A la Recerca de nous fàrmacs: el cas d'alguns antiretrovirals

En aquest treball es fa una breu història del desenvolupament de la terapèutica química i, en especial, del disseny racional de nous fàrmacs. Es presenta un exemple concret de l'ús de la tècnica computacional del docking a la recerca de noves «petites molècules» antiretrovirals.This paper gives a brief historical overview of the development of medicinal chemistry and especially of the rational design of new drugs. The specific example is presented of the use of the computer docking technique in the search for new small antiretroviral molecules

A study on the photoreaction of 2(5H)-furanones with substituted acetylenes : evidence for a mechanistic reformulation

The photoreaction of 2(5H)-furanones with alkynes has been investigated. The complexity of this process is evidenced by the variety of isolated products, which have allowed disclosing interesting mechanistic aspects. When the reaction is performed in acetonitrile under direct excitation, in addition to the primary [2+2] cycloadducts, products derived from an 1,3-acyl shift rearrangement are also formed. For unsymmetrical alkynes, the rearrangement of the head-to-tail primary adducts produces new regioisomers and, when the starting furanone is chiral, this rearrangement inverts the relative anti/syn geometry of the primary cycloadducts. In the reactions performed in acetone under photosensitized conditions, rearranged products were never detected, supporting that the 1,3-acyl shift takes place from the singlet excited state S 1 of the β,γ-unsaturated lactone. When bis(trimethylsilyl)acetylene is used as the alkyne partner, the major photoproducts are monocyclic bis(trimethylsilyl)lactone

Intramolecular photoreactions of (5S)-5-Oxymethyl-2(5H)-furanones as a tool for the stereoselective generation of diverse polycyclic scaffolds

The photoactivated evolution of a series of enantiomerically pure 5-oxymethyl-2(5H)-furanones has been investigated. The observed intramolecular photoreactions have proven to be a straightforward entry to diverse and stereochemically rich fragment-molecules, most of which contain the privileged tetrahydropyran (THP) scaffold. The formation of the THP involves a 1,5-hydrogen atom transfer process, leading to a diradical intermediate that recombines to form a new σ C-C bond. These reactions take place under both sensitized and nonsensitized conditions, and they are highly stereoselective. When the substrate contains an allyl residue, the intramolecular [2 + 2] cycloaddition leading to cyclobutanes competes advantageously. When the substrate contains a THP residue, the cyclization involves the concomitant formation of [6,6]-spiroketals with nonanomeric relationships

Stereodivergent synthesis of (+)- and (-)-isolineatin

A stereodivergent approach to (+)- and (-)-isolineatin using (S)-4-methyl-5-pivaloyloxymethyl-2(5H)-furanone as the single source of asymmetry by exploiting the inherent chirality at the C-5 stereocenter is described. © 2013 American Chemical Society

Synthesis, antiviral evaluation, and computational studies of cyclobutane and cyclobutene L-nucleoside analogues

This paper describes the stereoselective synthesis of a series of functionalized cyclobutane and cyclobutene L-nucleoside analogues featuring a methylene spacer between the carbocycle and the nucleobase. These L-nucleoside analogues were subjected to comprehensive screening for antiviral activity. To obtain knowledge at the molecular structural level relevant for designing future analogues, the mechanism of action of these L-nucleoside analogues as anti-herpes simplex virus agents was investigated by computational approaches. In particular, protein-ligand docking calculations were used to rationalize the ability of the prodrug candidates to be activated. Docking experiments were performed on the three kinases involved in the activation process of thymine and guanine derivatives