Regioselective Preparation of Benzo[<i>b</i>]furans from Phenols and α<i>-</i>Bromoketones

In this paper, a fully regiocontrolled synthesis of either 2- and 3-substituted benzo­[<i>b</i>]­furans is described. Direct reaction between phenols and α-bromoacetophenones in the presence of neutral alumina yields 2-substituted benzo­[<i>b</i>]­furans with complete regiocontrol. When a basic salt such as potassium carbonate is used, the corresponding 2-oxoether is obtained. Cyclization of these latter compounds promoted by neutral alumina yields the corresponding 3-substituted benzo­[<i>b</i>]­furans. Using the former method, Moracin M and other analogues can be obtained from commercial sources in two preparative steps. DFT calculations provide reasonable reaction paths to understand the formation of 2-substituted benzo­[<i>b</i>]­furans

Design, Synthesis and Functional Evaluation of Leuko-cyte-Function Associated Antigen-1 (LFA-1) Antagonists in Early and Late Stages of Cancer Development

The integrin Leukocyte Function-associated Antigen-1 (LFA-1) recognizes and binds the Intercellular Adhesion Molecule-1 (ICAM-1) by its alpha L chain Inserted domain (I-domain). This interaction plays a key role in cancer and other diseases. We report here the rational in silico design, small scale synthesis and biological activity evaluation of a novel family of potent LFA-1 antagonists. The structure based design led to the synthesis of a family of highly substituted homoquiral pyrrolidines that mimic key residues of the ICAM-1 moiety. Some of these compounds showed both antiproliferative and antimetastatic activity in a murine model of melanoma, as well as potent antiadhesive properties in several cancer cell lines in the low micromolar range. The molecular mechanism of action of selected antagonists have been investigated by NMR analysis of their binding to the isolated I-domain of LFA-1. We show that, in the isolated I-domain, the compounds bind to the I-domain Allosteric Site (IDAS), the binding site of other allosteric LFA-1 inhibitors. These results provide evidence of the potential therapeutic value of a new set of LFA-1 inhibitors, whose further development is facilitated by a synthetic strategy that is versatile and fully stereocontrolled

In vitro and in vivo activity of a new small-molecule inhibitor of HDAC6 in mantle cell lymphoma

Cancer origin and development is associated not only with genetic alterations, but also with the disturbance of epigenetic profiles.1 In this regard, the tumoral epigenome is characterized by both specific and general shifts in the DNA methylation and histone-modification landscapes.1 However, in contrast to genetic disruption, the effect of epigenetic modifications or marks may potentially be reversed by the use of drugs that target enzymes involved in adding, removing or signaling DNA methylation and histone modifications.1 This basic knowledge has been adopted into clinical practice, and inhibitors of histone deacetylases and DNA demethylating agents have been approved for use in the therapy of hematologic malignancies, such as cutaneous T-cell lymphoma and myelodysplastic syndrome, respectively.2 Other promising epigenetic drugs include inhibitors of histone methyltransferases,2 histone demethylases,2 histone kinases,3 and bromodomain proteins that interfere with the 'reading' of acetylated histone residues

Design, Synthesis, and Functional Evaluation of Leukocyte Function Associated Antigen‑1 Antagonists in Early and Late Stages of Cancer Development

The integrin leukocyte function associated antigen 1 (LFA-1) binds the intercellular adhesion molecule 1 (ICAM-1) by its α_L-chain inserted domain (I-domain). This interaction plays a key role in cancer and other diseases. We report the structure-based design, small-scale synthesis, and biological activity evaluation of a novel family of LFA-1 antagonists. The design led to the synthesis of a family of highly substituted homochiral pyrrolidines with antiproliferative and antimetastatic activity in a murine model of colon carcinoma, as well as potent antiadhesive properties in several cancer cell lines in the low micromolar range. NMR analysis of their binding to the isolated I-domain shows that they bind to the I-domain allosteric site (IDAS), the binding site of other allosteric LFA-1 inhibitors. These results provide evidence of the potential therapeutic value of a new set of LFA-1 inhibitors, whose further development is facilitated by a synthetic strategy that is versatile and fully stereocontrolled