Discovery of oxazoline enhancers of cellular progranulin release.

Phenotypic screening of an annotated small molecule library and initial SAR studies identified compound 2 as a robust enhancer of progranulin secretion. Detailed SAR development on conformationally restricted carbamate isosteres led to the identification of compound 60 with a 3-fold improvement in BV-2 potency and a 9-fold decrease in hERG inhibition over compound 2, substantially improving this important margin of safety relative to compound 2.

A New Class of Tunable Acid-Sensitive Linkers for Native Drug Release Based on the Trityl Protecting Group.

Core-cross-linked polymeric micelles (CCPMs) are a promising nanoparticle platform due to favorable properties such as their long circulation and tumor disposition exploiting the enhanced permeability and retention (EPR) effect. Sustained release of covalently linked drugs from the hydrophobic core of the CCPM can be achieved by a biodegradable linker that connects the drug and the core. This study investigates the suitability of trityl-based linkers for the design of acid-triggered native active pharmaceutical ingredient (API) release from CCPMs. Trityl linker derivatives with different substituent patterns were synthesized and conjugated to model API compounds such as DMXAA-amine, doxorubicin, and gemcitabine, and their release kinetics were studied. Hereafter, API release from CCPMs based on mPEG-b-pHPMAmLac block copolymers was investigated. Variation of the trityl substitution pattern showed tunability of the API release rate from the trityl-based linker with t1/2 varying from <1.0 to 5.0 h at pH 5.0 and t1/2 from 6.5 to >24 h at pH 7.4, all at 37 °C. A clear difference in release kinetics was found between gemcitabine and doxorubicin, with gemcitabine showing no detectable release for 72 h at pH 5.0 and doxorubicin showing a t1/2 of less than 1 h. Based on these findings, we show that the reaction mechanism of trityl deprotection plays an important role in the API release kinetics. The first step in this mechanism, which is protonation of the trityl-bound amine, is pKa-dependent, which explains the difference in release rate. In conclusion, acid-sensitive and tunable trityl linkers are highly promising for the design of linker-API conjugates and for their use in CCPMs.

Base-Induced Rearrangement of Perhydronaphthalene-1,4-diol Monosulfonate Esters to 11-Oxatricyclo[5.3.1.0(2,6)]undecanes. Total Synthesis of Furanether B.

It is observed that mesylate 1 on exposure to Li(Ot-Bu)(3)AlH in refluxing toluene rearranges selectively to the 11-oxatricyclo[5.3.1.0(2,6)]undecane derivative 3. A similar rearrangement, leading to a bridged tricyclic ether (14 --> 5), has been used as the key to the total synthesis of furanether B (4), a naturally occurring lactarane sesquiterpene, with the readily available ketone 8 as the starting material. Completion of the synthesis of the natural product is accomplished by an annulation method based on a Pummerer-induced cyclization reaction.

alpha-Cycloalkyl-substituted omega-keto-dicarboxylic acids as lipid regulating agents.

A series of cycloalkyl-substituted oxo-alkanedicarboxylic acids have been prepared by the TosMIC methodology departing from haloalkyl-substituted cycloalkylcarboxylic esters. cyclopropyl derivatives showed IC(50) activity in the 0.3-1.0 microM range on the de novo incorporation of radiolabeled acetate into lipids in primary cultures of rat hepatocytes, and they showed lipid-regulating properties when tested in vivo in female obese Zucker fatty rats.