FtsZ is a guanosine triphosphatase (GTPase) that mediates cytokinesis in bacteria. FtsZ is homologous in structure to eukaryotic tubulin and polymerizes in a similar head-to-tail fashion. The study of tubulin’s function in eukaryotic cells has benefited greatly from specific and potent small molecule inhibitors, including colchicine and taxol. Although many small molecule inhibitors of FtsZ have been reported, none has emerged as a generally useful probe for modulating bacterial cell division. With the goal of establishing a useful and reliable small molecule inhibitor of FtsZ, a broad biochemical cross-comparison of reported FtsZ inhibitors was undertaken. Several of these molecules, including phenolic natural products, are unselective inhibitors that seem to derive their activity from the formation of microscopic colloids or aggregates. Other compounds, including the natural product viriditoxin and the drug development candidate PC190723, exhibit no inhibition of GTPase activity using protocols in this work or under published conditions. Of the compounds studied, only zantrin Z3 exhibits good levels of inhibition, maintains activity under conditions that disrupt small molecule aggregates, and provides a platform for exploration of structure-activity relationships (SAR). Preliminary SAR studies have identified slight modifications to the two sidechains of this structure that modulate the inhibitory activity of zantrin Z3. Collectively these studies will help focus future investigations toward the establishment of probes for FtsZ that fill the roles of colchicine and taxol in studies of tubulin.
Introduction The chemokine receptor CCR5 has garnered significant attention in recent years as a target to treat HIV infection largely due to the approval and success of the drug Maraviroc. The side effects and inefficiencies with other first generation agents led to failed clinical trials, prompting the development of newer CCR5 antagonists. Areas covered This review aims to survey the current status of ‘next generation’ CCR5 antagonists in the preclinical pipeline with an emphasis on emerging agents for the treatment of HIV infection. These efforts have culminated in the identification of advanced second-generation agents to reach the clinic and the dual CCR5/CCR2 antagonist Cenicriviroc as the most advanced currently in phase II clinical studies. Expert opinion The clinical success of CCR5 inhibitors for treatment of HIV infection has rested largely on studies of Maraviroc and a second-generation dual CCR5/CCR2 antagonist Cenicriviroc. Although research efforts identified several promising preclinical candidates, these were dropped during early clinical studies. Despite patient access to Maraviroc, there is insufficient enthusiasm surrounding its use as front-line therapy for treatment of HIV. The non-HIV infection related development activities for Maraviroc and Cenicriviroc may help drive future interests.
An efficient, convergent synthesis of totarol by a diastereoselective epoxide/alkene/arene bicyclization is described. The reported synthesis enables the preparation of related diterpenes totaradiol and totarolone as well as previously unavailable derivatives that exhibit comparable inhibition of the bacterial cell division protein FtsZ.Bacterial cell division is a novel target for the development of new antibiotics to fight infections that are resistant to current therapies.1 FtsZ is the central protein of bacterial cell division that forms the Z-ring at mid-cell and enables septation.2 This GTPase is structurally related to eukaryotic tubulin, which has been successfully targeted as a treatment for cancer. Although tubulin is targeted by many small molecules, and several are in clinical use as drugs, inhibitors of FtsZ are significantly lower in number and in vitro potency. More significantly, three separate allosteric sites of inhibition on tubulin have been identified for taxol, colchicine, and the Vinca alkaloids. Similar knowledge regarding FtsZ is lacking, and no direct evidence for inactivation outside the GTP binding site has been reported.3 Our group is interested in developing efficient syntheses of natural products that target FtsZ with the long-term goal of using synthesis to elucidate the mechanism by which these compounds act on this protein. 4 , 5 Totarol is a diterpene produced in the sap of Podocarpus totara, a conifer native to New Zealand. The wood from the tree is prized for its resistance to rot and the antimicrobial properties of the secondary metabolites in the sap are well-established.6 Totarol is approved for use as an antimicrobial additive in several consumer products, including toothpaste and acne treatments.7 Although several previous studies have probed the origin of totarol's antimicrobial activity,8 FtsZ was only recently identified as a discrete molecular target.9We have undertaken the synthesis of totarol and related diterpenes as part of a broader research program aimed at discerning the mechanism by which FtsZ can be inactivated by shaw@chem.ucdavis.edu. Supporting Information Available Experimental procedures for the preparation of all new compounds. This information is available free of charge via the internet at http://pubs.acs.org. NIH Public Access Author ManuscriptOrg Lett. Author manuscript; available in PMC 2011 August 6. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript small molecules. Previous syntheses of totarol include routes to racemic material10 and semi-syntheses11 from chiral terpenoid precursors. Recent routes to related tricyclic systems have focused on electrophile-induced cyclization of polyene-derived precursors. Efficient syntheses of analogous ticyclic compounds have been reported using enantioselective protonation12 and halogenation13 of alkenes to effect polycyclization reactions. None of these efforts to date has resulted in the synthesis of the related diterpenoids totaradiol and totarolone. As a result, medicin...
Water‐soluble naphthalene diimides (NDIs) have found uses in a wide variety of applications including as electron acceptors in electron transfer reactions and as molecules that undergo spontaneous organization in aqueous solution. Many studies have looked at their interaction with nucleic acids including work with DNA duplexes, triplexes, quadruplexes, hairpins, and DNA–RNA heteroduplexes. In many of these interactions the NDIs serve as threading intercalators. Herein we describe the reversible hydroxide‐catalyzed hydrolysis of NDIs bearing aliphatic side chains, with ring opening first to the monoimide and then to the diamide. Examples with N‐methylpyrrolidinium groups placed two (1) and three (5) atoms from the central core were studied. The Ka values for the first and second hydrolyses for 1 were 2.5 ± 0.2 × 105 and 2.0 ± 0.1 × 102 M−1, respectively; for 5 they were 1.4 ± 0.1 × 105 and 44 ± 2 M−1, respectively. NDI 1 hydrolyzed 6.8 times faster than 5. The rates for the first and second ring opening of 1 in 100 mM hydroxide measured by stopped‐flow were 17.0 ± 0.2 and 0.53 ± 0.01 s−1, respectively. Capillary electrophoresis in borate buffer showed separation of the diimide and monoimide with the former eluting first. Nuclear magnetic resonance (NMR) showed both the syn and anti isomers of the diamide species. Overall, the rate of hydrolysis of the NDI is increased when the cationic charge is moved closer to the NDI core. Copyright © 2008 John Wiley & Sons, Ltd.
A structure-activity relationship study of potent TIQ15-derived CXCR4 antagonists is reported. In this investigation, the TIQ15 side-chain was constrained to improve its drug properties. The cyclohexylamino congener was found to be a potent CXCR4 inhibitor (IC = 33 nM in CXCL12-mediated Ca flux) with enhanced stability in liver microsomes and reduced inhibition of CYP450 (2D6). The improved CXCR4 antagonist has potential therapeutic application as a single agent or combinatory anticancer therapy.
CXCR4 is a G-protein-coupled receptor that interacts with its cognate ligand, CXCL12, to synchronize many physiological responses and pathological processes. Disruption of the CXCL12-CXCR4 circuitry by small-molecule antagonists has emerged as a promising strategy for cancer intervention. We previously disclosed a hit-to-lead effort that led to the discovery of a series of tetrahydroisoquinoline-based CXCR4 antagonists exemplified by the lead compound TIQ15. Herein, we describe our medicinal-chemistry efforts toward the redesign of TIQ15 as a result of high mouse-microsomal clearance, potent CYP2D6 inhibition, and poor membrane permeability. Guided by the in vitro ADME data of TIQ15, structural modifications were executed to provide compound 12a, which demonstrated a reduced potential for first-pass metabolism while maintaining CXCR4 potency. Subsequent SAR studies and multiparameter optimization of 12a resulted in the identification of compound 25o, a highly potent, selective, and metabolically stable CXCR4 antagonist possessing good intestinal permeability and low risk of CYP-mediated drug-drug interactions.
Efficient and stereoselective syntheses of pigmentosin A, talaroderxine A and its diastereomer talaroderxine B are reported. The binaphthyl ring system is assembled by vanadium-catalyzed phenolic coupling of tricyclic precursors. These key intermediates were prepared by Michael-Dieckmann annulation of a protected orsellinate ester, with the requisite pyranones accessed by a new variant of Ghosez’s sulfone-epoxide annulation. Preliminary biological experiments are reported for pigmentosin.
CXCR4 is a seven-transmembrane receptor expressed by hematopoietic stem cells and progeny, as well as by ≥48 different cancers types. CXCL12, the only chemokine ligand of CXCR4, is secreted within the tumor microenvironment, providing sanctuary for CXCR4 tumor cells from immune surveillance and chemotherapeutic elimination by (1) stimulating prosurvival signaling and (2) recruiting CXCR4 immunosuppressive leukocytes. Additionally, distant CXCL12-rich niches attract and support CXCR4 metastatic growths. Accordingly, CXCR4 antagonists can potentially obstruct CXCR4-mediated prosurvival signaling, recondition the CXCR4 leukocyte infiltrate from immunosuppressive to immunoreactive, and inhibit CXCR4 cancer cell metastasis. Current small molecule CXCR4 antagonists suffer from poor oral bioavailability and off-target liabilities. Herein, we report a series of novel tetrahydroisoquinoline-containing CXCR4 antagonists designed to improve intestinal absorption and off-target profiles. Structure-activity relationships regarding CXCR4 potency, intestinal permeability, metabolic stability, and cytochrome P450 inhibition are presented.
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