Steven J. Coats

Synthesis of Nucleoside Phosphate and Phosphonate Prodrugs

For many decades, the design of new nucleoside analogs as potential therapeutic agents focused on both sugar and nucleobase modifications. These nucleoside analogs rely on cellular kinases to undergo stepwise addition of phosphate groups to form the corresponding active nucleoside triphosphate to express their therapeutic effect.1 However, nucleosides triphosphates cannot be considered as viable drug candidates as they usually have poor chemical stability along with high polarity that hinders them from transporting across cell membranes. Within the nucleoside analog phosphate activation process, the first phosphorylation has often been identified as the limiting step, which led medicinal chemists to prepare stable “protected” monophosphate nucleosides capable of delivering nucleoside monophosphates intracellularly. These nucleoside monophosphate prodrugs are designed to efficiently cross the biological barriers (as opposed to nucleoside monophosphates; Figure u200bFigure1,1, eq 1) and reach the targeted cells or tissues. Once inside the cell, the biolabile protecting groups are then degraded enzymatically and/or chemically, releasing the free nucleoside analog in the monophosphate form, which can often efficiently express its therapeutical potency by intracellular conversion to the corresponding nucleoside triphosphate (Figure u200b(Figure1,1, eq 2). n n n n nOpen in a separate window n n nFigure 1 n n nMechanism of action of nucleoside monophosphate prodrugs.

Details associated with the bimolecular 1,4-dipolar cycloaddition reaction of cross-conjugated heteroaromatic betaines

Abstract A series of 3,3-disubstituted bicyclic anhydro-4-hydroxy-2-oxo-1,3-thiazinium hydroxides are easily prepared from the reaction of 3H-thiolactams with 1,3-bielectrophiles. These cross-conjugated heteroaromatic betaines undergo regio- and diastereospecific 1,4-dipolar cycloaddition with electron-rich and electron-deficient π-bonds to produce 1,4-cycloadducts containing a carbonyl sulfide bridge. A representative betaine dipole and a 1,4-cycloadduct were characterized by single crystal X-ray determinations. In certain cases, the initially formed cycloadduct can be induced to lose COS on further heating. The frontier orbital coefficients of the thiazinium betaine were determined by semi-empirical MOPAC calculations with the PM3 Hamiltonian. The HOMO of the 1,4-dipole is dominant for reactions with electron-deficient dipolarophiles such as N-phenylmaleimide, while the LUMO becomes important for cycloaddition to more electron-rich species such as ynamines or vinyl ethers.

Bimolecular 4+2-cycloaddition reactions of cross conjugated betaines with Electron rich π-systems

Abstract Bicyclic anhydro-2-oxo-4-hydroxy-1,3-thiazinium hydroxides undergo 1,4-dipolar cycloadditions with various electron rich π-systems to give 4+2-cycloadducts which on further heating, extrude carbonyl sulfide producing substituted α-pyridones.

Approaches for the development of antiviral compounds : the case of hepatitis C virus

Traditional methods for general drug discovery typically include evaluating random compound libraries for activity in relevant cell-free or cell-based assays. Success in antiviral development has emerged from the discovery of more focused libraries that provide clues about structure activity relationships. Combining these with more recent approaches including structural biology and computational modeling can work efficiently to hasten discovery of active molecules, but that is not enough. There are issues related to biology, toxicology, pharmacology, and metabolism that have to be addressed before a hit compound becomes nominated for clinical development. The objective of gaining early preclinical knowledge is to reduce the risk of failure in Phases 1, 2, and 3, leading to the goal of approved drugs that benefit the infected individual. This review uses hepatitis C virus (HCV), for which we still do not have an ideal therapeutic modality, as an example of the multidisciplinary efforts needed to discover new antiviral drugs for the benefit of humanity.

Substrate mimicry: HIV-1 reverse transcriptase recognizes 6-modified-3'-azido-2',3'-dideoxyguanosine-5'-triphosphates as adenosine analogs.

β-D-3′-Azido-2′,3′-dideoxyguanosine (3′-azido-ddG) is a potent inhibitor of HIV-1 replication with a superior resistance profile to zidovudine. Recently, we identified five novel 6-modified-3′-azido-ddG analogs that exhibit similar or superior anti-HIV-1 activity compared to 3′-azido-ddG in primary cells. To gain insight into their structure–activity–resistance relationships, we synthesized their triphosphate (TP) forms and assessed their ability to inhibit HIV-1 reverse transcriptase (RT). Steady-state and pre-steady-state kinetic experiments show that the 6-modified-3′-azido-ddGTP analogs act as adenosine rather than guanosine mimetics in DNA synthesis reactions. The order of potency of the TP analogs against wild-type RT was: 3′-azido-2,6-diaminopurine >3′-azido-6-chloropurine; 3′-azido-6-N-allylaminopurineu2009>u20092-amino-6-N,N-dimethylaminopurine; 2-amino-6-methoxypurine. Molecular modeling studies reveal unique hydrogen-bonding interactions between the nucleotide analogs and the template thymine base in the active site of RT. Surprisingly, the structure–activity relationship of the analogs differed in HIV-1 RT ATP-mediated excision assays of their monophosphate forms, suggesting that it may be possible to rationally design a modified base analog that is efficiently incorporated by RT but serves as a poor substrate for ATP-mediated excision reactions. Overall, these studies identify a promising strategy to design novel nucleoside analogs that exert profound antiviral activity against both WT and drug-resistant HIV-1.