiopharmaceutical for targeting the tumor cells.

Radiosynthesis, molecular modeling studies and biological evaluation of 99mTc-Ifosfamide complex as a novel probe for solid tumor imaging.

PURPOSE: Ifosfamide as a chemotherapeutic drug is used for the treatment of different cancer types. The purpose of this study is the preparation of 99mTc-ifosfamide complex to be evaluated as a potential candidate for tumor imaging. MATERIALS AND METHODS: The radiolabeling of ifosfamide with technetium-99m was carried out by mixing 4mg ifosfamide and 5 µg of SnCl2.2H2O with 400 MBq Na99mTcO4 at pH 9 for 30 min at room temperature. Computer simulation studies were performed using Accelrys Discovery Studio 2.5 operating system to illustrate the interaction of ifosfamide and 99mTc-ifosfamide complexes with DNA. The in-vivo biodistribution of 99mTc-ifosfamide was studied in tumor-bearing Albino mice. RESULTS: A new 99mTc-ifosfamide complex was synthesized with a good radiochemical yield of 90.3 ± 2.1% under the optimized conditions and exhibited in-vitro stability up to 2 h. Biodistribution studies showed good uptake in tumor site and high uptake in tumor site with T/NT ∼3 after 60 min post-injection. Besides, the molecular docking study confirmed that the complexation of ifosfamide with technetium-99m does not abolish its binding to the target receptor. CONCLUSION: These promising results afford a new radiopharmaceutical that could be used as a potential tumor imaging.

Rational design and synthesis of new tetralin-sulfonamide derivatives as potent anti-diabetics and DPP-4 inhibitors: 2D & 3D QSAR, in vivo radiolabeling and bio distribution studies.

Type 2 diabetes (T2D) is a severe disease and it is one of the most raising problems worldwide. This study deals with design, synthesis and in vivo determination of a new set of tetralin-sulfonamide derivatives as anti-diabetic and dipeptidyl peptidase-IV (DPP-4) inhibiting agents. Most of the new compounds exhibited significant hypoglycemic effect alongside with DPP-4 suppression potency considering sitagliptin as a reference drug. The most promising compounds 4, 15 showed 2.80 nM DPP-4 IC50 with 20-40 folds selectivity over DPP-8 and DPP-9. 2D and 3D QSAR models were performed using auto QSAR of Schrödinger, QuaSAR of MOE and 3D Field-based QSAR of Schrödinger, respectively. The experimental results revealed that the alignment-independent descriptors, electrostatic and steric field descriptors were significantly correlated with the antidiabetic activity of the new derivatives. In addition, the new compounds were docked in the active site of DPP-4 in reference to sitagliptin to rationalize the binding modes of the compounds with the amino acid residues of the enzyme. Furthermore, 131I-compound 4 complex was selected to evaluate the pharmacokinetic behavioral profile of compound 4 and its body organs uptakes alongside its elimination pathway as a representative example for the rest of the analogues. The bio distribution pattern of the tracer proved the selective accumulation of 131I-substrate in the pancreas and rapid clearance from most of the body organs.

Radioiodination and biological distribution of a new s-triazine derivative for tumor uptake evaluation.

A newly synthesized s-triazine derivative 1,1',1″-(((1,3,5-triazine-2,4,6-triyl) tris (azanediyl)) tris (benzene-4,1-diyl))tris (ethan-1-one), (1), was synthesized as a part of an ongoing research for development of novel s-triazine-based radiopharmaceuticals. In-vitro cell viability assay against different human cancer cell lines showed very promising inhibitory activity of the synthesized compound. This finding encouraged the radioiodination of 1 to study the degree of its localization in tumor site for evaluating the possibility of its use as a tumor imaging agent. The biodistribution study showed good localization of the radioiodinated derivative 2 at tumor site following i.v. administration in solid tumor-bearing mice. Finally, in a trial to understand the mechanism of the anticancer effect exerted by 1, a target prediction study and a docking study were performed. The results of the first study showed that focal adhesion kinase is a possible target for compound 1 and the docking study confirmed successful binding of both compound 1 and its radioiodinated derivative 2 to the binding site of focal adhesion kinase. As a conclusion, the results of this study suggest that, compound 2 could be used as a potential agent for tumor imaging after preclinical trials.

Development, Potential Anticancer Activity and the Receptor Profile of Different Functionalized 1,3,5-Triazine Derivatives.

1,3,5-Triazine-based compounds form a privileged class of compounds in the medicinal chemistry field as they are versatile synthetic scaffolds possessing wide spectra of biological effects including potential anticancer activity. 1,3,5-Triazine compounds explored for anticancer activities have been reported to act by various mechanisms on several molecular targets in human cells such as methyltransferase (DNMT), heat shock protein 90 (Hsp90) and phosphoinositide 3-kinase (PI3K). This review focuses on the synthetic strategies for current developments of 1,3,5-triazine-based anticancer agents and discuses the docking studies that confirm their unique binding modes in the targeted receptors active sites. This article also aims to highlight the future directions for the easy access to these frameworks of more potent and specific anticancer activity.

Design, synthesis and biological evaluation of some novel sulfonamide derivatives as apoptosis inducers.

Several novel thiazolidinone and fused thiazolidinone derivatives bearing benzenesulfonamide moiety were synthesized and confirmed via spectral and elemental analyses. The newly synthesized compounds were evaluated for their cytotoxic activity on colorectal cancer cell line (Caco-2). All the synthesized compounds showed better activity than the reference standards (Doxorubicin and 5-FU). Investigation of the apoptotic activity of the most active compounds revealed that compounds 3a, 5a, 5c and 6c activate both caspase-3 and Fas-ligand in Caco-2 cell line. Compound 3a was the most active compound with caspase-3 concentration of 0.43 nmol/mL and Fas-ligand concentration of 775.2 pg/mL in treated Caco-2 cells. Compound 3a was radiolabeled with 99mTc and its biodistribution pattern was evaluated in vivo using normal Swiss Albino mice. 99mTc-compound 3a complex didn't exhibit any accumulation in any body organs except for its accumulation in the colon; target organ; where it showed 8.97 ± 1.35 %ID/g at 15min p. i. that elevated till 16.02 ± 2.43 %ID/g at 120min p. i.