Synthesis, Characterization and Biological Evaluation of Indole-Pyrazole Amalgamated α-Cyano Substituted Chalcones

Background: Indole and pyrazole constitute a major class of biologically active scaffolds. The amalgamation of two or more pharmacophores would generate novel molecular templates that are likely to unveil remarkable biological properties. Objective: An efficient and high yielding synthesis of indole-pyrazole integrated α-cyano substituted chalcones and their in vitro antibreast cancer and antioxidant evaluation. Methods: The synthesis of a series of indole-pyrazole amalgamated α-cyano substituted chalcones (6a-o) was achieved by reacting substituted 3-cyanoacetyl indole 2 with substituted pyrazole aldehyde 5 in the presence of piperidine. All the newly synthesized compounds have been characterized by IR, 1H NMR and HRMS spectroscopy. Results: Anti-breast cancer evaluation of the synthesized compounds in vitro against MCF-7 cell line revealed high anti-breast cancer activities. Amongst the compounds screened 6f, 6g, 6h, 6c, 6d, 6e, 6i and 6k unveiled excellent activity against breast carcinoma (GI50 <0.1µM) as good as adriamycin (GI50 <0.1µM). The compounds were also screened against the normal Vero monkey cell line and the results demonstrated more selectivity against MCF-7. In other hand, compounds, 6b, 6c, 6d, 6h and 6i have shown moderate DPPH and NO radical scavenging activity. Conclusion: Most of the synthesized compounds exhibited significant antitumor activities. These results further support its safety margin by studying the activity on normal Vero monkey cell line. These results acclaim the possible use of these compounds for the design and development of potent anti-breast cancer agents.

Sequence amplification via cell passaging creates spurious signals of positive adaptation in influenza H3N2 hemagglutinin

Clinical influenza A isolates are frequently not sequenced directly. Instead, a majority of these isolates (~70% in 2015) are first subjected to passaging for amplification, most commonly in non-human cell culture. Here, we find that this passaging leaves distinct signals of adaptation in the viral sequences, which can confound evolutionary analyses of the viral sequences. We find distinct patterns of adaptation to Madin-Darby (MDCK) and monkey cell culture absent from unpassaged hemagglutinin sequences. These patterns also dominate pooled datasets not separated by passaging type, and they increase in proportion to the number of passages performed. By contrast, MDCK-SIAT1 passaged sequences seem mostly (but not entirely) free of passaging adaptations. Contrary to previous studies, we find that using only internal branches of the influenza phylogenetic trees is insufficient to correct for passaging artifacts. These artifacts can only be safely avoided by excluding passaged sequences entirely from subsequent analysis. We conclude that future influenza evolutionary analyses should appropriately control for potentially confounding effects of passaging adaptations.