New chemical inhibitors of protein–protein interactions are needed to propel advances in molecular pharmacology. Peptoids are peptidomimetic oligomers with the capability to inhibit protein-protein interactions by mimicking protein secondary structure motifs. Here we report the in silico design of a macrocycle primarily composed of peptoid subunits that targets the β-catenin:TCF interaction. The β-catenin:TCF interaction plays a critical role in the Wnt signaling pathway which is over-activated in multiple cancers, including prostate cancer. Using the Rosetta suite of protein design algorithms, we evaluate how different macrocycle structures can bind a pocket on β-catenin that associates with TCF. The in silico designed macrocycles are screened in vitro using luciferase reporters to identify promising compounds. The most active macrocycle inhibits both Wnt and AR-signaling in prostate cancer cell lines, and markedly diminishes their proliferation. In vivo potential is demonstrated through a zebrafish model, in which Wnt signaling is potently inhibited.

A convergent route to the synthesis of manassantins A and B, potent inhibitors of HIF-1, is described. Central to the synthesis is a stereoselective addition of an organozinc reagent to a 2-benzenesulfonyl cyclic ether to achieve the 2,3-cis-3,4-trans-4,5-cis-tetrahydrofuran of the natural products. Preliminary structure—activity relationships suggested that the (R)-configuration at C-7 and C-7″′ is not critical for HIF-1 inhibition. In addition, the hydroxyl group at C-7 and C-7″′ can be replaced with carbonyl group without loss of activity.

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We have shown that manassantin A downregulated the HIF-1α expression and inhibited the secretion of VEGF. We have also demonstrated that the 2,3-cis-3,4-trans-4,5-cis-configuration of the tetrahydrofuran is critical to the HIF-1 inhibition of manassantin A.Molecular oxygen (O 2 ) is required for aerobic metabolism to maintain intracellular bioenergetics and to serve as an electron acceptor in many organic and inorganic reactions. 1 Hypoxia, usually defined as ≤ 2% of O 2 , occurs in a variety of pathological conditions, including stroke, tissue ischemia, inflammation, and tumor growth. 2 Mammalian tissues have developed a number of essential mechanisms to cope with the stress of hypoxia. Among these coping mechanisms is the response mediated by the hypoxia-inducible transcription factor 1 (HIF-1). It is a basic helix-loop-helix (bHLH)-PER-ARNT-SIM (PAS) family protein that forms a heterodimer with its α and β subunits and acts as a transcription factor. 3 There are two additional HIF-1α-related bHLH-PAS proteins: HIF-2α and HIF-3α. 4 Like HIF-1α, they also bind to HIF-1β (ARNT) for activation. HIF-1 is a main regulator of hypoxia since it activates more than 60 genes involved in angiogenesis (VEGF), glucose transport (GLUT1), glycolytic pathways (LDHA), ROS signals (iNOS), and erythropoiesis (EPO), as well as a number of other processes. 5Through HIF-1, tumors adapt to hypoxia by increasing angiogenesis and metastatic potential, altering apoptosis, and regulating metabolism. 6 These adaptations make tumors more aggressive and treatment-resistant resulting in poor patient prognosis. 7 Immunohistochemical analyses have revealed that HIF-1 is overexpressed in many human cancers. 8 HIF-1 overexpression is not only involved in tumor progression but also associated with resistance to radiation 9 and chemotherapy. 10 It has been shown that inhibition of HIF-1 activity suppresses tumor growth, destroys blood vessels, enhances tumor apoptosis, and increases radiosensitivity, 11 making HIF-1 a good potential target for anti-cancer treatment.Due to the importance of HIF-1 in tumor development and progression, a considerable amount of effort has been made to identify HIF-1 inhibitors for treatment of cancer. 12 A variety of anticancer drugs, most of which were not developed as HIF-1 inhibitors, have been reported Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. to inhibit HIF-1. However, these compounds possess relatively low HIF-1 inhibitory activity (≥ micromolar range). In addition, most of them lack the desired selectivity for the HIF-1 signaling pathway or toxicity profil...

Oxepanes are found in a wide range of natural products; however, they are challenging synthetic targets due to enthalpic and entropic barriers. Organocatalytic oxa-conjugate addition reactions promoted by the gem-disubstituent (Thorpe–Ingold) effect stereoselectively provided α,α′-trans-oxepanes. In addition, the potential of an organocatalytic tandem oxa-conjugate addition/α-oxidation was demonstrated in a rapid generation of molecular complexity. These organocatalytic oxa-conjugate addition reactions would provide powerful tools for the synthesis of natural products that contain highly functionalized oxepanes.