RESUMO
A robust palladium-catalyzed hydroxycarbonylation of aryl halides on DNA has been developed. Instead of Mo(CO)6 as a source of carbon monoxide as previously described in the literature, chloroform was used as a surrogate in this report for the purpose of avoiding to use a large excess of molybdenum reagent which is not totally soluble in aqueous reaction mixtures.
Assuntos
Monóxido de Carbono/química , Clorofórmio/química , DNA/química , Estrutura MolecularRESUMO
DNA encoded libraries (DEL) have shown promise as a valuable technology for democratizing the hit discovery process. Although DEL provides relatively inexpensive access to libraries of unprecedented size, their production has been hampered by the idiosyncratic needs of the encoding DNA tag relegating DEL compatible chemistry to dilute aqueous environments. Recently reversible adsorption to solid support (RASS) has been demonstrated as a promising method to expand DEL reactivity using standard organic synthesis protocols. Here we demonstrate a suite of on-DNA chemistries to incorporate medicinally relevant and C-S, C-P and N-S linkages into DELs, which are underrepresented in the canonical methods.
Assuntos
DNA/síntese química , Adsorção , Técnicas de Química Sintética , Técnicas de Química Combinatória , Descoberta de Drogas , Indicadores e Reagentes , Bibliotecas de Moléculas Pequenas , Solubilidade , Sulfonas/química , Sulfóxidos/químicaRESUMO
Kadcyla® (T-DM1), an antibody-drug conjugates (ADCs) for HER2+ breast cancer treatment, has been approved by the Food and Drug Administration (FDA) in 2013. An ADC of random lysine conjugation, it has difficulties in DAR control and unsatisfactory PK due to uneven DAR distribution. It also gives rise to aggregation during conjugation because of the hydrophobicity nature of the cytotoxin, DM1. The linker-drug in T-DM1, SMCC-DM1 is hydrophobic and requires certain percentage of organic solvent such as DMA in the conjugation solution, limiting the manufacturing process in an organic-solvent-compatible device and adding extra costs. To address these problems, a site-specific conjugation method was developed involving full reduction of antibody and full conjugation with the bridge-like conjugator-drug, based on the work of Caddick and co-workers, to obtain a site-directed antibody-drug conjugate with DAR 4. The bridge-like conjugator was assembled with SMCC-DM1 and different lengths of hydrophilic polyethylene glycol (PEG) moiety. By applying PEG moiety in the side chain of the linker-drug, the organic solvent used in the conjugation can be reduced. When the PEG length is about 26 units, organic solvent is no longer needed in the conjugation. Reducing the amount of organic solvent in conjugation could also diminish the aggregation occurrence during the conjugation. Moreover, the conjugation configuration with the designed conjugator was also discussed in the article. The binding affinity of the resulting ADCs did not show significant decrease and the cell based assay and animal study have shown the comparable results with T-DM1.
Assuntos
Antineoplásicos/síntese química , Dissulfetos/química , Imunoconjugados/química , Maitansina/análogos & derivados , Polietilenoglicóis/síntese química , Trastuzumab/química , Animais , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Humanos , Interações Hidrofóbicas e Hidrofílicas , Imunoconjugados/uso terapêutico , Imunoconjugados/toxicidade , Maitansina/síntese química , Maitansina/uso terapêutico , Maitansina/toxicidade , Camundongos SCID , Estrutura Molecular , Oxirredução , Polietilenoglicóis/química , Polietilenoglicóis/uso terapêutico , Receptor ErbB-2/metabolismo , Solventes/química , Sulfetos/síntese química , Sulfetos/química , Sulfetos/uso terapêutico , Trastuzumab/uso terapêutico , Trastuzumab/toxicidadeRESUMO
The on-DNA synthesis of highly substituted cyclobutanes was achieved through a photocatalytic [2 + 2] cycloaddition reaction in aqueous solution. Readily available DNA-tagged styrene derivatives were reacted with structurally diverse cinnamates in the presence of an iridium-based photocatalyst, Ir(ppy)2(dtbbpy)PF6, to forge two new C(sp3)-C(sp3) bonds. This transformation was demonstrated to have excellent functional group tolerance and allowed for the facile installation of a variety of heteroaromatic substituents on a densely functionalized cyclobutane scaffold.
Assuntos
Ciclobutanos/química , DNA/síntese química , Catálise , Reação de Cicloadição , DNA/química , Estrutura Molecular , Processos FotoquímicosRESUMO
A new catalytic manifold that merges photoredox with nickel catalysis in aqueous solution is presented. Specifically, the combination of a highly active, yet air-stable, nickel precatalyst with a new electron-deficient pyridyl carboxamidine ligand was key to the development of a water-compatible nickel catalysis platform, which is a crucial requirement for the preparation of DNA-encoded libraries (DELs). Together with an iridium-based photocatalyst and a powerful light source, this dual catalysis approach enabled the efficient decarboxylative arylation of α-amino acids with DNA-tagged aryl halides. This C(sp2)-C(sp3) coupling tolerates a wide variety of functional groups on both the amino acid and the aryl halide substrates. Due to the mild and DNA-compatible reaction conditions, the presented transformation holds great potential for the construction of DELs. This was further evidenced by showing that well plate-compatible LED arrays can serve as competent light sources to facilitate parallel synthesis. Lastly, we demonstrate that this procedure can serve as a blueprint toward the adaptation of other established nickel metallaphotoredox transformations to the idiosyncratic requirements of a DEL.