Chloroxylon swietenia (Roxb.) DC induces cell death and apoptosis by down-regulating the NF-κB pathway in MCF-7 breast cancer cells: In vitro and in vivo investigations.

BACKGROUND: Natural products with targeted bioactivity have gained major attention in the field of cancer research owing to emerging anti-cancer drug resistance and off target toxicities. Chloroxylon swietenia (Roxb.) DC is recognized as a folklore medicinal plant and has numerous therapeutic benefits in the folklore medicine system, however the anti-cancer potential of this plant and its mechanism of action is poorly understood. AIMS: The aim of the study was to investigate the anti-breast cancer efficacy of C. swietenia leaves methanol extract (CSLME) against MCF-7 hormone dependent human breast cancer cell line with possible mechanism of action. METHODS AND RESULTS: The anti-breast cancer activity of CSLME against MCF-7 cells was assessed by evaluating its efficacy toward cytotoxicity, cell migration, colony formation, DNA fragmentation, apoptosis, cytoskeleton, angiogenesis, cell cycle regulation, and animal toxicity. The preliminary screening of CSLME against MCF-7 cells revealed the cytotoxicity (IC50 20 µg/ml), inhibited cell migration, colony formation, and angiogenesis. It was observed that CSLME induces apoptosis by nuclear fragmentation and disruption of cytoskeleton by actin derangement. The results of Annexin V-FITC assay and cell cycle analysis by flow cytometry clearly pointed out the sizable fraction of apoptotic cells, and arrested the cells at G2/M phase of cell cycle. The results of the immunoblotting experiments showed that CSLME activates intrinsic pathway of apoptosis with down regulation of anti-apoptotic marker like Bcl2, up regulation of pro-apoptotic markers like Bax & Bad, along with successful cleavage of Caspase-9 and PARP-1. Further, western blot analysis revealed the possible down regulation of NF-κB pathway by CSLME, which may be responsible for anti-cancer activity in MCF-7 cells. In vivo animal model studies using NOD-SCID mice demonstrated impressive anti-tumor activity with significant reduction in tumor volume of MCF-7 tumor xenograft. Of note, in-vivo acute oral toxicity study as per Organization for Economic Cooperation and Development 423 revealed the nontoxic nature of CSLME. CONCLUSION: The in vitro and in vivo findings clearly outline the potential of CSLME as inhibitor of growth and proliferation of MCF-7 cells. Mechanistically, CSLME seems to activate intrinsic pathway of apoptosis, arrest cell cycle, target actin cytoskeleton, inhibit growth, colony formation, migration, and angiogenesis, with down regulation of NF-κB pathway leading to cell death.

Synthesis and evaluation of N-(4-(substituted)-3-(trifluoromethyl) phenyl) isobutyramides and their N-ethyl analogous as anticancer, anti-angiogenic & antioxidant agents: In vitro and in silico analysis.

N-(4-(substituted)-3-(trifluoromethyl) phenyl) isobutyramides and their N-ethyl analogues (flutamides) are versatile scaffolds with a wide spectrum of biological activities. A series of new N-(4-(substituted)-3-(trifluoromethyl) phenyl) isobutyramides (8a-t) and their N-ethyl analogous (9a-t) were synthesized and characterized. The inhibitory potential of the synthesized compounds on the viability of three human cancer cell lines HEP3BPN 11 (liver), MDA-MB 453 (breast), and HL 60 (leukemia) were assessed. Among all the compounds 8 L, 8q, 9n and 9p showed higher inhibitory activity on the viability of HL 60 than the standard methotrexate. These lead molecules were then tested for their potential to inhibit the activity of proangiogenic cytokines. The compound 9n showed significantly better inhibition against two cytokines viz. TNFα and Leptin as compared to the standard suramin, while 9p has activity comparable to suramin against IGF1, VEGF, FGFb, and Leptin. The 8q is found to be strong antiangiogenic agent against IGF1, VEGF and TGFß; while 8 L has showed activity against TNFα, VEGF, and Leptin inhibition. Furthermore antioxidant potential of 8a-t and 9a-t compounds was screened using DPPH, OH and SOR radical scavenging activities. The OH radical scavenging activity of 8c and DPPH activities of 9n as well as 9o are significant as compared to respective standards ascorbic acid and α-tocopherol. The 8c, 9p and 9 h have also exhibited potential antioxidant activity. Additionally, we present in silico molecular docking data to provide the structural rationale of observed TNFα inhibition against newly synthesized compounds. Overall, the synthesized flutamide derivatives have not only anticancer activity, but also possess dual inhibitory effect (anti-angiogenesis and antioxidant) and hence can act as a promising avenue to develop further anticancer agents.

Design, synthesis and in silico study of pyridine based 1,3,4-oxadiazole embedded hydrazinecarbothioamide derivatives as potent anti-tubercular agent.

Development of novel, safe and effective drug candidates combating the emerging drug resistance has remained a major focus in the mainstream of anti-tuberculosis research. Here, we inspired to design and synthesize series of new pyridin-4-yl-1,3,4-oxadiazol-2-yl-thio-ethylidene-hydrazinecarbothioamide derivatives as potential anti-tubercular agents. The anti-tubercular bioactive assay demonstrated that the synthesized compounds exhibit potent anti-tubercular activity (MIC = 3.9-7.81 µg/mL) in comparison with reference drugs Rifampicin and Isoniazid.We employed pharmacophore probing approach for the identification of CYP51 as a possible drug target for the synthesized compounds. To understand the preferable binding mode, the synthesized molecules were docked onto the active site of Sterol 14 α-demethylases (CYP51) target. From the binding free energy of the docking results it was revealed that the compounds were effective CYP51 inhibitors and acts as antitubercular agent.

Synthesis and in silico investigation of thiazoles bearing pyrazoles derivatives as anti-inflammatory agents.

Searching novel, safe and effective anti-inflammatory agents has remained an evolving research enquiry in the mainstream of inflammatory disorders. In the present investigation series of thiazoles bearing pyrazole as a possible pharmacophore were synthesized and assessed for their anti inflammatory activity using in vitro and in vivo methods. In order to decipher the possible anti-inflammatory mechanism of action of the synthesized compounds, cyclooxygenase I and II (COX-I and COX-II) inhibition assays were also carried out. The results obtained clearly focus the significance of compounds 5d, 5h and 5i as selective COX-II inhibitors. Moreover, compound 5h was also identified as a lead molecule for inhibition of the carrageenin induced rat paw edema in animal model studies. Molecular docking results revealed significant interactions of the test compounds with the active site of COX-II, which perhaps can be explored for design and development of novel COX-II selective anti-inflammatory agents.

Synthesis and Evaluation of New 4-Chloro-2-(3-chloro-4-fluorophenyl)-5-(aliphatic/cyclic saturated amino)pyridazin-3(2H)-one Derivatives as Anticancer, Antiangiogenic, and Antioxidant Agents.

Pyridazinones are widely recognized as versatile scaffolds with a wide spectrum of biological activities. In the present work, a series of new 4-chloro-2-(3-chloro-4-fluorophenyl)-5-(aliphatic/cyclic saturated amino)pyridazin-3(2H)-one derivatives 4a-i were synthesized and characterized by spectral techniques. The inhibitory effects of the synthesized compounds 4a-i on the viability of three human cancer cell lines, HEP3BPN 11 (liver), MDA 453 (breast), and HL 60 (leukemia), were assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction assay. Among the compounds 4a-i screened, 4g and 4i exhibited inhibitory activity very close to the standard methotrexate; therefore, these lead compounds were further tested for their potential to inhibit the proangiogenic cytokines involved in tumor progression. Compound 4g was found to be a potent antiangiogenic agent against TNFα, VEGF, FGFb, and TGFß, whereas 4i showed potent antiangiogenic activity against TNFα, VEGF, FGFb, and leptin. All the compounds 4a-i were screened for their antioxidant activities using 2,2-diphenyl-1-picryl hydrazine (DPPH), OH, and superoxide anion radicals. Compound 4f showed better OH radical scavenging activity than the standard ascorbic acid.