Biomedical Engineering Reference
In-Depth Information
knowledge to create substances of increasing structural complexity. The initial
challenge was to convert elementary inorganic substances into more elaborated
organic molecules such as acetic acid [3]. Later, the field was influenced by a
spectacular stereoselective approach to (
)-glucose, a landmark in the history of total
synthesis [4] that led to the first Nobel Prize for organic synthesis awarded to Fischer
in 1902. Without a doubt, these early accomplishments demonstrated an unprece-
dented creative instinct, highlighted by the strong desire of synthetic chemists to
shape their own material. Surprisingly, natural product chemistry has not gained the
recognition it deserves, often perceived as a practical tour de force rather than an
intellectual challenge. This comment commonly encountered in the field deserves
additional attention. Nature has conceived fascinating structures that one may never
have imagined. The synthesis of such complex structures required the invention of
original reactions, new reagents and powerful catalysts, thus providing the scientific
community with an impressive arsenal of chemical tools, in addition to valuable
compounds with widespread physicochemical properties. Natural product chemistry
has not only set the scene for the discovery of appealing biologically active small
molecules but has also been an infinite source of knowledge and inspiration.
The role of total synthesis in drug discovery programs is undeniable. Indeed, a
plethora of drugs have been inspired from natural product structures. It appears,
however, that the success of pharmaceutical companies has not been in adequation
with their efforts. Medicinal chemists are often driven by an insatiable desire to create
the perfect molecule with the hope to regulate a given biological event, assuming that
a chosen target may be involved. Yet, a disease rarely originates from a single
dysfunction, but rather from a perturbation of the functional equilibrium of the cell
that most likely implicates multiple parameters. Therefore, identifying novel drugs
cannot solely rely on a hypothesis. Chemists must adopt a drastically different
approach that should be discovery based as opposed to hypothesis driven. Ultimately,
this approach would involve the preparation of large libraries of structurally diverse
small molecules to enable the independent and synergistic modulation of each
biological process. This would require the development of unbiased biological
evaluations to enhance the probability of discovering novel biological targets and
simultaneously identifying compounds with valuable properties.
The invention of solid-phase chemistry in the early 1960s [5] has permitted the
development of combinatorial chemistry; a technology established to prepare large
libraries of distinct small molecules. Usually, the central scaffold of these molecules
remains structurally unchanged, whereas the functionalities decorating the core
molecule exhibit a high degree of variability. Ellman and Bunin [6] and Hobbs
DeWitt [7] separately reported the first solid-phase syntheses of nonpolymeric
organic molecules of biological importance. In their reports, small libraries of
benzodiazepine analogues were synthesized, demonstrating an important step in the
development of solid-phase chemistry and its relevance to the preparation of drug
molecules. Combinatorial chemistry has expanded rapidly and has perhaps been
considered to be the most powerful and successful method used in drug discovery
programs. The solid support facilitates purification, enhances the yield, and greatly
improves split-pool methods, increasing the number of different small molecules
arising from the process. However, the lack of structural complexity and the fact that
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