Biorelevant dissolution studies of platelet aggregation inhibitor: Ticagrelor hydrochloride and its co-crystal with sodium salt of Aspirin

99-103The comparative dissolution characteristics of poorly soluble platelet aggregation inhibitor Ticagrelor hydrochloride and its co-crystal with sodium salt of Aspirin in biorelevant media have been demonstrated. The API and co-crystal both are subjected to simulated gastric fluid (SGF) and fasted intestinal fluid without micelle forming components (blank FASSIF). The release of API is online monitored through reverse phase liquid chromatography. Prior to online monitoring, the chromatographic method is statistically validated in accordance with ICH guidelines. Chromatographic data reveals that the overall release of Ticagrelor after 3 h is about 6μg/mL higher in co-crystal (24.5μg/mL) compared to unaccompanied API (18.6μg/mL) in simulated gastric fluid (SGF). Whereas in fasted intestinal fluid without micelle forming components (blank FASSIF) more than threefold high release of API is observed in co-crystal (12.14μg/mL) compared to API (4.22μg/mL) in free form. Results clearly indicate the improved solubility in the lower regions of the gastrointestinal tract and better absorption of drug. This type of co-crystal would also allow the simultaneous dosing in suitable formulation

A Combined DNA-Affinic Molecule and N-Mustard Alkylating Agent Has an Anti-Cancer Effect and Induces Autophagy in Oral Cancer Cells

Although surgery or the combination of chemotherapy and radiation are reported to improve the quality of life and reduce symptoms in patients with oral cancer, the prognosis of oral cancer remains generally poor. DNA alkylating agents, such as N-mustard, play an important role in cancer drug development. BO-1051 is a new 9-anilinoacridine N-mustard-derivative anti-cancer drug that can effectively target a variety of cancer cell lines and inhibit tumorigenesis in vivo. However, the underlying mechanism of BO-1051-mediated tumor suppression remains undetermined. In the present study, BO-1051 suppressed cell viability with a low IC50 in oral cancer cells, but not in normal gingival fibroblasts. Cell cycle analysis revealed that the tumor suppression by BO-1051 was accompanied by cell cycle arrest and downregulation of stemness genes. The enhanced conversion of LC3-I to LC3-II and the formation of acidic vesicular organelles indicated that BO-1501 induced autophagy. The expression of checkpoint kinases was upregulated as demonstrated with Western blot analysis, showing that BO-1051 could induce DNA damage and participate in DNA repair mechanisms. Furthermore, BO-1051 treatment alone exhibited a moderate tumor suppressive effect against xenograft tumor growth in immunocompromised mice. Importantly, the combination of BO-1051 and radiation led to a potent inhibition on xenograft tumorigenesis. Collectively, our findings demonstrated that BO-1051 exhibited a cytotoxic effect via cell cycle arrest and the induction of autophagy. Thus, the combination of BO-1051 and radiotherapy may be a feasible therapeutic strategy against oral cancer in the future

A concise synthetic strategy to functionalized chromenones via 5+1] heteroannulation and facile C-N/C-S/C-O bond formation with various nucleophiles

A highly efficient strategy to 2,3-substituted chromen-4H-ones has been developed. The methodology involves unexpected intramolecular heteroannulation of readily accessible substituted 2-hydroxy-omega-nitroacetophenone with carbon disulfide in the presence K(2)CO(3) followed by methylation with methyl iodide. These chromenones were further reacted with various nucleophiles such as amines, thiols, and alkoxide resulting in the facile C-N, C-S, and C-O bond formation. The scope and generality have been discussed. (C) 2010 Elsevier Ltd. All rights reserved

<span style="font-size:12.0pt;font-family: "Times New Roman";mso-fareast-font-family:"Times New Roman";mso-ansi-language: EN-GB;mso-fareast-language:EN-US;mso-bidi-language:AR-SA" lang="EN-GB">Fuller’s earth catalyzed rapid synthesis of bis(indolyl)methanes under solvent free condition</span>

1032-1038<span style="font-size:12.0pt;font-family: " times="" new="" roman";mso-fareast-font-family:"times="" roman";mso-ansi-language:="" en-gb;mso-fareast-language:en-us;mso-bidi-language:ar-sa"="" lang="EN-GB">A rapid and highly efficient synthesis of various bis(indolyl)methanes with high yield by the reaction of indoles 1a-c and arylaldehydes 2a'-m' in presence of fuller’s earth is demonstrated. This simple and versatile protocol is found to be an efficient catalyst for the electrophilic addition reaction of indole and works well under solvent free condition as well as in aqueous medium. The structure of newly synthesized compound 3m has been confirmed by single crystal X-ray crystallography.</span