Chemical Dimerization Technology

A major focus, following the initial reports, was on refining the tools used to achieve chemical dimerization - in particular, the dimerizers themselves. Important aims were to improve chemical feasibility, specificity, and pharmacological properties, the latter to permit studies in experimental animals. This section will describe the options that have evolved for different types of induced dimerization. The focus will be on the FKBP-based technologies and applications developed by the author s group and its collaborators, although other systems will also be mentioned. 

A series of FK1012 variants has been described with different linkers and, in some cases, facile syntheses using FK506 as a starting point (Fig. 4.2-2) [10], All of these can be used to effect dimerization between FKBP fusion proteins. 

In addition to FKBP-based systems, homodimerization has also been achieved using the naturally dimeric natural product coumermycin, which can dimerize proteins fused to Escherichia coli DNA gyrase [12]. 

Although early heterodimerization studies used molecules such as FK-CsA, the most common approach is the use of rapamycin, which naturally functions 

Because of its inherent directionality, heterodimerization is often a more precise tool than homodimerization and can be used in many configurations. For example, a protein can be inducibly recruited to the plasma membrane by fusing it to one of the drug-binding domains, and fusing the other to a myristoylation motif (see Fig. 4.2-l(b)) [4]. A major application of heterodimerization is in the control of transcription (see Section 4.2.3.4) [5, 6], 

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A complete list of publications describing use of chemical dimerization technologies can be found at, http //www.ariad.com/ regulationkits. 

The yeast three-hybrid (Y3H) system is a cellular assay system designed for the identification and characterization of small molecule-protein interactions in intact cells [25]. It uses yeast Saccharomyces cerevisiae as a host system and combines aspects of the yeast two-hybrid (Y2H) system [26] with recent developments in chemical dimerizer technology [27, 28],... 

With protein-protein interactions being pervasive throughout biology, chemically controlled dimerization has proved to be a remarkably versatile technology, and more than 300 papers have described use of the approach [9], These applications can be broadly separated into two classes. The first is the use of dimerization technologies in basic and applied biological research, to understand the functions of proteins or pathways, and to create... 

Should MTBE be banned, what would be the logical replacement(s) There are several options available. Several refiners opted to build MTBE capacity and avoid purchasing the ether on the open market. MTBE units were an option to use the facility s isobutylenes. Several licensed processes can be used to convert existing MTBE units. Kvaerner and Lyondell Chemical Co. offer technologies to convert an MTBE unit to produce iso-octane, as shown in Fig. 18.27.12 Snamprogetti SpA and CDTECH also have an iso-octene/iso-octane process. These processes can use various feedstocks such as pure iso-butane, steam-cracked C4 raffinate, 50/50 iso-butane/iso-butene feeds, and FCC butane-butane streams. The process selectively dimerizes C4 olefins to iso-octene and then hydrogenates the iso-octene (di-iso-butene) into iso-octane. The processes were developed to provide an alternative to MTBE. The dimerization reactor uses a catalyst similar to that for MTBE processes thus, the MTBE reactor can easily be converted to... 

Electrochemical processes are often touted as being green chemistry because electricity is considered inexpensive, and toxic metal reagents are usually avoided. Electrochemical processes have produced tons of bulk chemicals [37], the best-known of which may be adiponitrile from reductive dimerization of acrylonitrile (Figure 13.17) [38]. An electrochemical synthesis to manufacture fenoprofen is shown in Figure 13.18, with the magnesium provided as a sacrificial electrode [39], Flow cell technology has been used for these operations on a commercial basis. 

This conceptually simple approach, described more than 10 years ago [3], has proved broadly applicable and has been widely adopted not only in the chemical biology community but also across biological research in general. It has also spawned several related technologies, such as systems for reverse dimerization . This chapter will review the various protein-ligand systems that have been designed, and describe examples of their use, both in research and drug discovery. 

BP Chemicals studied the use of chloroaluminates as acidic catalysts and solvents for aromatic alkylation [43]. At present, the AICI3 existing technology (based on red oil catalyst) is still used industrially, but continues to suffer from poor catalyst separation and recycle [44]. The aim of the work was to evaluate the AlCls-based ionic liquids, with the emphasis placed on the development of a clean and recyclable system for the production of ethylbenzene (benzene/ethene alkylation) and synthetic lubricants (alkylation of benzene with 1-decene). The production of linear alkyl benzene (LAB) has also been developed by Akzo [45]. The eth)4benzene experiments were run by BP in a pilot loop reactor similar to that described for the dimerization (Fig. 5.4-8). 

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