ABSTRACT
The compatibility of free boronic acid building blocks in multicomponent reactions to readily create large libraries of diverse and complex small molecules was investigated. Traditionally, boronic acid synthesis is sequential, synthetically demanding, and time-consuming, which leads to high target synthesis times and low coverage of the boronic acid chemical space. We have performed the synthesis of large libraries of boronic acid derivatives based on multiple chemistries and building blocks using acoustic dispensing technology. The synthesis was performed on a nanomole scale with high synthesis success rates. The discovery of a protease inhibitor underscores the usefulness of the approach. Our acoustic dispensing-enabled chemistry paves the way to highly accelerated synthesis and miniaturized reaction scouting, allowing access to unprecedented boronic acid libraries.
Subject(s)
Boronic Acids/chemistry , Molecular Structure , Small Molecule Libraries/chemistry , Boronic Acids/chemical synthesis , Boronic Acids/classification , Cyanides/chemical synthesis , Cyanides/chemistry , Mass Spectrometry/methods , Microwaves , Small Molecule Libraries/chemical synthesis , Small Molecule Libraries/classificationABSTRACT
A flexible synthetic approach towards biologically active sphingoid base-like compounds with an integrated azobenzene framework was achieved via installing a chiral amino-alcohol fragment into the azobenzene system by utilizing the Wittig olefination of substituted (E)-triphenyl[4-(phenyldiazenyl)benzyl]phosphonium salts and d-isoascorbic acid derived aldehydes. All the prepared derivatives underwent a series of experiments to probe their photochromic properties, including the reversible E/Z isomerisation, material fatigue and thermal relaxation rate. The targeted E- and Z-isomeric sphingoid analogues were screened in vitro for anticancer activity on a panel of seven human malignant cell lines. Cell viability experiments revealed outstanding antiproliferative/cytotoxic activities of all the tested compounds with IC50 values in the low micromolar range for the most active derivatives. The biological activity of E- and Z-isomeric forms is different. Their entirely accurate differentiation is prevented by the rapid thermal relaxation of the corresponding Z-isomers.
Subject(s)
Antineoplastic Agents/pharmacology , Azo Compounds/pharmacology , Sphingosine/pharmacology , Animals , Antineoplastic Agents/chemistry , Azo Compounds/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Mice , Molecular Structure , NIH 3T3 Cells , Sphingosine/analogs & derivatives , Sphingosine/chemistry , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Boronic acids are amongst the most useful synthetic intermediates, frequently used by modern drug design. However, their access and fast synthesis of libraries are often problematic. We present a methodology on the synthesis of drug-like scaffolds via IMCRs with unprotected phenylboronic acids. To demonstrate an application of our approach, we also performed one-pot Suzuki couplings on the primary MCR scaffolds. Moreover, we performed a thorough data-mining of the Cambridge Structural Database, revealing interesting geometrical features.