Fahad Al-Obeidi

Microwave-Assisted Solid-phase Synthesis (MASS): Parallel and Combinatorial Chemical Library Synthesis

The use of microwave technology in solid-phase organic synthesis has attracted much attention in recent years. The combination of solid support, either as a medium for chemical synthesis or as a carrier for organic reagents, with microwave heating offers several advantages over conventional techniques. Rapid and elevated heating of reaction mixtures can induce the completion of chemical transformations in minutes while several hours or days may be required for the same chemistry under conventional conditions. With decreased time of exposure to high temperatures and lessened thermal degradation, microwave accelerated chemistries often deliver products of higher purity when compared to conventional heating techniques. Several chemical syntheses on solid-phase employing microwave irradiation have been reported in the literature. The reagents, solvents, and equipment selected for microwave-mediated synthesis are important contributors to the success of the chemical transformation. Owing to the timesavings in performing chemical synthesis under microwave irradiation, the technique has become an emerging partner in solid-phase organic synthesis.

Factor Xa inhibitors by classical and combinatorial chemistry

Abstract A high-priority goal in the search for new antithrombotic agents is the identification of small-molecule compounds that selectively inhibit the blood coagulation Factor Xa. These compounds should limit blood loss while controlling thrombosis following surgery, heart attacks, infection by Gram-negative organisms, and other coagulation disorders. Three naturally occurring small proteins (antistasin, tick anticoagulant peptide and yagin) and a diverse collection of small-molecule inhibitors of Factor Xa, originating from both structure-based design and screening of historical compounds and combinatorial libraries, have been described. This review summarizes recent entries into preclinical research, including a series of unique Factor Xa inhibitors recently uncovered in combinatorial peptide libraries.

Monoclonal 1- and 3-Phosphohistidine Antibodies: New Tools to Study Histidine Phosphorylation

Histidine phosphorylation (pHis) is well studied in bacteria; however, its role in mammalian signaling remains largely unexplored due to the lack of pHis-specific antibodies and the lability of the phosphoramidate (P-N) bond. Both imidazole nitrogens can be phosphorylated, forming 1-phosphohistidine (1-pHis) or 3-phosphohistidine (3-pHis). We have developed monoclonal antibodies (mAbs) that specifically recognize 1-pHis or 3-pHis; they do not cross-react with phosphotyrosine or the other pHis isomer. Assays based on the isomer-specific autophosphorylation of NME1 and phosphoglycerate mutase were used with immunoblotting and sequencing IgG variable domains to screen, select, and characterize anti-1-pHis and anti-3-pHis mAbs. Their sequence independence was determined by blotting synthetic peptide arrays, and they have been tested for immunofluorescence staining and immunoaffinity purification, leading to putative identification of pHis-containing proteins. These reagents should be broadly useful for identification of pHis substrates and functional study of pHis using a variety of immunological, proteomic, and biological assays.

Microwave-assisted solid-phase synthesis (MASS) of 2,6,9-trisubstituted purines

Abstract In an attempt to discover a high-throughput method for the synthesis of 2,6,9-trisubstituted purines, it was found that microwave irradiation was beneficial in accelerating the nucleophilic displacement of halogens by amines at the C-2 position of the purine nucleus. A method for microwave-assisted solid-phase synthesis (MASS) of 2,6,9-trisubstituted purines is presented.

Synthesis of 2,5-dihalothiazole-4-carboxylates

Abstract An efficient synthesis of 2,5-dihalothiazole-4-carboxylates has been described. Halogenation of aminothiazole carboxylate with NBS or NCS and subsequent diazotization with isoamyl nitrite and halogenation with CuBr 2 , CuCl 2 or CH 2 I 2 provided the corresponding diahalothiazole derivatives. The four-step process described is amenable to scale-up and requires no chromatographic purification in all the steps.

An alternative method for the preparation of resin-bound secondary amines

Difficulties encountered in the synthesis of resin-bound secondary amines attached via an acid-labile linker encouraged us to employ an alternative approach. A one-pot, scalable procedure for the synthesis of Fmoc-protected, amine/linker constructs is reported. These compounds can be efficiently coupled to a solid support and be used in the synthesis of carboxamides and sulfonamides. The advantages of the method are the elimination of problems associated with variability of alkoxybenzaldehyde resins, minimization of difficulties encountered in solid-phase reductive aminations, and a means for quantifying the resin loading of the secondary amine.