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Colon cancer is one of the most incident cancers in the Western World. While both genetic and epigenetic factors may contribute to the development of colon cancer, it is known that chronic inflammation associated to excessive production of reactive oxygen and nitrogen species by phagocytes may ultimately initiate the multistep process of colon cancer development. Phenolic compounds, which reveal antioxidant and antiproliferative activities in colon cancer cells, can be a good approach to surpass this problem. In this work, hydroxycinnamic amides and the respective acid precursors were tested in vitro for their capacity to modulate human neutrophils’ oxidative burst and simultaneously to inhibit growth of colon cancer cells. A phenolic amide derivative, caffeic acid hexylamide (CAHA) ( 4 ) was found to be the most active compound in both assays, inhibiting human neutrophils’ oxidative burst, restraining the inflammatory process, inhibiting growth of colon cancer cells and triggering mitochondrial dysfunction that leads cancer cells to apoptosis. Altogether, these achievements can contribute to the understanding of the relationship between antioxidant and anticancer activities and based on the structure–activity relationships (SAR) established can be the starting point to find more effective phenolic compounds as anticancer agents. [ABSTRACT FROM AUTHOR]

In this work, new potent steroidal aromatase inhibitors both in microsomes and in breast cancer cells have been found. The synthesis of the 3,4-(ethylenedioxy)androsta-3,5-dien-17-one ( 12 ), a new steroid containing a heterocycle dioxene fused in the A-ring, led to the discovery of a new reaction for which a mechanism is proposed. New structure–activity relationships were established. Some 5β-steroids, such as compound 4β,5β-epoxyandrostan-17-one ( 9 ), showed aromatase inhibitory activity, because they adopt a similar A-ring conformation as those of androstenedione, the natural substrate of aromatase. Moreover, new chemical features to increase planarity were disclosed, specifically the 3α,4α-cyclopropane ring, as in 3α,4α-methylen-5α-androstan-17-one ( 5 ) (IC 50 = 0.11 μM), and the Δ 9–11 double bond in the C-ring, as in androsta-4,9(11)-diene-3,17-dione ( 13 ) (IC 50 = 0.25 μM). In addition, induced-fit docking (IFD) simulations and site of metabolism (SoM) predictions helped to explain the recognition of new potent steroidal aromatase inhibitors within the enzyme. These insights can be valuable tools for the understanding of the molecular recognition process by the aromatase and for the future design of new steroidal inhibitors. [ABSTRACT FROM AUTHOR]

Melanogenesis is a physiological pathway for the formation of melanin. Tyrosinase catalyzes the first step of this process and down-regulation of its activity is responsible for the inhibition of melanogenesis. The search for molecules capable of controlling hyperpigmentation is a trend topic in health and cosmetics. A series of heteroarylcoumarins have been synthesized and evaluated. Compounds 4 and 8 exhibited higher tyrosinase inhibitory activities (IC 50 = 0.15 and 0.38 μM, respectively), than the reference compound, kojic acid (IC 50 = 17.9 μM). Compound 4 acts as competitive, while compound 8 as uncompetitive inhibitor of mushroom tyrosinase. Furthermore, compounds 2 and 8 inhibited tyrosinase activity and melanin production in B16F10 cells. In addition, compounds 2 – 4 and 8 proved to have an interesting antioxidant profile in both ABTS and DPPH radicals scavenging assays. Docking experiments were carried out in order to study the interactions between these heteroarylcoumarins and mushroom tyrosinase. [ABSTRACT FROM AUTHOR]

[Display omitted] • Olefin and oxime groups combined are important for cytotoxicity of steroidal oximes. • Steroidal oxilmes' cytotoxicity induced by apoptosis/necroptosis and ROS production. • Steroidal oximes were selective towards colorectal cancer cells. • Steroidal oximes proven to be safe for IV administration. Steroidal compounds were proven to be efficient drugs against several types of cancer. Oximes are also chemical structures frequently associated with anticancer activity. The main goal of this work was to combine the two referred structures by synthesizing steroidal oximes and evaluating them in several cancer cell lines. Compounds (17 E)-5α-androst-3-en-17-one oxime (3,4 – OLOX), (17 E)-3α,4α-epoxy-5α-androstan-17-one oxime (3,4 – EPOX), (17 E)-androst-4-en-17-one oxime (4,5 – OLOX) and (17 E)-4α,5α-epoxyandrostan-17-one oxime (4,5 – EPOX) were synthesized and their cytotoxicity evaluated in four human cancer cell lines, namely colorectal adenocarcinoma (WiDr), non-small cell lung cancer (H1299), prostate cancer (PC3) and hepatocellular carcinoma (HepG2). A human non-tumour cell line, CCD841 CoN (normal colon cell line) was also used. MTT assay, flow cytometry, fluorescence and hemocompatibility techniques were performed to further analyse the cytotoxicity of the compounds. 3,4 – OLOX was the most effective compound in decreasing tumour cell proliferation in all cell lines, especially in WiDr (IC 50 = 9.1 μM) and PC3 (IC 50 = 13.8 μM). 4,5 – OLOX also showed promising results in the same cell lines (IC 50 = 16.1 μM in WiDr and IC 50 = 14.5 μM in PC3). Further studies also revealed that 3,4 – OLOX and 4,5 – OLOX induced a decrease in cell viability accompanied by an increase in cell death, mainly by apoptosis/necroptosis for 3,4 – OLOX in both cell lines and for 4,5 – OLOX in WiDr cells, and by necrosis for 4,5 – OLOX in PC3 cells. These compounds might also exert their cytotoxicity by ROS production and are not toxic for non-tumour CCD841 CoN cells. Additionally, both compounds did not induce haemoglobin release, proving to be safe for intravenous administration. 3,4 – OLOX and 4,5 – OLOX might be the starting point for an optimization program towards the discover of new steroidal oximes for anticancer treatment. [ABSTRACT FROM AUTHOR]