Drug design: hiding in full view

Abstract

Compounds that can produce potent biological effects in cells encompass a variety of structural motifs. Many of these compounds share a structural feature that has rarely been noted. It is an allylic cluster of atoms, a 3-carbon chain with a double bond between two of the atoms and an oxygen atom at the other end. The oxygen can be in a hydroxyl group, or in an ether or ketal or ester linkage, or simply a carbonyl form. In the latter case, the linkage is an allylic ketone (ene-one) structure. Nitrogen is often seen in equivalent forms. Inclusion of at least one allylic moiety appears to be able to turn a modestly active or inert compound into an effective drug or toxin. Some compounds lack the allylic moiety but develop one by enzymatic action, usually via cytochrome P-450 enzymes. These metabolites probably represent the active drug forms. The above concepts seem to be radically simplistic and improbable, but the evidence supporting them and the explanations for the biological activities are hidden ''in plain view.'' Comparisons with the pleiotropic activities of the allylic sphingolipid, ceramide, indicate that many allylic drugs operate by controlling the state of protein phosphorylation, by activating proteases, by generating reactive oxygen species, by slowing mitochondrial electron transport, or by lowering cellular glutathione concentrations. Drug Dev Res 69: [15][16][17][18][19][20][21][22][23][24][25] 2008 r2008 Wiley-Liss, Inc.

1,5-Diaryl-3-oxo-1,4-pentadienes: A Case for Antineoplastics with Multiple Targets

“…Second, a recent review indicated that many bioactive compounds contain an allylic group with an oxygen atom at one end of this substituent [82]. The oxygen atom can be located in a hydroxy, ester, ether, ketal or carbonyl substituents.…”

Transition-Metal-Free Superbase-Promoted Stereoselective α-Vinylation of Ketones with Arylacetylenes: A General Strategy for Synthesis of β,γ-Unsaturated Ketones

“…The importance of the vinylation reactions of ketones stems not only from frequent appearance of the C–C double bond-carbonyl entities in natural products and biologically active compounds but also from the rich and well-studied chemistry of β,γ-unsaturated ketones that enables expedient synthesis of complex structures . Many synthetic approaches to β,γ-unsaturated ketones have been documented.…”

Base-Catalyzed Addition of Ketones to Alkynes as a Key Step in the One-Pot Synthesis of 1-Formyl-2-pyrazolines

“…The importance of the vinylation reactions of ketones stems not only from the frequent appearance of the C=C bond carbonyl entities in natural products and biologically active compounds, 2 but also from the rich and well-studied chemistry of β,γ-unsaturated ketones 3 that enables expedient synthesis of complex structures. 4 Promising synthetic building blocks are also intermediates of this reaction, for example, dienolate 3, which may be C-and O-alkylated in situ and participate in Diels-Alder synthesis as well as form various heterocyclic compounds attaching different binucleophiles.…”