Annual Activities Report 2011 - INCT-Inofar - UFRJ

Annual Report 2011 | INCT-INOFAR
37
Highlights
HIGHLIGHTS
The Methylation
Effect in Medicinal
Chemistry
Eliezer J. Barreiro* Arthur E. Kümmerle and Carlos A. M.
Fraga. Chemical Reviews 111 (2011) 5215-5246. DOI:
10.1021/cr200060g
In this review, we aimed to highlight the importance of the simple methyl group as a very useful structural
modification in the rational design of bioactive compounds and drugs. The methyl effect, alter both
biological phases of a drug, represented by its pharmacodynamics and pharmacokinetics profile, due to
the modifications introduced in the stereoelectronic properties. The methyl group is very important in
the molecular recognition of endogenous and exogenous organic compounds by bioreceptors. Although
it only participates in London dispersion interactions, which are the weakest of all intermolecular
interactions, 1 methyl groups have stereoelectronic effects 2 on micromolecules and biomacromolecules,
thereby leading to diverse biological effects, including selectivity among bioreceptors, increased potency,
and protection against enzyme metabolism. 3 Cognizant of the methyl group’s importance in molecular
recognition, Wermuth wrote: 3 “The methyl group, so often considered as chemically inert, is able to alter
deeply the pharmacological properties of a molecule.”
The stereoelectronic changes promoted by methyl groups are directly involved in many biological process. 4
For example, in pyrimidine bases described in Figure 1, one difference between DNA and RNA is the
exchange of a thymine for a uracil, two pyrimidine bases that are differentiated by a methyl group at
position 5 of the pyrimidine ring of thymine (Figure 1A).